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Xu B, Kang B, Li S, Chen J, Zhou J. Association between sodium-glucose cotransporter 2 inhibitors and cancer: a systematic review and meta-analysis of randomized active-controlled trials. Int J Clin Pharm 2025:10.1007/s11096-025-01924-0. [PMID: 40293640 DOI: 10.1007/s11096-025-01924-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Accepted: 04/12/2025] [Indexed: 04/30/2025]
Abstract
BACKGROUND The effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cancer incidence compared to other hypoglycemic drugs remains unclear. AIM This systematic review and meta-analysis was designed to investigate the association of SGLT2 inhibitors with cancer compared to active comparators. METHOD A systematic search was conducted up to March 11, 2024 across Web of Science, PubMed, and ClinicalTrials.gov, and included trials with a follow-up period of at least 52 weeks. The Mantel-Haenszel statistical method was utilized, applying risk ratio (RR) and 95% confidence intervals (CI) for binary variables. RESULTS Twenty trials covering 16,399 type 2 diabetes mellitus patients were included. Median follow-up duration was 1.0 (1.0) years. The effect of SGLT2 inhibitors on the overall risk of cancer was neutral compared to active comparators (RR 1.00; 95%CI 0.71-1.40; p = 0.99; moderate certainty of evidence). SGLT2 inhibitors did not have a significant impact on breast cancer, endometrial/uterine cancer, gastrointestinal cancer, prostate cancer, renal cancer, or respiratory cancer. Subgroup analysis indicated a significant reduction in the risk of gastrointestinal cancer with SGLT2 inhibitors compared to metformin (RR 0.23; 95%CI 0.06-0.95; p = 0.04). SGLT2 inhibitors potentially increased gastrointestinal cancer risk relative to sulfonylureas (RR 3.52; 95%CI 0.91-13.64; p = 0.07). CONCLUSION SGLT2 inhibitors showed neutral cancer risk in T2DM patients but may reduce gastrointestinal cancer versus metformin, guiding tailored therapy based on patient risk profiles.
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Affiliation(s)
- Bo Xu
- The First Affiliated Hospital, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Bo Kang
- The First Affiliated Hospital, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Shaoqian Li
- The First Affiliated Hospital, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- The Affiliated Nanhua Hospital, Department of Docimasiology, Hengyang Medical School, University of South China, Hengyang, 421002, Hunan, China
| | - Jixiang Chen
- The First Affiliated Hospital, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Jiecan Zhou
- The First Affiliated Hospital, Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
- The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
- The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
- School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
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Geng L, Sun B, Chen Y. A meta-analysis of randomized controlled studies examining the effects of sodium-glucose co-transporter-2 inhibitors on peripheral artery disease and risk of amputations. Diabetes Obes Metab 2024; 26:5376-5389. [PMID: 39267269 DOI: 10.1111/dom.15901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 08/09/2024] [Accepted: 08/10/2024] [Indexed: 09/17/2024]
Abstract
AIM Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are used to maintain glycaemic control as well as for their beneficial cardiovascular and renal effects in diabetes patients. However, increased risk of amputation and peripheral artery disease (PAD) have been observed with the use of some SGLT-2is. A meta-analysis was conducted to understand the effect of SGLT-2is on amputation and PAD events using data from randomized controlled trials (RCT). MATERIALS AND METHODS A systematic literature review was conducted using Medline and Central databases for RCTs that involved the administration of SGLT-2is versus placebo/active comparators to diabetic patients. The primary outcome was amputation events and PAD. A random-effects model was used to calculate the pooled odds ratio, and subgroup analyses was performed. RESULTS A total of 51 RCTs were included in the meta-analysis with data from 97 589 patients. Meta-analysis of the data showed that there was a significant increase in PAD risk (p = 0.04) but no significant increase in amputation risk with SGLT-2i use versus placebo/active comparators (p = 0.43). Subgroup analyses demonstrated no significant difference between SGLT-2i type, duration of treatment or patient risk factors on amputation or PAD incidence. However, length of drug treatment (> 100 weeks) was associated with a significant increase in both PAD and amputation risks in the SGLT-2i treatment groups. CONCLUSIONS The results of the meta-analysis showed no significant association between SGLT-2i use and PAD and amputation risks in diabetic patients when used for shorter treatment durations.
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Affiliation(s)
- Li Geng
- Department of Vascular Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Bing Sun
- Department of Neurology, Changchun Central Hospital, Changchun, China
| | - Yan Chen
- Department of Endocrinology, The Second Hospital of Jilin University, Changchun, China
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Lee DH, Oh JH, Jeon HJ, Oh TK. The Efficacy and Safety of Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors in Real-World Clinical Practice: Potential Cautionary Use in Elderly Patients with Type 2 Diabetes (T2D). Diabetes Ther 2024; 15:1615-1626. [PMID: 38771472 PMCID: PMC11211288 DOI: 10.1007/s13300-024-01604-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 05/02/2024] [Indexed: 05/22/2024] Open
Abstract
INTRODUCTION Sodium-glucose co-transporter 2 (SGLT2) inhibitors have shown safe and therapeutic efficacy in randomized controlled trials (RCT) to reduce adverse cardiorenal events in high-risk patients with type 2 diabetes (T2D). In this study, we investigated the efficacy and safety of SGLT2 intervention in patients with T2D in a real-world clinical practice to confirm the validity of the RCT results. METHODS As a retrospective study, we evaluated medical records from 596 patients with T2D treated with SGLT2 inhibitors (dapagliflozin or empagliflozin) in addition to their prior drug regimen to improve glucose control between 2015 and 2019 in the Endocrinology Department at Chungbuk National University Hospital. No control arm was evaluated to compare the effects of adding SGLT inhibitors to the pre-existing regimen. The primary objective was the measurement of glycated hemoglobin (HbA1c) from each individual patient over a 36-month period at 6-month intervals. The secondary parameters were the measurement of fasting plasma glucose (FPG) and body weight (Bwt) changes, as well as the monitoring of adverse events (AEs) and determining the reasons for drug discontinuation. RESULTS HbA1c levels were reduced at each of the time points throughout the 36-month period and were significantly reduced by 12.5% (P < 0.01) from time 0 (8.8 ± 1.3%) to 36 months (7.7 ± 1.0%). FPG levels [from basal (180 ± 60 mg/dL) to 36 months (138 ± 38 mg/dL)] and Bwt [from basal (74 ± 15 kg) to 36 months (72 ± 15 kg)] were also significantly reduced (P < 0.01) for both measurements in the SGLT2 inhibitor add-on group. Similar to HbA1c profile, the FPG and Bwt were measured at a consistently lower level at 6 months until the end of the study. The most common AEs were hypoglycemia (n = 57), genitourinary infection (GUI) (n = 31), and polyuria (n = 28). In the elderly population (≥ 75 years old), AEs (31%) were generally more prevalent (P < 0.001) than those (21%) in the adult (< 75 years old) patients. Over the study period, 211 (35%) patients either dropped or completely discontinued the use of the SGLT2 inhibitor, and the elderly patients tended to have a higher discontinuation rate (52%; P = 0.005) than the adults (33%). CONCLUSIONS In this study, we demonstrated that SGLT2 inhibitors are an effective and durable hypoglycemic agent to control blood glucose levels with reduced maintenance of Bwt, but their use in the elderly (≥ 75 years old) patients with T2D may warrant some additional caution due to increased probability of AEs and discontinuation of drug use.
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Affiliation(s)
- Dong-Hwa Lee
- Department of Endocrinology, Chungbuk National University Hospital, Cheongju, South Korea
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, 776, 1 Sunhwan-ro, Seowon-gu, Cheongju-City, 28644, Republic of Korea
| | - Ji Hwan Oh
- Department of Endocrinology, Chungbuk National University Hospital, Cheongju, South Korea
| | - Hyun Jeong Jeon
- Department of Endocrinology, Chungbuk National University Hospital, Cheongju, South Korea
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, 776, 1 Sunhwan-ro, Seowon-gu, Cheongju-City, 28644, Republic of Korea
| | - Tae Keun Oh
- Department of Endocrinology, Chungbuk National University Hospital, Cheongju, South Korea.
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, 776, 1 Sunhwan-ro, Seowon-gu, Cheongju-City, 28644, Republic of Korea.
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Nguyen AT, Amigo Z, McDuffie K, MacQueen VC, Bell LD, Truong LK, Batchi G, McMillin SM. Effects of Empagliflozin-Induced Glycosuria on Weight Gain, Food Intake and Metabolic Indicators in Mice Fed a High-Fat Diet. Endocrinol Diabetes Metab 2024; 7:e00475. [PMID: 38475903 DOI: 10.1002/edm2.475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 12/31/2023] [Accepted: 02/08/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND Sodium glucose-linked transporter 2 (SGLT2) inhibitors promote glucose, and therefore calorie, excretion in the urine. Patients taking SGLT2 inhibitors typically experience mild weight loss, but the amount of weight loss falls short of what is expected based on caloric loss. Understanding the mechanisms responsible for this weight loss discrepancy is imperative, as strategies to improve weight loss could markedly improve type 2 diabetes management and overall metabolic health. METHODS Two mouse models of diet-induced obesity were administered the SGLT2 inhibitor empagliflozin in the food for 3 months. Urine glucose excretion, body weight, food intake and activity levels were monitored. In addition, serum hormone measurements were taken, and gene expression analyses were conducted. RESULTS In both mouse models, mice receiving empagliflozin gained the same amount of body weight as their diet-matched controls despite marked glucose loss in the urine. No changes in food intake, serum ghrelin concentrations or activity levels were observed, but serum levels of fibroblast growth factor 21 (FGF21) decreased after treatment. A decrease in the levels of deiodinase 2 (Dio2) was also observed in the white adipose tissue, a primary target tissue of FGF21. CONCLUSION These findings suggest that compensatory metabolic adaptations, other than increased food intake or decreased physical activity, occur in response to SGLT2 inhibitor-induced glycosuria that combats weight loss, and that reductions in FGF21, along with subsequent reductions in peripheral Dio2, may play a role.
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Affiliation(s)
- Anh T Nguyen
- Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA
| | - Zachary Amigo
- Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA
| | - Kathleen McDuffie
- Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA
| | - Victoria C MacQueen
- Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA
| | - Lane D Bell
- Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA
| | - Lan K Truong
- Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA
| | - Gloria Batchi
- Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA
| | - Sara M McMillin
- Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA
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Coats AJS, Butler J, Tsutsui H, Doehner W, Filippatos G, Ferreira JP, Böhm M, Chopra VK, Verma S, Nordaby M, Iwata T, Nitta D, Ponikowski P, Zannad F, Packer M, Anker SD. Efficacy of empagliflozin in heart failure with preserved ejection fraction according to frailty status in EMPEROR-Preserved. J Cachexia Sarcopenia Muscle 2024; 15:412-424. [PMID: 38158636 PMCID: PMC10834334 DOI: 10.1002/jcsm.13393] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/22/2023] [Accepted: 11/06/2023] [Indexed: 01/03/2024] Open
Abstract
BACKGROUND Frailty is a severe, common co-morbidity associated with heart failure (HF) with preserved ejection fraction (HFpEF). The impact of frailty on HFpEF outcomes may affect treatment choices in HFpEF. The impact of frailty on HFpEF patients and any impact on the clinical benefits of sodium glucose co-transporter 2 (SGLT2) inhibition in HFpEF have been described in only a limited number of trials. Whether the SGLT2 inhibitor empagliflozin would improve or worsen frailty status when given to HFpEF patients is also not known. The aims of this study were, therefore, to evaluate, in HFpEF patients enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), the impact of frailty on clinical outcomes, and on the effects of empagliflozin, as well as the effect of empagliflozin on frailty status during treatment period. METHODS We calculated a cumulative deficit-derived frailty index (FI) using 44 variables including clinical, laboratory and quality of life parameters recorded in EMPEROR-Preserved. Patients were classified into four groups: non-frail (FI < 0.21), mild frailty (0.21 to <0.30), moderate frailty (0.30 to <0.40) and severe frailty (≥0.40). Clinical outcomes and health-related quality of life were evaluated according to baseline FI along with the effect of empagliflozin on chronological changes in FI (at 12, 32 and 52 weeks). RESULTS The patient distribution was 1514 (25.3%), 2100 (35.1%), 1501 (25.1%) and 873 (14.6%) in non-frail, mild frailty, moderate frailty and severe frailty, respectively. Severe frailty patients tended to be female and have low Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, more co-morbidities and more polypharmacy. Incidence rates of the primary outcome of cardiovascular death or HF hospitalization increased as frailty worsened (hazard ratio [HR] of each FI category compared with the non-frail group: 1.10 [95% confidence interval, CI, 0.89-1.35], 2.00 [1.63-2.47] and 2.61 [2.08-3.27] in the mild frailty, moderate frailty and severe frailty groups, respectively; P trend < 0.001). Compared with placebo, empagliflozin reduced the risk for the primary outcome across the four FI categories, HR: 0.59 [95% CI 0.42-0.83], 0.79 [0.61-1.01], 0.77 [0.61-0.96] and 0.90 [0.69-1.16] in non-frail to severe frailty categories, respectively (P value for trend = 0.097). Empagliflozin also improved other clinical outcomes and KCCQ score across frailty categories. Compared with placebo, empagliflozin-treated patients had a higher likelihood of being in a lower FI category at Weeks 12, 32 and 52 (P < 0.05), odds ratio: 1.12 [95% CI 1.01-1.24] at Week 12, 1.21 [1.09-1.34] at Week 32 and 1.20 [1.09-1.33] at Week 52. CONCLUSIONS Empagliflozin improved key efficacy outcomes with a possible diminution of effect in very frail patients. Empagliflozin also improved frailty status during follow-up.
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Affiliation(s)
| | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, TX, USA
- University of Mississippi Medical Center, Jackson, MS, USA
| | - Hiroyuki Tsutsui
- School of Medicine and Graduate School, International University of Health and Welfare, Okawa, Japan
| | - Wolfram Doehner
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin, Berlin, Germany
- Deutsches Herzzentrum der Charité, Department of Cardiology (Campus Virchow), Charité Universitätsmedizin, Berlin, Germany
- German Centre for Cardiovascular Research (DZHK) Partner Site Berlin, Charité Universitätsmedizin, Berlin, Germany
| | - Gerasimos Filippatos
- National and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Athens, Greece
| | - João Pedro Ferreira
- Cardiovascular R&D Centre-UnIC@RISE, Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine of the University of Porto, Porto, Portugal
- Department of Internal Medicine, Heart Failure Clinic, Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal
- Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, U1116, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France
| | - Michael Böhm
- Department of Internal Medicine III, University Hospital Saarland, Saarland University, Homburg, Germany
| | | | - Subodh Verma
- Division of Cardiac Surgery, St Michael's Hospital, University of Toronto, Toronto, ON, Canada
| | - Matias Nordaby
- Boehringer Ingelheim International GmbH, Ingelheim, Germany
| | - Tomoko Iwata
- Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
| | - Daisuke Nitta
- Medicine Division, Nippon Boehringer Ingelheim Co. Ltd, Tokyo, Japan
| | - Piotr Ponikowski
- Center for Heart Diseases, University Hospital, Wroclaw Medical University, Wrocław, Poland
| | - Faiez Zannad
- Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, U1116, CHRU de Nancy, F-CRIN INI-CRCT, Nancy, France
| | - Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX, USA
- Imperial College, London, UK
| | - Stefan D Anker
- Department of Cardiology (CVK) of German Heart Center Charité; Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin, Berlin, Germany
- Institute of Heart Diseases, Wroclaw Medical University, Wrocław, Poland
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Yadav J, Ahsan F, Panda P, Mahmood T, Ansari VA, Shamim A. Empagliflozin-A Sodium Glucose Co-transporter-2 Inhibitor: Overview ofits Chemistry, Pharmacology, and Toxicology. Curr Diabetes Rev 2024; 20:e230124226010. [PMID: 38265382 DOI: 10.2174/0115733998271026231127051545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 09/24/2023] [Accepted: 10/17/2023] [Indexed: 01/25/2024]
Abstract
BACKGROUND Empagliflozin is a sodium glucose co-transporter-2 (SGLT2) inhibitor that has gained significant attention in the treatment of type 2 diabetes mellitus. Understanding its chemistry, pharmacology, and toxicology is crucial for the safe and effective use of this medication. OBJECTIVE This review aims to provide a comprehensive overview of the chemistry, pharmacology, and toxicology of empagliflozin, synthesizing the available literature to present a concise summary of its properties and implications for clinical practice. METHODS A systematic search of relevant databases was conducted to identify studies and articles related to the chemistry, pharmacology, and toxicology of empagliflozin. Data from preclinical and clinical studies, as well as post-marketing surveillance reports, were reviewed to provide a comprehensive understanding of the topic. RESULTS Empagliflozin is a selective SGLT2 inhibitor that works by constraining glucose reabsorption in the kidneys, causing increased urinary glucose elimination. Its unique mechanism of action provides glycemic control, weight reduction, and blood pressure reduction. The drug's chemistry is characterized by its chemical structure, solubility, and stability. Pharmacologically, empagliflozin exhibits favorable pharmacokinetic properties with rapid absorption, extensive protein binding, and renal elimination. Clinical studies have demonstrated its efficacy in improving glycemic control, reducing cardiovascular risks, and preserving renal function. However, adverse effects, for instance, urinary tract infections, genital infections, and diabetic ketoacidosis have been reported. Toxicological studies indicate low potential for organ toxicity, mutagenicity, or carcinogenicity. CONCLUSION Empagliflozin is a promising SGLT2 inhibitor that offers an innovative approach to the treatment of type 2 diabetes mellitus. Its unique action mechanism and favorable pharmacokinetic profile contribute to its efficacy in improving glycemic control and reducing cardiovascular risks. While the drug's safety profile is generally favorable, clinicians should be aware of potential adverse effects and monitor patients closely. More study is required to determine the longterm safety and explore potential benefits in other patient populations. Overall, empagliflozin represents a valuable addition to the armamentarium of antidiabetic medications, offering significant benefits to patients suffering from type 2 diabetes mellitus. This study covers all aspects of empagliflozin, including its history, chemistry, pharmacology, and various clinical studies, case reports, and case series.
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Affiliation(s)
- Jyoti Yadav
- Department of Pharmacy, Integral University, Dasauli, Kursi Road, Lucknow (U.P.), 226026, India
| | - Farogh Ahsan
- Department of Pharmacy, Integral University, Dasauli, Kursi Road, Lucknow (U.P.), 226026, India
| | - Prabhudatta Panda
- Department of Pharmacy, Institute of Technology & Management, Gorakhpur (U.P.), 226026, India
| | - Tarique Mahmood
- Department of Pharmacy, Integral University, Dasauli, Kursi Road, Lucknow (U.P.), 226026, India
| | - Vaseem Ahamad Ansari
- Department of Pharmacy, Integral University, Dasauli, Kursi Road, Lucknow (U.P.), 226026, India
| | - Arshiya Shamim
- Department of Pharmacy, Integral University, Dasauli, Kursi Road, Lucknow (U.P.), 226026, India
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Tanrıverdi M, Baştemir M, Demirbakan H, Ünalan A, Türkmen M, Tanrıverdi GÖ. Association of SGLT-2 inhibitors with bacterial urinary tract infection in type 2 diabetes. BMC Endocr Disord 2023; 23:211. [PMID: 37789335 PMCID: PMC10548559 DOI: 10.1186/s12902-023-01464-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 09/18/2023] [Indexed: 10/05/2023] Open
Abstract
OBJECTIVE We aimed to investigate the factors associated with UTI in patients with T2D whether being treated with SGLT-2i or not. METHODS Adult patients with T2D, whose urine culture results were available, were analyzed retrospectively. Urine culture was obtained from mid-flow urine. Antibacterial treatment was given to the patients with UTI, which was defined by positive urine cultures and/or clinical findings. We grouped the patients as follows: Group A, those treated with SGLT-2i; and Group B, those not treated with SGLT-2i. RESULTS A total of 101 patients were included. Median age was 56 (45-67), 56.4% (n = 57) of the patients were female. Urine culture was positive in 54.9% (n = 28) and 16% (n = 8) of Group A (n = 51) and Group B (n = 50), respectively. Of those for whom urine culture was positive, Escherichia coli was isolated in 83.3% (n = 30), and both Escherichia coli and Klebsiella pneumoniae (K.pneumoniae) were isolated in 16.7% (n = 6). Klebsiella pneumoniae was isolated only from Group A. The need for and duration of hospitalization were higher in Group A (p < 0.001). UTI was detected in 60 patients. ROC analysis showed that a HbA1c of > 5.8% was associated with UTI with good accuracy (AUC: 0.835, p < 0.001). In multiple logistic regression analysis, SGLT-2i use and glucosuria were positive predictors for UTI (p = 0.004, Odds Ratio: 1984.013; and p = 0.028, and Odds Ratio: 12.480, respectively). CONCLUSION Besides the association of HbA1c and BMI with UTI, SGLT-2i use and glucosuria predicted UTI. Urine culture is important with respect to the choice of antibacterial treatment, especially in those patients under SGLT-2i treatment. The effect of SGLT-2i on the development of UTI is independent of baseline BMI score or HbA1c.
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Affiliation(s)
- Mustafa Tanrıverdi
- Department of Infectious Diseases, SANKO University Faculty of Medicine, Gazimuhtar Paşa Bulvar? No:36 - 27090 Şehitkamil, Gaziantep, Turkey.
| | - Mehmet Baştemir
- Department of Medical Microbiology, SANKO University Faculty of Medicine, Gaziantep, Turkey
| | - Hadiye Demirbakan
- Department of Medical Microbiology, SANKO University Faculty of Medicine, Gaziantep, Turkey
| | - Alperen Ünalan
- Department of Internal Medicine, SANKO University Faculty of Medicine, Gaziantep, Turkey
| | - Merve Türkmen
- Department of Infectious Diseases, SANKO University Faculty of Medicine, Gazimuhtar Paşa Bulvar? No:36 - 27090 Şehitkamil, Gaziantep, Turkey
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Fatima A, Rasool S, Devi S, Talha M, Waqar F, Nasir M, Khan MR, Ibne Ali Jaffari SM, Haider A, Shah SU, Sapna F, Varrassi G, Khatri M, Kumar S, Mohamad T. Exploring the Cardiovascular Benefits of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors: Expanding Horizons Beyond Diabetes Management. Cureus 2023; 15:e46243. [PMID: 37908957 PMCID: PMC10613932 DOI: 10.7759/cureus.46243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Accepted: 09/30/2023] [Indexed: 11/02/2023] Open
Abstract
Globally, cardiovascular disease (CVD) continues to be the primary cause of morbidity and mortality. The risk of cardiovascular disease is markedly increased in individuals with type 2 diabetes mellitus (T2DM), making managing cardiovascular health a top priority. Initially developed for their glucose-lowering properties, sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as a transformative class of pharmaceuticals with profound cardiovascular benefits that extend far beyond glycemic control. One of the most striking findings is the substantial reduction in major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular mortality, observed in clinical trials evaluating SGLT2 inhibitors. These extraordinary cardioprotective effects are demonstrated by landmark trials such as EMPA-REG OUTCOME, CANVAS, and DECLARE-TIMI 58, which are discussed in detail. In addition, SGLT2 inhibitors have demonstrated positive outcomes in heart failure (HF) with reduced ejection fraction, which has led to their incorporation into HF treatment guidelines. SGLT2 inhibitors offer renoprotection by delaying the progression of diabetic kidney disease, reducing albuminuria, preserving glomerular filtration rates, and their immediate cardiovascular benefits. We investigate the potential mechanisms underlying these renal benefits, focusing on the role of hemodynamic alterations and intraglomerular pressure reduction. In addition, SGLT2 inhibitors have a distinct diuretic effect that can contribute to volume reduction and symptom alleviation in patients with heart failure (HF). This diuretic action, distinct from conventional diuretics, warrants additional research to optimize their use in T2DM and HF patients. The risk of euglycemic diabetic ketoacidosis, genital mycobacterial infections, and bone fractures are also discussed. Understanding these issues is essential for making educated clinical decisions. In conclusion, SGLT2 inhibitors have transcended their initial function as anti-diabetic agents to become essential components of cardiovascular and renal protection strategies in T2DM patients. Their diverse benefits, which include cardioprotection, renoprotection, and the potential for HF management, highlight their potential to transform cardiovascular medicine. Optimizing the use of SGLT2 inhibitors in clinical practice bears the promise of improved cardiovascular outcomes for patients with T2DM and beyond as we navigate this changing landscape.
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Affiliation(s)
- Aroob Fatima
- Medicine, Fatima Memorial Hospital College of Medicine and Dentistry, Lahore, PAK
| | - Sohaib Rasool
- Medicine, Bakhtawar Amin Medical and Dental College, Multan, PAK
| | - Sapna Devi
- Internal Medicine, Ziauddin University, Karachi, PAK
| | - Muhammad Talha
- Internal Medicine, Nishtar Medical University, Multan, PAK
| | - Fahad Waqar
- Medicine, Allama Iqbal Medical College, Lahore, PAK
| | - Muhammad Nasir
- Medicine, Rural Health Center (RHC) Dhonkal, Dhonkal Morr, PAK
| | - Mohammad R Khan
- Internal Medicine, Bakhtawar Amin Trust Teaching Hospital, Multan, PAK
| | | | - Anum Haider
- Internal Medicine, International Medical Graduates Helping Hand, Karachi, PAK
| | - Syeda U Shah
- Medical College, Jinnah Sindh Medical University, Karachi, PAK
| | - Fnu Sapna
- Pathology, Albert Einstein College of Medicine, Bronx, USA
| | | | - Mahima Khatri
- Medicine and Surgery, Dow University of Health Sciences, Karachi, PAK
| | - Satesh Kumar
- Medicine and Surgery, Shaheed Mohtarma Benazir Bhutto Medical College, Karachi, PAK
| | - Tamam Mohamad
- Cardiovascular Medicine, Wayne State University, Detroit, USA
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9
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Varshney A, Rawat R. Comparison of safety and efficacy of dapagliflozin and empagliflozin in type 2 diabetes mellitus patients in India. REVISTA DA ASSOCIACAO MEDICA BRASILEIRA (1992) 2023; 69:e20230090. [PMID: 37585983 PMCID: PMC10427181 DOI: 10.1590/1806-9282.20230090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 05/20/2023] [Indexed: 08/18/2023]
Affiliation(s)
- Amit Varshney
- Kanti Devi Medical College Hospital and Research Center, Department of Emergency Medicine – Mathura (UP), India
| | - Ramakant Rawat
- Uttar Pradesh University of Medical Sciences, Department of Medicine – Etawah (UP), India
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10
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Sugawara M, Fukuda M, Sakuma I, Wakasa Y, Funayama H, Kondo A, Itabashi N, Maruyama Y, Kamiyama T, Utsunomiya Y, Yamauchi A, Yoshii H, Yamada H, Mochizuki K. Overall Efficacy and Safety of Sodium-Glucose Cotransporter 2 Inhibitor Luseogliflozin Versus Dipeptidyl-Peptidase 4 Inhibitors: Multicenter, Open-Label, Randomized-Controlled Trial (J-SELECT study). Diabetes Ther 2023:10.1007/s13300-023-01438-w. [PMID: 37410308 PMCID: PMC10363101 DOI: 10.1007/s13300-023-01438-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 06/16/2023] [Indexed: 07/07/2023] Open
Abstract
INTRODUCTION Evidence of a direct comparison between dipeptidyl-peptidase 4 inhibitors (DPP-4is) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) remains lacking, and no clear treatment strategy or rationale has been established using these drugs. This study aimed to compare the overall efficacy and safety of DPP-4is and the SGLT2i luseogliflozin in patients with type 2 diabetes mellitus (T2DM). METHODS Patients with T2DM who had not used antidiabetic agents or who had used antidiabetic agents other than SGLT2is and DPP-4is were enrolled in the study after written informed consent had been obtained. The enrolled patients were subsequently randomly assigned to either the luseogliflozin or DPP-4i group and followed up for 52 weeks. The primary (composite) endpoint was the proportion of patients who showed improvement in ≥ 3 endpoints among the following five endpoints from baseline to week 52: glycated hemoglobin (HbA1c), weight, estimated glomerular filtration rate (eGFR), systolic blood pressure, and pulse rate. RESULTS A total of 623 patients were enrolled in the study and subsequently randomized to either the luseogliflozin or DPP-4i groups. The proportion of patients who showed improvement in ≥ 3 endpoints at week 52 was significantly higher in the luseogliflozin group (58.9%) than in the DPP-4i group (35.0%) (p < 0.001). When stratified by body mass index (BMI) (< 25 or ≥ 25 kg/m2) or age (< 65 or ≥ 65 years), regardless of BMI or age, the proportion of patients who achieved the composite endpoint was significantly higher in the luseogliflozin group than in the DPP-4i group. Hepatic function and high-density lipoprotein-cholesterol were also significantly improved in the luseogliflozin group compared with the DPP-4i group. The frequency of non-serious/serious adverse events did not differ between the groups. CONCLUSION This study showed the overall efficacy of luseogliflozin compared with DPP-4is over the mid/long term, regardless of BMI or age. The results suggest the importance of assessing multiple aspects regarding the effects of diabetes management. TRIAL REGISTRATION NUMBER jRCTs031180241.
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Affiliation(s)
- Masahiro Sugawara
- Sugawara Clinic, 3-9-16 Syakujii-machi, Nerima, Tokyo, 177-0041, Japan.
| | - Masahiro Fukuda
- Fukuda Clinic, 1-6-1, Miyahara, Yodogawa, Osaka-shi, Osaka, 532-0003, Japan
| | - Ichiro Sakuma
- Caress Sapporo Hokko Memorial Clinic, Kita-17, Higashi-8, 1-15, Sapporo, Hokkaido, 065-0027, Japan
| | - Yutaka Wakasa
- Wakasa Medical Clinic, 3-16-25, Sainen, Kanazawa, Ishikawa, 920-0024, Japan
| | - Hideaki Funayama
- Funayama Medical Clinic, 1-13-14 Tomioka, Koto, Tokyo, 135-0047, Japan
| | - Akira Kondo
- Kondo Hospital, 1-6-25 Nishi-Shinhama-cho, Tokushima, 770-8008, Japan
| | - Naoki Itabashi
- Itabashi Clinic, 815-1, Higashi-Ushigaya, Koga, Ibaraki, 306-0232, Japan
| | - Yasuyuki Maruyama
- Iwatsuki-Minami Hospital, 2256 Kuroya Iwatsuki, Saitama-shi, Saitama, 339-0033, Japan
| | - Takashi Kamiyama
- Kamiyama Clinic, 5-21-18, Takanodai, Nerima, Tokyo, 177-0033, Japan
| | | | - Akira Yamauchi
- Suruga Clinic, 9-23, Shoufuku-cho, Shimizu, Shizuoka, Shizuoka, 424-0855, Japan
| | - Hidenori Yoshii
- Department of Diabetes and Endocrinology, Juntendo Tokyo Koto Geriatric Medical Center, 3-3-20 Shinsuna, Koto, Tokyo, 136-0075, Japan
| | | | - Koichi Mochizuki
- Mochizuki Naika Clinic, 4-5, Aioi-cho, Itabashi, Tokyo, 174-0044, Japan
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11
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Tsai PC, Chuang WJ, Ko AMS, Chen JS, Chiu CH, Chen CH, Yeh YH. Neutral effects of SGLT2 inhibitors in acute coronary syndromes, peripheral arterial occlusive disease, or ischemic stroke: a meta-analysis of randomized controlled trials. Cardiovasc Diabetol 2023; 22:57. [PMID: 36915157 PMCID: PMC10012509 DOI: 10.1186/s12933-023-01789-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 03/03/2023] [Indexed: 03/15/2023] Open
Abstract
BACKGROUND Patients with type 2 diabetes are at increased risk for cardiovascular diseases. Sodium-glucose transport 2 inhibitors (SGLT2i) have been shown to enhance cardiovascular health since their debut as a second-line therapy for diabetes. Acute coronary syndrome (ACS), peripheral arterial occlusive disease (PAOD), and ischemic stroke (IS) are types of atherosclerotic cardiovascular disease (ASCVD), although the benefits of treating these disorders have not been shown consistently. METHODS We searched four databases (PubMed, Embase, the Cochrane library, and clinicaltrial.gov) for randomized clinical trials (RCTs) until November of 2022. Comparisons were made between SGLT2i-treated and control individuals with type 2 diabetes. Primary outcomes were ACS, PAOD, and IS; secondary outcomes included cardiovascular mortality and all-cause mortality. Risk ratio (RR) and 95% confidence intervals (CI) were determined using a fixed effects model. Cochrane's risk-of-bias (RoB2) instrument was used to assess the validity of each study that met the inclusion criteria. RESULTS We enrolled 79,504 patients with type 2 diabetes from 43 RCTs. There was no difference in the risk of ACS (RR = 0.97, 95% CI 0.89-1.05), PAOD (RR = 0.98, 95% CI 0.78-1.24), or IS (RR = 0.95, 95% CI 0.79-1.14) among patients who took an SGLT2i compared to those who took a placebo or oral hypoglycemic drugs. Subgroup analysis revealed that none of the SGLT2i treatments (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) significantly altered outcomes when analyzed separately. Consistent with prior findings, SGLT2i reduced the risk of cardiovascular mortality (RR = 0.85, 95% CI 0.77-0.93) and all-cause mortality (RR = 0.88, 95% CI 0.82-0.94). CONCLUSION Our results appear to contradict the mainstream concepts regarding the cardiovascular effects of SGLT2i since we found no significant therapeutic benefits in SGLT2i to reduce the incidence of ACS, PAOD, or IS when compared to placebo or oral hypoglycemic drugs.
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Affiliation(s)
- Pei-Chien Tsai
- Department and Graduate Institute of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
- Master's Program in Clinical Trials and Assessment, Department of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
- Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, No. 5, Fuxing st., Guishan Dist., Taoyuan City, 333, Taiwan
- Healthy Aging Research Center, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
| | - Wei-Jung Chuang
- Master's Program in Clinical Trials and Assessment, Department of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
| | - Albert Min-Shan Ko
- Department and Graduate Institute of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
- Master's Program in Clinical Trials and Assessment, Department of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
- Healthy Aging Research Center, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
- Cardiovascular Department, Chang Gung Memorial Hospital, No. 5, Fuxing st., Guishan Dist., Taoyuan City, 333, Taiwan
| | - Jui-Shuan Chen
- Master's Program in Clinical Trials and Assessment, Department of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
| | - Cheng-Hsun Chiu
- Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, No. 5, Fuxing st., Guishan Dist., Taoyuan City, 333, Taiwan
- Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, No. 5, Fuxing st., Guishan Dist., Taoyuan City, 333, Taiwan
| | - Chun-Han Chen
- Master's Program in Clinical Trials and Assessment, Department of Biomedical Sciences, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan
| | - Yung-Hsin Yeh
- Cardiovascular Department, Chang Gung Memorial Hospital, No. 5, Fuxing st., Guishan Dist., Taoyuan City, 333, Taiwan.
- School of Medicine, Chang Gung University, No. 259, Wenhua 1st Rd, Guishan Dist., Taoyuan City, 33302, Taiwan.
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12
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Hossain MS, Jahan S, Al Rezwan Rahman S, Rahman M, Kumar D, Paul S, Chandra Rajbangshi J. Design expert software assisted development and evaluation of empagliflozin and sitagliptin combination tablet with improved in-vivo anti-diabetic activities. Heliyon 2023; 9:e14259. [PMID: 36938401 PMCID: PMC10015239 DOI: 10.1016/j.heliyon.2023.e14259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 02/23/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Background The combination of empagliflozin and sitagliptin to treat type-2 diabetes might be more economical and patient compliance with an additive improvement in glycemic control due to complementary modes of action. Aim of the study To design, formulate and optimize an immediate tablet dosage form containing empagliflozin and sitagliptin utilizing statistically reliable study design followed by in-vitro and in-vivo testing. Method ology: To determine the effects of copovidone (X1) and croscarmellose sodium (X2) amounts on the dependent variables of disintegration time and percent drug release, the formulation was developed using Design Expert Software v.13's direct compression method-based central composite design optimization study. The formulations' assay, dissolution, friability, hardness, weight variation, disintegration, and anti-diabetic effects were evaluated in comparison to the standard drug. The analysis included the use of high performance liquid chromatography (HPLC) assay methods. Mice were employed to investigate the efficacy of an anti-diabetic drug after they were administered a high-fat diet and two injections of streptozotocin at a dosage of 30 mg/kg BW each. Results Formulation of F3 out of nine had all in-vitro parameters at the most satisfactory condition. It was found that assay of the best formulation is 100.99% and 100.19% for empagliflozin and sitagliptin respectively. The disintegration time of F3 was found at 5.32 min. Percentage release of empagliflozin in 30 min was found 89.05% while sitagliptin was with 93.76%. The results showed that administration of F3 significantly reduced FBG (68.61%, p < 0.0001), total cholesterol levels (70.29 ± 0.48; p < 0.0001), triglycerides (70.20 ± 0.40, p < 0.0001); HDL levels (52.50 ± 0.31; p < 0.0001), LDL levels (33.34 ± 0.28; p < 0.0001), compared to diabetic control, this effect was comparable to metformin treatment. Conclusion The direct compression approach has been used to develop, and optimize a new combination tablet incorporating empagliflozin and sitagliptin with better dissolution rate and anti-diabetic action.
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Affiliation(s)
- Md Saddam Hossain
- Department of Pharmacy, Faculty of Science, Comilla University, Bangladesh
| | - Sadia Jahan
- Department of Pharmacy, Faculty of Science, Comilla University, Bangladesh
- Corresponding author. Department of Pharmacy, Faculty of Science, Comilla University, Cumilla, 3506, Bangladesh.
| | | | - Mashiur Rahman
- Bangladesh Reference Institute for Chemical Measurements, Dhaka, Bangladesh
| | - Diponkor Kumar
- Department of Pharmacy, Faculty of Life and Earth Sciences, Jagannath University, Bangladesh
| | - Susmita Paul
- Pharmacy Discipline, Khulna University, Khulna, Bangladesh
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13
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Dissanayake H, Dilrukshi S, Ratnasamy V, Soysa P, Samarathunga T, Bandara P, De Silva L, Katulanda P. Empagliflozin in South Asians with type 2 diabetes: Real world data on effects on cardiometabolic parameters, safety and determinants of response to therapy from a diabetes practice in Sri Lanka. Prim Care Diabetes 2023; 17:98-104. [PMID: 36460591 DOI: 10.1016/j.pcd.2022.11.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 10/19/2022] [Accepted: 11/19/2022] [Indexed: 12/05/2022]
Abstract
AIMS SGLT2 inhibitors provide cardiovascular and renal protection in people with type 2 diabetes (T2DM). Real-world data on their effect on improving glucose and cardiovascular risk factors, and adverse effects in South Asians are limited. METHODS We retrospectively analyzed clinical, demographic, anthropometric and biochemical data among adults with T2DM, commenced on empagliflozin and followed up for at least one month in a diabetes clinic in Colombo. RESULTS Among 1523 participants (men 49.6 %, age 54.9 (± 10.8) years, diabetes duration 11.5 (± 7.6) years, body mass index 28.2 (± 4.5 kg/m2), over a median follow up of 12 months (range: 1-24 months), reduction in HbA1c, weight, systolic blood pressure (SBP) and urine albumin-creatinine ratio were evident within the first month. Benefits sustained up to two-years (mean changes from baseline: HbA1c - 0.31 (± 1.49), weight - 1.14 (± 4.17), SBP - 3.44 (± 21.75), UACR - 19.84 (± 108.22) follow up. eGFR declined by the third month, returned to baseline by 12th and remained stable over 24 months. Higher baseline HbA1c, weight and SBP predicted greater decline in HbA1c, weight and SBP respectively. Weight reduction independently predicted the SBP reduction. Eighteen participants per 100 patient-years discontinued therapy due to adverse effects: genital mycotic infections and features of hypovolaemia were the commonest. We observed only two events of diabetic ketoacidosis. CONCLUSIONS Empagliflozin effectively improves glucose, weight and SBP and retards progression of renal impairment in South Asians with T2D. Genital mycotic infections and hypovolaemia were the commonest reasons for discontinuation. Careful patient selection and advice can avoid other sinister complications.
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Affiliation(s)
- Harsha Dissanayake
- Diabetes Research Unit, Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka; Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka.
| | - Shani Dilrukshi
- University Medical Unit, National Hospital of Sri Lanka, Sri Lanka
| | | | - Pasindu Soysa
- Diabetes Research Unit, Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka
| | - Thilina Samarathunga
- Diabetes Research Unit, Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka
| | - Prabhath Bandara
- Diabetes Research Unit, Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka
| | - Laksara De Silva
- Diabetes Research Unit, Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka
| | - Prasad Katulanda
- Diabetes Research Unit, Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka; Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka; Cruddas Link Fellow, Harris Manchester College, University of Oxford, UK
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14
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Harada M, Kondo Y, Sugiyama M, Ohira A, Ichikawa M, Akiyama T, Orime K, Takai T, Yamakawa T, Terauchi Y. The METRO study: a retrospective analysis of the efficacy of metformin for type 2 diabetes in Japan. Endocr J 2023; 70:121-128. [PMID: 36261368 DOI: 10.1507/endocrj.ej22-0330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Metformin monotherapy as first-line treatment for patients with type 2 diabetes (T2D) has been shown to effectively improve blood glucose levels and motivation to undergo treatment and prevent complications. However, no studies have reported its effect when combined with other drugs or compared the effect based on administration time. This study aimed to investigate the effect of metformin administration in Japanese patients with T2D, examine how the introduction line impacts the effect of metformin, and examine the characteristics of patients demonstrating improved blood glucose levels. Data on characteristics of patients who were newly prescribed metformin with no shifting of hypoglycemic agents in the subsequent 24-week observation period, and their age [mean, 56.8 years], body mass index [mean, 27.5 kg/m2], glycated hemoglobin [HbA1c] [mean, 8.1%], and duration of diabetes [mean, 3.0 years] were obtained from the medical records of 201 patients. The changes in HbA1c by introduction line after 24 weeks were -1.59%, -0.91%, -0.89%, and -0.65% in the first, second, third, and fourth induction lines, respectively; earlier introduction more significantly improved blood glucose. The factors significantly associated with HbA1c changes were early introduction, high baseline HbA1c, high estimated glomerular filtration rate, decreased insulin secretion, short estimated duration of diabetes, and increased metformin dose. Furthermore, factors contributing to the largest HbA1c improvement by metformin were high baseline HbA1c and early administration. Metformin is expected to lower blood glucose levels in Japanese patients with T2D, even in those with decreased insulin secretion, due to its early introduction as a first-line drug.
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Affiliation(s)
- Marina Harada
- Department of Endocrinology and Diabetes, Yokohama City University Medical Center, Yokohama 232-0024, Japan
| | - Yoshinobu Kondo
- Tsunashima East Internal Medicine and Diabetes Clinic, Yokohama 223-0052, Japan
| | - Mai Sugiyama
- Department of Endocrinology and Diabetes, Yokohama City University Medical Center, Yokohama 232-0024, Japan
| | - Akeo Ohira
- Department of Endocrinology and Diabetes, Yokohama City University Medical Center, Yokohama 232-0024, Japan
| | - Masahiro Ichikawa
- Department of Endocrinology and Diabetes, Yokohama City University Medical Center, Yokohama 232-0024, Japan
| | - Tomoaki Akiyama
- Department of Endocrinology and Diabetes, Yokohama City University Medical Center, Yokohama 232-0024, Japan
| | - Kazuki Orime
- Department of Endocrinology and Diabetes, Yokohama City University Medical Center, Yokohama 232-0024, Japan
| | - Takanori Takai
- Urafune Kanazawa Internal Medicine Clinic, Yokohama 232-0024, Japan
| | - Tadashi Yamakawa
- Department of Endocrinology and Diabetes, Yokohama City University Medical Center, Yokohama 232-0024, Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Yokohama City University School of Medicine, Yokohama 236-0004, Japan
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15
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Anker SD, Khan MS, Butler J, Ofstad AP, Peil B, Pfarr E, Doehner W, Sattar N, Coats AJS, Filippatos G, Ferreira JP, Zannad F, Pocock S, Packer M. Weight change and clinical outcomes in heart failure with reduced ejection fraction: insights from EMPEROR-Reduced. Eur J Heart Fail 2023; 25:117-127. [PMID: 36325584 PMCID: PMC10098519 DOI: 10.1002/ejhf.2728] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 10/20/2022] [Accepted: 10/22/2022] [Indexed: 11/06/2022] Open
Abstract
AIMS Baseline body mass index (BMI) and weight loss promoted by sodium-glucose cotransporter 2 inhibitors may impact outcomes in patients with heart failure with reduced ejection fraction (HFrEF). We assessed in the EMPEROR-Reduced population treated with empagliflozin versus placebo the relationship between baseline BMI, weight loss and effects on the primary (time to first hospitalization for heart failure [HHF] or cardiovascular death) and key secondary outcomes. METHODS AND RESULTS We categorized patients according to their baseline BMI: <20 kg/m2 (n = 180); 20 to <25 kg/m2 (n = 1038); 25 to <30 kg/m2 (n = 1345); 30 to <35 kg/m2 (n = 774) and ≥35 kg/m2 (n = 393). The treatment effect of empagliflozin on the primary outcome was consistent across all BMI categories (hazard ratios in subgroups 0.66-0.88, interaction trend p = 0.32), as was the effect on total (first plus recurrent) HHF (interaction trend p = 0.31). Empagliflozin reduced the rate of estimated glomerular filtration rate decline consistently across the BMI categories (interaction trend p = 0.67). Overall, incidence rates of any or serious adverse events were comparable between the treatment groups across all BMI categories. A total of 313 (17.4%) patients treated with empagliflozin experienced a weight loss of more than 5% at week 52 versus 230 (12.8%) in placebo. When analysed separately within each treatment group, presence of weight loss was similarly associated with an increased risk of all-cause mortality. CONCLUSION The benefits of empagliflozin versus placebo were consistently present across all BMI categories in HFrEF patients. Weight loss was associated with higher risk of all-cause mortality, regardless of treatment group.
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Affiliation(s)
- Stefan D. Anker
- Department of Cardiology and Berlin Institute of Health Center for Regenerative Therapies, and German Centre for Cardiovascular Research (DZHK) partner site BerlinCharité Universitätsmedizin BerlinBerlinGermany
- Institute of Heart DiseasesWrocław Medical UniversityWrocławPoland
| | | | - Javed Butler
- Baylor Scott and White Research InstituteDallasTXUSA
- Department of MedicineUniversity of Mississippi School of MedicineJacksonMSUSA
| | - Anne Pernille Ofstad
- Medical DepartmentBoehringer Ingelheim Norway KSAskerNorway
- Oslo Diabetes Research CenterOsloNorway
| | - Barbara Peil
- Boehringer Ingelheim Pharma GmbH & Co. KGIngelheimGermany
| | - Egon Pfarr
- Boehringer Ingelheim Pharma GmbH & Co. KGIngelheimGermany
| | - Wolfram Doehner
- Department of Cardiology and Berlin Institute of Health Center for Regenerative Therapies, and German Centre for Cardiovascular Research (DZHK) partner site BerlinCharité Universitätsmedizin BerlinBerlinGermany
| | - Naveed Sattar
- School of Cardiovascular and Metabolic Health University of GlasgowBHF Glasgow Cardiovascular Research Centre (GCRC)GlasgowUK
| | | | - Gerasimos Filippatos
- National and Kapodistrian University of Athens School of MedicineAthens University Hospital AttikonAthensGreece
| | - João Pedro Ferreira
- Centre d'Investigation Clinique‐Plurithématique INSERM CIC‐P 1433, and INSERM U1116 CHRU Nancy Brabois F‐CRIN INI‐CRCTUniversité de LorraineNancyFrance
- UnIC@RISE, Cardiovascular R&D Center, Faculty of MedicineUniversity of PortoPortoPortugal
| | - Faiez Zannad
- Centre d'Investigation Clinique‐Plurithématique INSERM CIC‐P 1433, and INSERM U1116 CHRU Nancy Brabois F‐CRIN INI‐CRCTUniversité de LorraineNancyFrance
| | - Stuart Pocock
- London School of Hygiene and Tropical MedicineLondonUK
| | - Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical CenterDallasTXUSA
- Imperial CollegeLondonUK
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16
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The Cardiovascular Benefits and Infections Risk of SGLT2i versus Metformin in Type 2 Diabetes: A Systemic Review and Meta-Analysis. Metabolites 2022; 12:metabo12100979. [PMID: 36295882 PMCID: PMC9610220 DOI: 10.3390/metabo12100979] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/05/2022] [Accepted: 10/09/2022] [Indexed: 11/17/2022] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and metformin are both widely accepted anti-hyperglycemic agents. However, there is still no systematic review evaluating the cardiovascular benefits and risk of infections of SGLT2i versus metformin. To make that clear, we designed this study. Public databases, including the Cochrane library database, PubMed, and Embase were searched for randomized clinical trials (RCTs) fitting the inclusion criteria. Two reviewers extracted the data and appraised the study quality independently. Thirteen RCTs enrolling 4189 patients were eligible for this analysis. Our results showed that compared with metformin, SGLT2i increased the risk of genitourinary tract infections (p < 0.00001). Further subgroup analysis suggested that the occurrence of urinary tract infections (UTI) was not statistically significant (p = 0.18), but the incidence of reproductive tract infections (RTI) was significantly increased in patients in the SGLT2i group compared with that in the metformin group (p < 0.00001). In addition, SGLT2i markedly decreased the levels of cardiovascular risk factor, including body weight, blood pressure, and triglyceride level, and significantly increased the HDL-cholesterol level (p < 0.00001) in patients versus that of metformin. For type 2 diabetes patients with obesity, SGLT2i was associated with more significant reductions in weight and blood pressure compared to metformin without an increased risk of genitourinary infections, and the reduction in fasting plasma glucose was superior in the SGLT2i group; the decrease in HbA1c was similar in both groups. Additionally, no significant publication bias was seen. Based on these findings, SGLT2i provided the similar antihyperglycemic effects, additional cardiovascular benefits, and a potential RTI risk compared with that of metformin. Our results indicate that SGLT2i is a good choice for those patients with metformin intolerance or resistance.
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17
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Cao X, Du X, Jiao H, An Q, Chen R, Fang P, Wang J, Yu B. Carbohydrate-based drugs launched during 2000 -2021. Acta Pharm Sin B 2022; 12:3783-3821. [PMID: 36213536 PMCID: PMC9532563 DOI: 10.1016/j.apsb.2022.05.020] [Citation(s) in RCA: 103] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/18/2022] [Accepted: 05/12/2022] [Indexed: 01/09/2023] Open
Abstract
Carbohydrates are fundamental molecules involved in nearly all aspects of lives, such as being involved in formating the genetic and energy materials, supporting the structure of organisms, constituting invasion and host defense systems, and forming antibiotics secondary metabolites. The naturally occurring carbohydrates and their derivatives have been extensively studied as therapeutic agents for the treatment of various diseases. During 2000 to 2021, totally 54 carbohydrate-based drugs which contain carbohydrate moities as the major structural units have been approved as drugs or diagnostic agents. Here we provide a comprehensive review on the chemical structures, activities, and clinical trial results of these carbohydrate-based drugs, which are categorized by their indications into antiviral drugs, antibacterial/antiparasitic drugs, anticancer drugs, antidiabetics drugs, cardiovascular drugs, nervous system drugs, and other agents.
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Affiliation(s)
- Xin Cao
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Xiaojing Du
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Heng Jiao
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Quanlin An
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Ruoxue Chen
- Zhongshan Hospital Institute of Clinical Science, Fudan University Shanghai Medical College, Shanghai 200032, China
| | - Pengfei Fang
- State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
| | - Jing Wang
- State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
| | - Biao Yu
- State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
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18
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Efficacy and Safety of Empagliflozin in Type 2 Diabetes Mellitus Saudi Patients as Add-On to Antidiabetic Therapy: A Prospective, Open-Label, Observational Study. J Clin Med 2022; 11:jcm11164769. [PMID: 36013008 PMCID: PMC9410062 DOI: 10.3390/jcm11164769] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/10/2022] [Accepted: 08/12/2022] [Indexed: 11/17/2022] Open
Abstract
The Saudi Food and Drug Authority (SFDA) approved sodium-glucose cotransporter-2 (SGLT2) inhibitors in 2018. The efficacy and safety of empagliflozin (EMPA) have been confirmed in the U.S., Europe, and Japan for patients with type 2 diabetes mellitus (T2DM); however, analogous evidence is lacking for Saudi T2DM patients. Therefore, the current study aimed to assess the efficacy and safety of EMPA in Saudi patients (n = 256) with T2DM. This is a 12-week prospective, open-label, observational study. Adult Saudi patients with T2DM who had not been treated with EMPA before enrolment were eligible. The exclusion criteria included T2DM patients less than 18 years of age, adults with type one diabetes, pregnant women, paediatric population. The results related to efficacy included a significant decrease in haemoglobin A1c (HbA1c) (adjusted mean difference −0.93% [95% confidence interval (CI) −0.32, −1.54]), significant improvements in fasting plasma glucose (FPG) (−2.28 mmol/L [95% CI −2.81, −1.75]), and a reduction in body weight (−0.874 kg [95% CI −4.36, −6.10]) following the administration of 25 mg of EMPA once daily as an add-on to ongoing antidiabetic therapy after 12 weeks. The primary safety endpoints were the change in the mean blood pressure (BP) values, which indicated significantly reduced systolic and diastolic BP (−3.85 mmHg [95% CI −6.81, −0.88] and −0.06 mmHg [95% CI −0.81, −0.88], respectively) and pulse rate (−1.18 [95% CI −0.79, −3.15]). In addition, kidney function was improved, with a significant reduction in the urine albumin/creatinine ratio (UACR) (−1.76 mg/g [95% CI −1.07, −34.25]) and a significant increase in the estimated glomerular filtration rate (eGFR) (3.54 mL/min/1.73 m2 [95% CI 2.78, 9.87]). Furthermore, EMPA reduced aminotransferases (ALT) in a pattern (reduction in ALT > AST). The adjusted mean difference in the change in ALT was −2.36 U/L [95% CI −1.031, −3.69], while it was −1.26 U/L [95% CI −0.3811, −2.357] for AST and −1.98 U/L [95% CI −0.44, −3.49] for GGT. Moreover, in the EMPA group, serum high-density lipoprotein (HDL) significantly increased (0.29 mmol/L [95% CI 0.74, 0.15]), whereas a nonsignificant increase was seen in low-density lipoprotein (LDL) (0.01 mmol/L [95% CI 0.19, 0.18]) along with a significant reduction in plasma triglyceride (TG) levels (−0.43 mmol/L [95% CI −0.31, −1.17]). Empagliflozin once daily is an efficacious and tolerable strategy for treating Saudi patients with insufficiently controlled T2DM as an add-on to ongoing antidiabetic therapy.
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19
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He L, Wang J, Ping F, Yang N, Huang J, Li W, Xu L, Zhang H, Li Y. Dipeptidyl peptidase-4 inhibitors and gallbladder or biliary disease in type 2 diabetes: systematic review and pairwise and network meta-analysis of randomised controlled trials. BMJ 2022; 377:e068882. [PMID: 35764326 PMCID: PMC9237836 DOI: 10.1136/bmj-2021-068882] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To examine the association between dipeptidyl peptidase-4 inhibitors and gallbladder or biliary diseases. DESIGN Systematic review and pairwise and network meta-analysis. DATA SOURCES PubMed, EMBASE, Web of Science, and CENTRAL from inception until 31 July 2021. ELIGIBILITY CRITERIA Randomised controlled trials of adult patients with type 2 diabetes who received dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors compared with placebo or other antidiabetes drugs. MAIN OUTCOME MEASURES Composite of gallbladder or biliary diseases, cholecystitis, cholelithiasis, and biliary diseases. DATA EXTRACTION AND DATA SYNTHESIS Two reviewers independently extracted the data and assessed the quality of the studies. The quality of the evidence for each outcome was assessed using the Grading of Recommendations, Assessment, Development and Evaluations framework (GRADE) approach. The meta-analysis used pooled odds ratios and 95% confidence intervals. RESULTS A total of 82 randomised controlled trials with 104 833 participants were included in the pairwise meta-analysis. Compared with placebo or non-incretin drugs, dipeptidyl peptidase-4 inhibitors were significantly associated with an increased risk of the composite of gallbladder or biliary diseases (odds ratio 1.22 (95%confidence interval 1.04 to 1.43); risk difference 11 (2 to 21) more events per 10 000 person years) and cholecystitis (odds ratio 1.43 (1.14 to 1.79); risk difference 15 (5 to 27) more events per 10 000 person years) but not with the risk of cholelithiasis and biliary diseases. The associations tended to be observed in patients with a longer duration of dipeptidyl peptidase-4 inhibitor treatment. In the network meta-analysis of 184 trials, dipeptidyl peptidase-4 inhibitors increased the risk of the composite of gallbladder or biliary diseases and cholecystitis compared with sodium-glucose cotransporter-2 inhibitors but not compared with glucagon-like peptide-1 receptor agonists. CONCLUSIONS Dipeptidyl peptidase-4 inhibitors increased the risk of cholecystitis in randomised controlled trials, especially with a longer treatment duration, which requires more attention from physicians in clinical practice. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42021271647.
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Affiliation(s)
- Liyun He
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jialu Wang
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fan Ping
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Na Yang
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jingyue Huang
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Li
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lingling Xu
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huabing Zhang
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuxiu Li
- Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Translation Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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20
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Singh AK, Singh R. Relook at DPP-4 inhibitors in the era of SGLT-2 inhibitors. World J Diabetes 2022; 13:466-470. [PMID: 35800411 PMCID: PMC9210541 DOI: 10.4239/wjd.v13.i6.466] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/19/2022] [Accepted: 05/23/2022] [Indexed: 02/06/2023] Open
Abstract
SGLT-2 inhibitors (SGLT-2Is) have significantly improved cardio-renal outcomes and are preferred agents in people with cardiovascular diseases, heart failure, and diabetic kidney disease. Similarly, GLP-1 receptor agonists (GLP-1RAs) have significantly improved atherosclerotic cardiovascular outcomes. To this end, DPP-4 inhibitors (DPP-4Is) are cardiac-neutral drugs. While long-acting GLP-1RAs have shown a favorable HbA1c lowering compared to DPP-4Is, there is no clinically meaningful HbA1c lowering difference between SGLT-2Is vs DPP-4Is. Moreover, the glucose-lowering potential of SGLT-2Is gets compromised with a progressive decline in renal functions, unlike DPP-4Is. Furthermore, the HbA1c lowering potential of DPP-4Is is favorable in people with T2DM having a modest baseline HbA1c (8.0%-8.5%) compared with SGLT-2Is which lowers HbA1c larger in a background of higher baseline HbA1c (> 8.5%-9.0%). These findings suggest that the role of DPP-4Is in the management of type 2 diabetes mellitus cannot be completely ignored even in the era of SGLT-2Is.
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Affiliation(s)
- Awadhesh Kumar Singh
- Department of Diabetes & Endocrinology, G.D Hospital & Diabetes Institute, Kolkata 700013, West Bengal, India
| | - Ritu Singh
- Department of Diabetes & Endocrinology, G.D Hospital & Diabetes Institute, Kolkata 700013, West Bengal, India
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21
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Xu B, Li S, Kang B, Zhou J. The current role of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus management. Cardiovasc Diabetol 2022; 21:83. [PMID: 35614469 PMCID: PMC9134641 DOI: 10.1186/s12933-022-01512-w] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic, complex metabolic disease characterized by chronic hyperglycemia causing from insufficient insulin signaling because of insulin resistance or defective insulin secretion, and may induce severe complications and premature death. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are oral drugs used to reduce hyperglycemia in patients with T2DM, including empagliflozin, ertugliflozin, dapagliflozin and canagliflozin. The primary objective of this article is to examine the clinical benefit, safety, and tolerability of the four SGLT2 inhibitors approved by the US FDA. SGLT2 inhibitors increase urinary glucose excretion via inhibiting SGLT2 to decrease renal reabsorption of filtered glucose and reduce the renal threshold for glucose. Rather than stimulating insulin release, SGLT2 inhibitors improve β-cell function by improving glucotoxicity, as well as reduce insulin resistance and increase insulin sensitivity. Early clinical trials have confirmed the beneficial effects of SGLT2 in T2DM with acceptable safety and excellent tolerability. In recent years, SGLT2 inhibitors has been successively approved by the FDA to decrease cardiovascular death and decrease the risk of stroke and cardiac attack in T2DM adults who have been diagnosed with cardiovascular disease, treating heart failure (HF) with reduced ejection fraction and HF with preserved ejection fraction, and treat diabetic kidney disease (DKD), decrease the risk of hospitalization for HF in T2DM and DKD patients. SGLT2 inhibitors are expected to be an effective treatment for T2DM patients with non alcoholic fatty liver disease. SGLT2 inhibitors have a similar safety profile to placebo or other active control groups, with major adverse events such as Ketoacidosis or hypotension and genital or urinary tract infections.
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Affiliation(s)
- Bo Xu
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Shaoqian Li
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Bo Kang
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Jiecan Zhou
- The First Affiliated Hospital, Pharmacy Department, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. .,The First Affiliated Hospital, Hengyang Clinical Pharmacology Research Center, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. .,The First Affiliated Hospital, Hengyang Key Laboratory of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. .,School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
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22
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Angelidi AM, Belanger MJ, Kokkinos A, Koliaki CC, Mantzoros CS. Novel Noninvasive Approaches to the Treatment of Obesity: From Pharmacotherapy to Gene Therapy. Endocr Rev 2022; 43:507-557. [PMID: 35552683 PMCID: PMC9113190 DOI: 10.1210/endrev/bnab034] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Indexed: 02/08/2023]
Abstract
Recent insights into the pathophysiologic underlying mechanisms of obesity have led to the discovery of several promising drug targets and novel therapeutic strategies to address the global obesity epidemic and its comorbidities. Current pharmacologic options for obesity management are largely limited in number and of modest efficacy/safety profile. Therefore, the need for safe and more efficacious new agents is urgent. Drugs that are currently under investigation modulate targets across a broad range of systems and tissues, including the central nervous system, gastrointestinal hormones, adipose tissue, kidney, liver, and skeletal muscle. Beyond pharmacotherapeutics, other potential antiobesity strategies are being explored, including novel drug delivery systems, vaccines, modulation of the gut microbiome, and gene therapy. The present review summarizes the pathophysiology of energy homeostasis and highlights pathways being explored in the effort to develop novel antiobesity medications and interventions but does not cover devices and bariatric methods. Emerging pharmacologic agents and alternative approaches targeting these pathways and relevant research in both animals and humans are presented in detail. Special emphasis is given to treatment options at the end of the development pipeline and closer to the clinic (ie, compounds that have a higher chance to be added to our therapeutic armamentarium in the near future). Ultimately, advancements in our understanding of the pathophysiology and interindividual variation of obesity may lead to multimodal and personalized approaches to obesity treatment that will result in safe, effective, and sustainable weight loss until the root causes of the problem are identified and addressed.
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Affiliation(s)
- Angeliki M Angelidi
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA
- Department of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Matthew J Belanger
- Department of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Alexander Kokkinos
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Chrysi C Koliaki
- First Department of Propaedeutic Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Christos S Mantzoros
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA, USA
- Department of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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23
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Fang HSA, Gao Q, Tan WY, Lee ML, Hsu W, Tan NC. The effect of oral diabetes medications on glycated haemoglobin (HbA1c) in Asians in primary care: a retrospective cohort real-world data study. BMC Med 2022; 20:22. [PMID: 35078484 PMCID: PMC8790837 DOI: 10.1186/s12916-021-02221-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 12/15/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Clinical trials have demonstrated that initiating oral anti-diabetic drugs (OADs) significantly reduce glycated hemoglobin (HbA1c) levels. However, variability in lifestyle modifications and OAD adherence impact on their actual effect on glycemic control. Furthermore, evidence on dose adjustments and discontinuation of OAD on HbA1c is lacking. This study aims to use real-world data to determine the effect of OAD initiation, up-titration, down-titration, and discontinuation on HbA1c levels, among Asian patients managed in primary care. METHODS A retrospective cohort study over a 5-year period, from Jan 2015 to Dec 2019 was conducted on a cohort of multi-ethnic adult Asian patients with clinical diagnosis of type 2 diabetes mellitus (T2DM) managed by a network of primary care clinics in Singapore. Nine OADs from five different classes (biguanides, sulphonyurea, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium-glucose cotransporter-2 [SGLT-2] inhibitors, and alpha-glucosidase inhibitors) were evaluated. Patients were grouped into "No OAD", "Non-titrators," and "Titrators" cohorts based on prescribing patterns. For the "Titrators" cohort, the various OAD titrations were identified. Subsequently, a descriptive analysis of HbA1c values before and after each titration was performed to compute a mean difference for each unique titration identified. RESULTS Among the cohort of 57,910 patients, 43,338 of them had at least one OAD titration, with a total of 76,990 pairs of HbA1c values associated with an OAD titration. There were a total of 206 unique OAD titrations. Overall, initiation of OADs resulted in a reduction of HbA1c by 3 to 12 mmol/mol (0.3 to 1.1%), respectively. These results were slightly lower than those reported in clinical trials of 6 to 14 mmol/mol (0.5 to 1.25%). The change of HbA1c levels due to up-titration, down-titration, and discontinuation were -1 to -8 mmol/mol (-0.1 to -0.7%), +1 to 7 mmol/mol (+0.1 to +0.6%), and +2 to 11 mmol/mol (+0.2 to +1.0%), respectively. The HbA1c lowering effect of initiating newer OADs, namely DPP-4 inhibitors and SGLT-2 inhibitors was 8 to 11 mmol/mol (0.7 to 0.9%) and 7 to 11 mmol/mol (0.6 to 1.0%), respectively. CONCLUSION The real-world data on Asians with T2DM in this study show that the magnitudes of OAD initiation and dose titration are marginally lower than the results from clinical trials. During shared decision-making in selecting treatment options, the results enable physicians to communicate realistic expectation of the effect of oral medications on the glycemic control of their patients in primary care.
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Affiliation(s)
- Hao Sen Andrew Fang
- SingHealth Polyclinics, SingHealth, 167, Jalan Bukit Merah, Connection One, Tower 5, #15-10, Singapore, P.O. 150167, Singapore.
| | - Qiao Gao
- Institute of Data Science, National University of Singapore, Singapore, Singapore
| | - Wei Ying Tan
- Institute of Data Science, National University of Singapore, Singapore, Singapore
| | - Mong Li Lee
- Institute of Data Science, National University of Singapore, Singapore, Singapore.,School of Computing, National University of Singapore, Singapore, Singapore
| | - Wynne Hsu
- Institute of Data Science, National University of Singapore, Singapore, Singapore.,School of Computing, National University of Singapore, Singapore, Singapore
| | - Ngiap Chuan Tan
- SingHealth Polyclinics, SingHealth, 167, Jalan Bukit Merah, Connection One, Tower 5, #15-10, Singapore, P.O. 150167, Singapore.,Family Medicine Academic Clinical Programme, SingHealth-Duke NUS Academic Medical Centre, Singapore, Singapore
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24
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Zhou B, Shi Y, Fu R, Ni H, Gu L, Si Y, Zhang M, Jiang K, Shen J, Li X, Sun X. Relationship Between SGLT-2i and Ocular Diseases in Patients With Type 2 Diabetes Mellitus: A Meta-Analysis of Randomized Controlled Trials. Front Endocrinol (Lausanne) 2022; 13:907340. [PMID: 35692406 PMCID: PMC9178099 DOI: 10.3389/fendo.2022.907340] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 04/25/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND This meta-analysis was conducted to explore the association between sodium-glucose cotransporter 2 inhibitors (SGLT-2is) and ocular diseases in type 2 diabetes mellitus (T2DM) patients. METHODS PubMed, Cochrane Central Registry of Controlled Trials, Web of Science and Springer were searched for articles on randomized controlled trials (RCTs) involving T2DM patients treated with SGLT-2i versus placebo or other hypoglycemic agents published prior to August 2021. The primary outcome of this meta-analysis was incidence of ocular diseases, which was assessed using risk ratios (RR) and 95% confidence intervals (CI). We reviewed 47 papers and compared the effect of SGLT-2i with the effect of the control groups (placebo and other hypoglycemic drugs) on the incidence of ocular diseases. RESULTS Compared with controls, overall SGLT-2i use in T2DM patients was not associated with incidences of cataract, glaucoma, retinal disease and vitreous disease. Ertugliflozin (RR=0.47, P=0.01) reduced the risk for retinal disease, while empagliflozin (RR=0.44, P=0.05) reduced the risk for diabetic retinopathy (DR) compared with controls. SGLT-2i (RR=0.50, P=0.02), perhaps empagliflozin (RR=0.47, P=0.06), reduced the risk of retinal disease compared with active hypoglycemic agents. Canagliflozin (RR=4.50, P=0.03) increased the risk for vitreous disease compared with placebo. CONCLUSIONS There was no significant correlation between overall SGLT-2i and ocular diseases (cataract, glaucoma, retinal disease, vitreous disease, corneal disease, conjunctival disease, uveal disease, eye haemorrhage and vision problems) in T2DM patients. Ertugliflozin and empagliflozin may protect against ocular diseases, but canagliflozin may promote ocular diseases.
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Affiliation(s)
- Bin Zhou
- Department of General Surgery, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China
| | - Yetan Shi
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Rongrong Fu
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Haixiang Ni
- The Department of Endocrinology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Lihu Gu
- Department of General Surgery, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
- Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China
| | - Yuexiu Si
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Mengting Zhang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Ke Jiang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jingyi Shen
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xiangyuan Li
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xing Sun
- Department of General Surgery, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
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Wang DD, Mao YZ, Yang Y, Wang TY, Zhu P, He SM, Chen X. Effects of Sodium-Glucose Cotransporter-2 Inhibitors on Weight in Type 2 Diabetes Mellitus and Therapeutic Regimen Recommendation. J Diabetes Res 2022; 2022:4491900. [PMID: 35342769 PMCID: PMC8956429 DOI: 10.1155/2022/4491900] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 02/17/2022] [Accepted: 03/01/2022] [Indexed: 12/13/2022] Open
Abstract
AIMS The present study is aimed at exploring the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on weight in type 2 diabetes mellitus (T2DM) and therapeutic regimen recommendations. METHODS 20,019 patients with T2DM were enrolled. The maximal effect (E max) models, whose evaluation index was change rate of body weight from baseline value, were used to analyze data using nonlinear mixed effect modeling (NONMEM). RESULTS For SGLT-2 inhibitors, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin and tofogliflozin, the E max, and treatment duration to reach half of the maximal effects (ET50) were -3.72% and 3.35 weeks, -5.59% and 16.8 weeks, -2.84% and 3.42 weeks, -3.43% and 3.09 weeks, -3.04% and 4.38 weeks, and -2.45% and 3.16 weeks, respectively. In addition, for T2DM patients, 100 mg/day canagliflozin needs to be taken 13.4 weeks for the plateau of effect on weight; 10 mg/day empagliflozin needs to be taken 67.2 weeks for the plateau of effect on weight; 5 mg/day ertugliflozin needs to be taken 13.68 weeks for the plateau of effect on weight; 50 mg/day ipragliflozin needs to be taken 12.36 weeks for the plateau of effect on weight; 2.5 mg/day luseogliflozin needs to be taken 17.52 weeks for the plateau of effect on weight; 20 mg/day tofogliflozin needs to be taken 12.64 weeks for the plateau of effect on weight. CONCLUSIONS This was the first study to explore effects of SGLT-2 inhibitors on weight in T2DM; meanwhile, the optimum dosages and treatment durations on weight from canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, and tofogliflozin were recommended, respectively.
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Affiliation(s)
- Dong-Dong Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy & School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China
| | - Yi-Zhen Mao
- School Infirmary, Jiangsu Normal University, Xuzhou, Jiangsu 221132, China
| | - Yang Yang
- Department of Pharmacy, The Affiliated Changzhou Children's Hospital of Nantong University, Changzhou 213003, China
| | - Tian-Yun Wang
- Department of Pharmacy, Huaian Hospital of Huaian City, Huaian, Jiangsu 223200, China
| | - Ping Zhu
- Department of Endocrinology, Huaian Hospital of Huaian City, Huaian, Jiangsu 223200, China
| | - Su-Mei He
- Department of Pharmacy, The Affiliated Suzhou Science & Technology Town Hospital of Nanjing Medical University, Suzhou Jiangsu 215153, China
| | - Xiao Chen
- Department of Pharmacy, Children's Hospital of Fudan University, Shanghai 201102, China
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Masajtis-Zagajewska A, Hołub T, Pęczek K, Makówka A, Nowicki M. Different Effects of Empagliflozin on Markers of Mineral-Bone Metabolism in Diabetic and Non-Diabetic Patients with Stage 3 Chronic Kidney Disease. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:1352. [PMID: 34946298 PMCID: PMC8705759 DOI: 10.3390/medicina57121352] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 12/02/2021] [Accepted: 12/08/2021] [Indexed: 02/07/2023]
Abstract
Background and objectives: Treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors decrease tubular reabsorption of phosphate, which may explain the reduction of bone mineral density and an excess of bone fractures observed in some studies with this class of drugs. Since an increased risk of bone fractures may also be a result of diabetes itself, our study aimed to compare the effect of empagliflozin on the markers of mineral-bone metabolism between diabetic (DKD) and non-diabetic (ND-CKD) patients with stage 3 chronic kidney disease (CKD). Materials and Methods: Forty-two patients with stage 3 CKD and A2 albuminuria, including 18 with DKD and 24 ND-CKD, were investigated. All subjects received 10 mg empagliflozin for 7 days. Serum calcium, phosphate, parathormone (PTH), calcitriol, bone alkaline phosphatase (BAP), FGF-23 and urine calcium, phosphate, albumin and the renal tubular maximum reabsorption rate of phosphate to the glomerular filtration rate (TmP-GFR) were measured before and after empagliflozin administration. Differences in biomarkers response to empagliflozin between DKD and ND-CKD were the main measures of outcome. Results: There was a significant increase of PTH, FGF-23 and phosphate in DKD but not in ND-CKD whereas BAP and TmP/GFR did not change in either group. The reduction of albuminuria was only significant in ND-CKD. Conclusions: The effect of SGLT2 inhibitor on serum mineral and bone markers and on albuminuria in patients with CKD may be differently modified by the presence of diabetes mellitus.
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Affiliation(s)
| | | | | | | | - Michał Nowicki
- Department of Nephrology, Hypertension and Kidney Transplantation, Medical University of Lodz, Central University Hospital, 92-213 Lodz, Poland; (A.M.-Z.); (T.H.); (K.P.); (A.M.)
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Ku EJ, Lee DH, Jeon HJ, Oh TK. Long-term effectiveness and safety of quadruple combination therapy with empagliflozin versus dapagliflozin in patients with type 2 diabetes: 3-year prospective observational study. Diabetes Res Clin Pract 2021; 182:109123. [PMID: 34740742 DOI: 10.1016/j.diabres.2021.109123] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 10/18/2021] [Accepted: 10/31/2021] [Indexed: 10/19/2022]
Abstract
AIMS To investigate the long-term effectiveness and safety of two distinct sodium-glucose co-transporter 2 (SGLT2) inhibitors, empagliflozin and dapagliflozin, in inadequately controlled type 2 diabetes (T2D) despite a combined administration of metformin, glimepiride and dipeptidyl peptidase-4 inhibitor. METHODS A total of 362 patients with T2D were enrolled for this 3-year open-label, prospective observational study. Empagliflozin (25 mg/day, n = 185) or dapagliflozin (10 mg/day, n = 177) was added to the existing triple drug regimen. HbA1c, fasting plasma glucose (FPG), body weight, and other cardiometabolic variables and adverse events were evaluated. RESULTS At 3 years, changes in HbA1c and FPG were -1.7% (standard error [SE] 0.10) and -60.0 mg/dL(2.2), and -1.1%(0.12) and -48.1 mg/dL(3.6), for empagliflozin and dapagliflozin group, respectively (P = 0.001 and P = 0.055). Empagliflozin group showed significantly greater body weight reduction (-4.5 kg [SE 0.35] vs. -1.0 kg [SE 0.40], P = 0.024) and had beneficial effects on HDL cholesterol and LDL cholesterol (both P < 0.05). The overall incidence of adverse events, cardiovascular events and mortality did not differ between the two groups. CONCLUSIONS Quadruple combination therapy with either empagliflozin or dapagliflozin showed a positive long-term effect in the glycemic control and body weight reduction with generally well tolerance. In general, the use of empagliflozin performed better than dapagliflozin. Clinical Trial Number NCT03748810 (ClinicalTrials.gov).
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Affiliation(s)
- Eu Jeong Ku
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Republic of Korea
| | - Dong-Hwa Lee
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Republic of Korea
| | - Hyun Jeong Jeon
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Republic of Korea
| | - Tae Keun Oh
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Republic of Korea.
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Wu Q, Liu M, Fang Z, Li C, Zou F, Hu L, Zhang W. Efficacy and safety of empagliflozin at different doses in patients with type 2 diabetes mellitus: A network meta-analysis based on randomized controlled trials. J Clin Pharm Ther 2021; 47:270-286. [PMID: 34544199 DOI: 10.1111/jcpt.13521] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/07/2021] [Accepted: 08/17/2021] [Indexed: 12/24/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE As an oral hypoglycaemic drug that significantly reduces cardiovascular risk, empagliflozin is often used in patients with type 2 diabetes mellitus (T2DM). However, the dosage and administration of empagliflozin are still controversial clinically. To determine the most appropriate dose, we performed this network meta-analysis. METHODS We identified randomized controlled trials (RCTs) about empagliflozin from eight databases. We analysed the pharmacodynamics, adverse effects (AEs), and pharmacokinetics of empagliflozin at different doses. RESULTS We identified 8264 articles, of which 23 RCTs with 10518 patients were included. Regarding haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG), high-daily doses (10, 25, 50 mg) were significantly better than low doses (1, 2.5, 5 mg). For total AEs, there was a dose-response trend in which safety decreased with increasing doses. According to SUCRA sequencing, the order for lowering HbA1c was 25 > 50 > 10 > 5 > 1 mg, for lowering FPG was 50 > 25 > 10 > 5 > 2.5 > 1 mg and for safety was 1> 5 > 10 > 25> 2.5 > 50 mg. When considering HbA1c, FPG and total AEs, we performed a hierarchical cluster analysis and network meta-analysis to find that 25 mg performed best among different doses, which was more significant after long-term use (≥ 12 weeks). Pharmacokinetic parameters exhibited significant dose-response relationships. WHAT IS NEW AND CONCLUSION High-daily doses (10, 25, 50 mg) had better efficacy than low doses (1, 2.5, 5 mg). When considering HbA1c, FPG and total AEs, 25 mg performed best among the different doses in patients with T2DM.
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Affiliation(s)
- Qian Wu
- Department of Endocrinology, The second affiliated hospital of Nanchang University, Nanchang, China
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Miaowen Liu
- Department of Endocrinology, The second affiliated hospital of Nanchang University, Nanchang, China
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Zige Fang
- Department of Endocrinology, The second affiliated hospital of Nanchang University, Nanchang, China
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Chenxi Li
- Department of Endocrinology, The second affiliated hospital of Nanchang University, Nanchang, China
- Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Fang Zou
- Department of Endocrinology, The second affiliated hospital of Nanchang University, Nanchang, China
| | - Lei Hu
- Department of Endocrinology, The second affiliated hospital of Nanchang University, Nanchang, China
| | - Wenxiong Zhang
- Department of Cardio-Thoracic Surgery, The second affiliated hospital of Nanchang University, Nanchang, China
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Wang S, Wu T, Zuo Z, Jin P, Luo X, Deng M. Comparison of cardiovascular outcomes and cardiometabolic risk factors between patients with type 2 diabetes treated with sodium-glucose cotransporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors: a meta-analysis. Eur J Prev Cardiol 2021; 28:1840-1849. [PMID: 34136913 DOI: 10.1093/eurjpc/zwab099] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/11/2021] [Accepted: 05/25/2021] [Indexed: 01/21/2023]
Abstract
AIMS Prevention of cardiovascular outcomes is a goal of the management of patients with type 2 diabetes mellitus patients as important as lowering blood glucose levels. Among the various glucose-lowering agents, the effects of sodium-glucose cotransporter-2 inhibitors (SGLT-2Is) and dipeptidyl peptidase-4 inhibitors (DPP-4Is) on cardiovascular outcomes have become the focus of recent researches. METHODS AND RESULTS A systematic search was performed through several online database. All studies that compared the effects of SGLT-2Is and DPP-4Is on cardiovascular outcomes and cardiometabolic risk factors were reviewed. A total of 30 studies were included. Compared with DPP-4Is, SGLT-2Is treatment reduced the risk of stroke [risk ratio (RR) = 0.80; 95% confidence interval (CI), 0.76-0.84], myocardial infarction (RR = 0.85; 95% CI, 0.81-0.89), heart failure (RR = 0.58; 95% CI, 0.54-0.62), cardiovascular mortality (RR = 0.55; 95% CI, 0.51-0.60), and all-cause mortality (RR = 0.60; 95% CI, 0.57-0.63). In addition, SGLT-2Is presented favourable effects on hemoglobinA1c, fasting plasma glucose, systolic blood pressure, and diastolic blood pressure. The differences in blood lipids were also compared. CONCLUSION Sodium-glucose cotransporter-2 inhibitors are superior to DPP-4Is in terms of cardiovascular outcomes. Sodium-glucose cotransporter-2 inhibitors bring more benefits with respect to the cardiometabolic risk factors.
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Affiliation(s)
- Siwen Wang
- Department of Biochemistry and Molecular Biology & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha 410013, China.,Xiangya School of Medicine, Central South University, Changsha 410013, China.,Hunan Key Laboratory of Animal Models for Human Diseases, Hunan Key Laboratory of Medical Genetics & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410013, China
| | - Ting Wu
- Department of Biochemistry and Molecular Biology & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha 410013, China.,Hunan Key Laboratory of Animal Models for Human Diseases, Hunan Key Laboratory of Medical Genetics & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410013, China.,Department of Cardiovascular Medicine, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Zhihong Zuo
- Department of Biochemistry and Molecular Biology & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha 410013, China.,Xiangya School of Medicine, Central South University, Changsha 410013, China.,Hunan Key Laboratory of Animal Models for Human Diseases, Hunan Key Laboratory of Medical Genetics & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410013, China
| | - Ping Jin
- Department of Endocrinology, The Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Xuan Luo
- Hunan Yuanpin Cell Biotechnology Co., Ltd, Dongwu Road, Changsha Economic and Technological Development Zone, Changsha 410129, China
| | - Meichun Deng
- Department of Biochemistry and Molecular Biology & Hunan Province Key Laboratory of Basic and Applied Hematology, School of Life Sciences, Central South University, Changsha 410013, China.,Xiangya School of Medicine, Central South University, Changsha 410013, China.,Hunan Key Laboratory of Animal Models for Human Diseases, Hunan Key Laboratory of Medical Genetics & Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410013, China
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Shi N, Shi Y, Xu J, Si Y, Yang T, Zhang M, Ng DM, Li X, Xie F. SGLT-2i and Risk of Malignancy in Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials. Front Public Health 2021; 9:668368. [PMID: 34164370 PMCID: PMC8215266 DOI: 10.3389/fpubh.2021.668368] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 05/03/2021] [Indexed: 12/25/2022] Open
Abstract
Background: Currently, the association between sodium-glucose cotransporter 2 inhibitor (SGLT-2i) and malignancy risk has yet to be fully elucidated. This meta-analysis aimed to determine the relationship between SGLT-2i and malignancy risk in type 2 diabetes (T2D) patients. Methods: We searched PubMed, ScienceDirect, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science to identify randomized controlled trials (RCTs) published up to August 2020 related to T2D patients treated with SGLT-2i vs. placebo or other hypoglycemic agents. The meta-analysis's primary outcome was malignancies' incidence, and the results were evaluated using risk ratio (RR) and 95% confidence interval (CI). Results: We reviewed 76 articles (77 RCTs), comprising 45,162 and 43,811 patients in SGLT-2i and control groups, respectively. Compared with the control group, SGLT-2i had no significant association with augmented overall malignancy risk in T2D patients (RR = 1.05, 95% CI = 0.97–1.14, P = 0.20), but ertugliflozin may upsurge the risk (RR = 1.80, 95% CI = 1.02–3.17, P = 0.04). Compared with active hypoglycemic agents, dapagliflozin may increase (RR = 2.71, 95% CI = 1.46–6.43, P = 0.02) and empagliflozin may decrease (RR = 0.67, 95% CI = 0.45–0.98, P = 0.04) the malignancy risk. Compared with placebo, empagliflozin may exhibit risk increase (RR = 1.25, 95% CI = 1.05–1.49, P = 0.01), primarily in digestive system (RR = 1.48, 95% CI = 0.99–2.21, P = 0.05). Conclusions: Our results proposed that in diverse comparisons, ertugliflozin and dapagliflozin seemed to increase the malignancy risk in T2D patients. Empagliflozin may cause malignancy risk reduction compared with active hypoglycemic agents but increase overall risk primarily in the digestive system compared with placebo. In short, the relationship between SGLT-2i and malignancy in T2D patients remains unclear.
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Affiliation(s)
- Nanjing Shi
- Department of Endocrinology, Affiliated Hangzhou First People' Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yetan Shi
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jingsi Xu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yuexiu Si
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Tong Yang
- Department of Tumor High Intensity Focused Ultrasound Therapy, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Mengting Zhang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | | | - Xiangyuan Li
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Fei Xie
- Department of Endocrinology, Ningbo Yinzhou No. 2 Hospital, Ningbo, China
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Li X, Zhang Q, Zhou X, Guo S, Jiang S, Zhang Y, Zhang R, Dong J, Liao L. The different hypoglycemic effects between East Asian and non-Asian type 2 diabetes patients when treated with SGLT-2 inhibitors as an add-on treatment for metformin: a systematic review and meta-analysis of randomized controlled trials. Aging (Albany NY) 2021; 13:12748-12765. [PMID: 33973870 PMCID: PMC8148508 DOI: 10.18632/aging.202945] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/27/2021] [Indexed: 12/19/2022]
Abstract
Aims: To investigate the efficacy and safety of SGLT-2 inhibitors as an add-on treatment for metformin between Asian and non-Asian T2DM. Methods: A systematic literature search of PubMed, EMBASE, and the Cochrane Library was performed through August 2020 with the following keywords: Sodium-Glucose Transporter 2 Inhibitors, Sodium Glucose Transporter 2 Inhibitors, SGLT2 inhibitor, SGLT-2 inhibitors, type 2 diabetes, and randomized controlled trials. Double-blinded RCTs comparing SGLT-2 inhibitors as an add-on treatment for metformin and metformin monotherapy in adults with type 2 diabetes were included. A random effects model was used to calculate overall effect sizes. Results: 5 RCTs with 1193 Asian patients and 7 RCTs with 2098 non-Asian patients were investigated. The improvement in HbA1c and fasting blood glucose in the Asian patients (WMD, −0.73%; 95% CI, −1.01% to −0.46%, p < 0.01; WMD, −1.51; 95% CI, −1.81 to −1.21, p < 0.01, respectively) were both significantly better than in the non-Asians (WMD, −0.45%; 95% CI, −0.62% to −0.29%, p < 0.01; WMD, −1.03; 95% CI, −1.27 to −0.78, p < 0.01, respectively). The effect of weight loss was similar in the non-Asian patients and Asian patients. There was little difference in the improvement of systolic blood pressure between them. The risk of serious adverse events was not significantly increased between the Asian and non-Asian patients. Conclusion: SGLT-2 inhibitors as an add-on treatment for metformin are more efficacious in East Asian T2DM patients than in non-Asian T2DM patients without an additional risk of severe adverse events.
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Affiliation(s)
- Xianzhi Li
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Institute of Nephrology, Ji-nan, Shandong 250014, China.,Department of Endocrinology and Metabology, Shandong Provincial Qianfoshan Hospital, Shandong University, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Institute of Nephrology, Ji-nan, Shandong 250014, China
| | - Qianping Zhang
- Division of Endocrinology, Department of Internal Medicine, Dezhou Municipal Hospital, Dezhou, Shandong 253000, China
| | - Xiaojun Zhou
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Institute of Nephrology, Ji-nan, Shandong 250014, China.,Department of Endocrinology and Metabology, Shandong Provincial Qianfoshan Hospital, Shandong University, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Institute of Nephrology, Ji-nan, Shandong 250014, China
| | - Siyi Guo
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, Shandong 250012, China
| | - Shan Jiang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, Shandong 250012, China
| | - Yuhan Zhang
- Department of Endocrinology and Metabology, Shandong Provincial Qianfoshan Hospital, Shandong University, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Institute of Nephrology, Ji-nan, Shandong 250014, China
| | - Ruzhen Zhang
- Department of Endocrinology and Metabology, Shandong Provincial Qianfoshan Hospital, Shandong University, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Institute of Nephrology, Ji-nan, Shandong 250014, China
| | - Jianjun Dong
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Ji-nan, Shandong 250012, China
| | - Lin Liao
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Institute of Nephrology, Ji-nan, Shandong 250014, China.,Department of Endocrinology and Metabology, Shandong Provincial Qianfoshan Hospital, Shandong University, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Institute of Nephrology, Ji-nan, Shandong 250014, China
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Abstract
SGLT2 inhibitors increase renal glucose excretion and thus decrease both fasting and postprandial plasma glucose levels. The effects of SGLT2 inhibition outweigh those on glycemic control and are also associated with the induction of hemodynamic changes that improve cardiovascular and renal function in people with type 2 diabetes. The exact mechanisms have not yet been completely clarified. This review is focused on the potential relationship between SGLT2 inhibition and sympathetic nerve activity. There is accumulating evidence for a suppressive effect of SGLT2 inhibitors on the sympathetic nerve tone, which might be a putative mechanism for cardiovascular protection in subjects with type 2 diabetes.
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Affiliation(s)
- Rumyana Dimova
- Department of Endocrinology, Medical University of Sofia, Sofia, Bulgaria
| | - Tsvetalina Tankova
- Department of Endocrinology, Medical University of Sofia, Sofia, Bulgaria
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Jia S, Wang Z, Han R, Zhang Z, Li Y, Qin X, Zhao M, Xiang R, Yang J. Incretin mimetics and sodium-glucose co-transporter 2 inhibitors as monotherapy or add-on to metformin for treatment of type 2 diabetes: a systematic review and network meta-analysis. Acta Diabetol 2021; 58:5-18. [PMID: 32514989 DOI: 10.1007/s00592-020-01542-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 04/27/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE Although there are many different methods of treating type 2 diabetes (T2D), it is still difficult to draw coincident conclusions concerning the efficacy and safety of different classes of new drugs, and the recommendation level of them has still kept uncertain as second anti-diabetic agents. Therefore, the aim of this study was to summarize evidence on the efficacy and safety of DPP-4is, GLP-1RAs and SGLT-2is as monotherapy or add-on to metformin (Met) for treatment of T2D. MATERIALS AND METHODS We searched PubMed, Embase, Cochrane library and ClinicalTrials.gov for relevant articles in keeping with established methods using terms associated with anti-diabetic agents up to February, 2020, with no start date restriction. Weighted mean difference and risk ratios with 95% confidence intervals were calculated within traditional and network meta-analysis. Primary outcomes were the mean change in hemoglobin A1c (HbA1c), fasting plasma glucose (FPG) change and the frequency of hypoglycemic events from baseline after 12 weeks of treatment. RESULTS In total, 64 eligible studies comprising 37,780 patients and 7 treatment strategies were included. The results of primary outcomes showed that GLP-1RAs were significantly more effective than DPP-4is or SGLT-2is in reducing HbA1c when add-on to Met. For FPG, both GLP-1RAs and SGLT-2is significantly reduced FPG compared with DPP-4is whether add-on to Met or not. For hypoglycemia, monotherapy has a lower risk than combination therapy except for SGLT-2is. Ranking probability analysis indicated that GLP-1RAs and SGLT-2is, respectively, reduced HbA1c and FPG most when add-on to Met. Meanwhile, GLP-1RAs took the lowest risk to induce the hypoglycemia, whereas GLP-1RAs plus Met the highest. CONCLUSIONS Both GLP-1RAs and SGLT-2is have their own advantages in efficacy and safety. Monotherapy is beneficial for reducing the risk of hypoglycemia. The recommendation should be a patient-centered approach when selecting treatment choices.
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Affiliation(s)
- Shubing Jia
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Zhiying Wang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Ruobing Han
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Zinv Zhang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Yuping Li
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Xiaotong Qin
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Mingyi Zhao
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Rongwu Xiang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Jingyu Yang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, China.
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Sánchez-García A, Simental-Mendía M, Millán-Alanís JM, Simental-Mendía LE. Effect of sodium-glucose co-transporter 2 inhibitors on lipid profile: A systematic review and meta-analysis of 48 randomized controlled trials. Pharmacol Res 2020; 160:105068. [PMID: 32652200 DOI: 10.1016/j.phrs.2020.105068] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 07/03/2020] [Accepted: 07/03/2020] [Indexed: 12/13/2022]
Abstract
Previous studies have suggested additional beneficial effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors including the lipid-lowering effect; however, results on lipid profile are controversial. Thus, this meta-analysis aimed to determine the effect of SGLT2 inhibitors treatment on lipid levels in patients with type 2 diabetes. Randomized controlled trials assessing the impact of SGLT2 inhibitors on lipid parameters were searched in PubMed-MEDLINE, SCOPUS, Web of Science, and Google Scholar databases. Meta-analysis was conducted using a random-effects model and generic inverse variance method. Meta-analysis of 48 randomized controlled trials revealed that SGLT2 inhibitors therapy had a significant increase on total cholesterol (WMD: 0.09 mmol/L, 95 % CI: 0.05, 0.13, I2 = 79 %, p < 0.0001), LDL-cholesterol (WMD: 0.10 mmol/L, 95 % CI: 0.07, 0.12, I2 = 94 %, p < 0.00001), HDL-cholesterol (WMD: 0.06 mmol/L, 95 % CI: 0.05, 0.08, I2 = 99 %, p < 0.00001), and non-HDL-cholesterol (WMD: 0.09 mmol/L, 95 % CI: 0.06, 0.12, I2 = 96 %, p < 0.00001). Additionally, SGLT2 inhibitors administration showed a significant decrease in triglyceride levels (WMD: -0.10 mmol/L, 95 % CI: -0.13, -0.07, I2 = 96 %, p < 0.00001). Finally, no significant alteration was found on LDL/HDL ratio after SGLT2 inhibitors treatment (WMD: -0.01 mmol/L, 95 % CI: -0.05, 0.03, I2 = 99 %, p = 0.65). In conclusion, SGLT2 inhibitors significantly increase total cholesterol, LDL-cholesterol, non-HDL-cholesterol, and HDL-cholesterol, and decrease triglyceride levels.
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Affiliation(s)
- Adriana Sánchez-García
- Universidad Autónoma de Nuevo León, Endocrinology Division, Hospital Universitario "Dr. José E. González", Facultad de Medicina, Monterrey, NL, Mexico
| | - Mario Simental-Mendía
- Universidad Autónoma de Nuevo León, Department of Orthopedics and Traumatology, Hospital Universitario "Dr. José E. González", Facultad de Medicina, Monterrey, NL, Mexico
| | - Juan Manuel Millán-Alanís
- Universidad Autónoma de Nuevo León, Plataforma Invest-KER Unit México, Hospital Universitario "Dr. José E. González", Facultad de Medicina, Monterrey, NL, Mexico
| | - Luis E Simental-Mendía
- Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Durango, México.
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Gnesin F, Thuesen ACB, Kähler LKA, Madsbad S, Hemmingsen B. Metformin monotherapy for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev 2020; 6:CD012906. [PMID: 32501595 PMCID: PMC7386876 DOI: 10.1002/14651858.cd012906.pub2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Worldwide, there is an increasing incidence of type 2 diabetes mellitus (T2DM). Metformin is still the recommended first-line glucose-lowering drug for people with T2DM. Despite this, the effects of metformin on patient-important outcomes are still not clarified. OBJECTIVES To assess the effects of metformin monotherapy in adults with T2DM. SEARCH METHODS We based our search on a systematic report from the Agency for Healthcare Research and Quality, and topped-up the search in CENTRAL, MEDLINE, Embase, WHO ICTRP, and ClinicalTrials.gov. Additionally, we searched the reference lists of included trials and systematic reviews, as well as health technology assessment reports and medical agencies. The date of the last search for all databases was 2 December 2019, except Embase (searched up 28 April 2017). SELECTION CRITERIA We included randomised controlled trials (RCTs) with at least one year's duration comparing metformin monotherapy with no intervention, behaviour changing interventions or other glucose-lowering drugs in adults with T2DM. DATA COLLECTION AND ANALYSIS Two review authors read all abstracts and full-text articles/records, assessed risk of bias, and extracted outcome data independently. We resolved discrepancies by involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall certainty of the evidence by using the GRADE instrument. MAIN RESULTS We included 18 RCTs with multiple study arms (N = 10,680). The percentage of participants finishing the trials was approximately 58% in all groups. Treatment duration ranged from one to 10.7 years. We judged no trials to be at low risk of bias on all 'Risk of bias' domains. The main outcomes of interest were all-cause mortality, serious adverse events (SAEs), health-related quality of life (HRQoL), cardiovascular mortality (CVM), non-fatal myocardial infarction (NFMI), non-fatal stroke (NFS), and end-stage renal disease (ESRD). Two trials compared metformin (N = 370) with insulin (N = 454). Neither trial reported on all-cause mortality, SAE, CVM, NFMI, NFS or ESRD. One trial provided information on HRQoL but did not show a substantial difference between the interventions. Seven trials compared metformin with sulphonylureas. Four trials reported on all-cause mortality: in three trials no participant died, and in the remaining trial 31/1454 participants (2.1%) in the metformin group died compared with 31/1441 participants (2.2%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on SAE: in two trials no SAE occurred (186 participants); in the other trial 331/1454 participants (22.8%) in the metformin group experienced a SAE compared with 308/1441 participants (21.4%) in the sulphonylurea group (very low-certainty evidence). Two trials reported on CVM: in one trial no CVM was observed and in the other trial 4/1441 participants (0.3%) in the metformin group died of cardiovascular reasons compared with 8/1447 participants (0.6%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on NFMI: in two trials no NFMI occurred, and in the other trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 15/1441 participants (1.0%) in the sulphonylurea group (very low-certainty evidence). One trial reported no NFS occurred (very low-certainty evidence). No trial reported on HRQoL or ESRD. Seven trials compared metformin with thiazolidinediones (very low-certainty evidence for all outcomes). Five trials reported on all-cause mortality: in two trials no participant died; the overall RR was 0.88, 95% CI 0.55 to 1.39; P = 0.57; 5 trials; 4402 participants). Four trials reported on SAE, the RR was 0,95, 95% CI 0.84 to 1.09; P = 0.49; 3208 participants. Four trials reported on CVM, the RR was 0.71, 95% CI 0.21 to 2.39; P = 0.58; 3211 participants. Three trial reported on NFMI: in two trials no NFMI occurred and in one trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 25/1456 participants (1.7%) in the thiazolidinedione group. One trial reported no NFS occurred. No trial reported on HRQoL or ESRD. Three trials compared metformin with dipeptidyl peptidase-4 inhibitors (one trial each with saxagliptin, sitagliptin, vildagliptin with altogether 1977 participants). There was no substantial difference between the interventions for all-cause mortality, SAE, CVM, NFMI and NFS (very low-certainty evidence for all outcomes). One trial compared metformin with a glucagon-like peptide-1 analogue (very low-certainty evidence for all reported outcomes). There was no substantial difference between the interventions for all-cause mortality, CVM, NFMI and NFS. One or more SAEs were reported in 16/268 (6.0%) of the participants allocated to metformin compared with 35/539 (6.5%) of the participants allocated to a glucagon-like peptide-1 analogue. HRQoL or ESRD were not reported. One trial compared metformin with meglitinide and two trials compared metformin with no intervention. No deaths or SAEs occurred (very low-certainty evidence) no other patient-important outcomes were reported. No trial compared metformin with placebo or a behaviour changing interventions. Four ongoing trials with 5824 participants are likely to report one or more of our outcomes of interest and are estimated to be completed between 2018 and 2024. Furthermore, 24 trials with 2369 participants are awaiting assessment. AUTHORS' CONCLUSIONS There is no clear evidence whether metformin monotherapy compared with no intervention, behaviour changing interventions or other glucose-lowering drugs influences patient-important outcomes.
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Affiliation(s)
- Filip Gnesin
- Department of Endocrinology, Diabetes and Metabolism, Department 7652, Rigshospitalet, Copenhagen, Denmark
| | - Anne Cathrine Baun Thuesen
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Faculty of Health and Medical Sciences, University of Copenhagen, Novo Nordisk Foundation Center for Basic Metabolic Research, Copenhagen, Denmark
| | | | - Sten Madsbad
- Department of Endocrinology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
| | - Bianca Hemmingsen
- Cochrane Metabolic and Endocrine Disorders Group, Institute of General Practice, Medical Faculty of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
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Tsoutsouki J, Wunna W, Chowdhury A, Chowdhury TA. Advances in the management of diabetes: therapies for type 2 diabetes. Postgrad Med J 2020; 96:610-618. [DOI: 10.1136/postgradmedj-2019-137404] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/28/2020] [Accepted: 04/29/2020] [Indexed: 12/15/2022]
Abstract
The incidence of type 2 diabetes is rapidly rising worldwide leading to an increasing burden of cardiovascular and microvascular complications. The aim of treatment of the condition is to improve quality of life and reduce such complications. To this end, improvement in glucose control remains an important consideration. In recent years, important therapeutic advances have occurred in the management of hyperglycaemia in people with type 2 diabetes. These include the use of dipeptidylpeptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium glucose transporter-2 inhibitors. The latter two classes appear to have some specific beneficial effects on cardiovascular and renal outcomes, independent of their antihyperglycaemic effects. This review aims to outline the current state of diagnosis and management of diabetes for the general physician, with a particular focus on new therapeutic agents for management of glucose in patients with type 2 diabetes.
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Uhrig JL, Page SO, Mishriky BM, Patil SP, Powell JR, Sewell K, Mian MR, Cummings DM. Should Baseline Hemoglobin A 1c or Dose of SGLT-2i Guide Treatment With SGLT-2i Versus DPP-4i in People With Type 2 Diabetes? A Meta-Analysis and Systematic Review. J Clin Pharmacol 2020; 60:980-991. [PMID: 32396236 DOI: 10.1002/jcph.1599] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 02/03/2020] [Indexed: 12/25/2022]
Abstract
Our aim was to explore whether the baseline hemoglobin A1c or the dose of sodium glucose cotransporter-2 inhibitor (SGLT-2i) chosen better predicted the efficacy of SGLT-2i versus dipeptidyl peptidase-4 inhibitor (DPP-4i) in type 2 diabetes. We searched for randomized trials that compared SGLT-2i with DPP-4i in type 2 diabetes and reported a change in hemoglobin A1c over time. We created 2 separate analyses (one based on baseline hemoglobin A1c and the other according to US Food and Drug Administration [FDA]-approved SGLT-2i dose). Thirteen trials were included. In the analysis according to baseline hemoglobin A1c , there was a significantly greater reduction in hemoglobin A1c when baseline hemoglobin A1c was ≥8.5%, favoring SGLT-2i over DPP-4i but not when baseline hemoglobin A1c was <8.5% (mean difference [95%CI], -0.36% [-0.53% to -0.18%] and 0.04% [-0.09% to 0.17%], respectively). On restricting the analysis to trials stratifying hemoglobin A1c to <8.0% or ≥8.0%, results did not change. In the analysis based on FDA-approved SGLT-2i doses, higher SGLT-2i doses caused a significantly greater hemoglobin A1c reduction at ≤26 and ≥52 weeks compared with the highest DPP-4i doses (mean difference [95%CI], -0.11% [-0.18% to -0.04%] and -0.24% [-0.34% to -0.15%], respectively). Lower SGLT-2i doses caused a significantly greater hemoglobin A1c reduction at ≥52 weeks but not at ≤26 weeks compared with the highest DPP-4i doses (mean difference [95%CI], -0.12% [-0.23% to -0.02%] and 0.01% [-0.05% to 0.07%], respectively). In people with type 2 diabetes and a baseline hemoglobin A1c ≥ 8.0%, SGLT-2i produced significantly greater reductions in hemoglobin A1c compared with DPP-4i and may be preferred. SGLT-2i dose titration to a higher FDA-approved dose is recommended in suitable patients.
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Affiliation(s)
- Jarrod L Uhrig
- Department of Endocrinology, Carilion Clinic, Roanoke, Virginia, USA
| | - Stephanie O Page
- Department of Family Medicine, Mount Sinai Hospital, New York, New York, USA
| | - Basem M Mishriky
- Department of Internal Medicine, East Carolina University, Greenville, North Carolina, USA
| | - Shivajirao P Patil
- Department of Family Medicine, East Carolina University, Greenville, North Carolina, USA
| | - James R Powell
- Department of Internal Medicine, East Carolina University, Greenville, North Carolina, USA
| | - Kerry Sewell
- Laupus Health Sciences Library, East Carolina University, Greenville, North Carolina, USA
| | - Muna R Mian
- Department of Internal Medicine, East Carolina University, Greenville, North Carolina, USA
| | - Doyle M Cummings
- Department of Family Medicine, East Carolina University, Greenville, North Carolina, USA
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Shao SC, Chang KC, Lin SJ, Chien RN, Hung MJ, Chan YY, Kao Yang YH, Lai ECC. Favorable pleiotropic effects of sodium glucose cotransporter 2 inhibitors: head-to-head comparisons with dipeptidyl peptidase-4 inhibitors in type 2 diabetes patients. Cardiovasc Diabetol 2020; 19:17. [PMID: 32050968 PMCID: PMC7014757 DOI: 10.1186/s12933-020-0990-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 01/16/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Sodium glucose cotransporter 2 (SGLT2) inhibitors have shown greater reductions of cardiovascular event risks than dipeptidyl peptidase-4 (DPP4) inhibitors, whereby possible mechanisms may involve the better pleiotropic effects of SGLT2 inhibitors. However, no published data are currently available to directly compare glycemic and pleiotropic effects in real-world type 2 diabetes patients initiating SGLT2 inhibitors or DPP4 inhibitors. METHOD We conducted a retrospective cohort study by analyzing the Chang Gung Research Database, the largest multi-institutional electronic medical records database in Taiwan. We included patients newly receiving SGLT2 inhibitor or DPP4 inhibitor intensification therapy for type 2 diabetes from 2016 to 2017. We matched SGLT2 inhibitor users to DPP4 inhibitor users (1:4) by propensity scores to ensure comparable characteristics between the groups. We primarily evaluated 1-year post-treatment changes of hemoglobin A1c (HbA1c) after SGLT2 inhibitor or DPP4 inhibitor initiation, using two-tailed independent t-test. We also evaluated post-treatment changes in body weight, systolic blood pressure (SBP), alanine aminotransferase (ALT) and estimated glomerular filtration rate (eGFR) values, associated with SGLT2 inhibitors and DPP4 inhibitors. RESULTS We identified a cohort of 2028 SGLT2 inhibitors and 8112 matched DPP4 inhibitors new users. SGLT2 inhibitors and DPP4 inhibitors showed similar HbA1c reductions (- 1.0 vs. - 1.1%; P = 0.076), but patients receiving SGLT2 inhibitors had greater improvements in body weight (- 1.5 vs. - 1.0 kg; P = 0.008), SBP (- 2.5 vs. - 0.7 mmHg; P < 0.001) and ALT values (- 4.1 vs. - 0.0 U/l; P < 0.001) and smaller declines in eGFR values (- 2.0 vs. - 3.5 ml/min/1.73 m2; P < 0.001) when compared to DPP4 inhibitors. CONCLUSION SGLT2 inhibitors had glucose-lowering effects comparable to those of DPP4 inhibitors but more favorable pleiotropic effects on body weight, ALT and eGFR changes, potentially improving type 2 diabetes patients' cardio-metabolic disease risks.
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Affiliation(s)
- Shih-Chieh Shao
- Department of Pharmacy, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
- School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701 Taiwan
| | - Kai-Cheng Chang
- School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701 Taiwan
- Department of Pharmacy, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Swu-Jane Lin
- Department of Pharmacy Systems, Outcomes and Policy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL USA
| | - Rong-Nan Chien
- Liver Research Unit, Linkou Chang Gung Memorial Hospital and University, Taoyuan, Taiwan
| | - Ming-Jui Hung
- Section of Cardiology, Department of Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
- Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Yuk-Ying Chan
- Department of Pharmaceutical Materials Management, Chang Gung Medical Foundation, Taoyuan, Taiwan
| | - Yea-Huei Kao Yang
- School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701 Taiwan
| | - Edward Chia-Cheng Lai
- School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan, 701 Taiwan
- Department of Pharmacy, National Cheng Kung University Hospital, Tainan, Taiwan
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Thomson SC, Vallon V. Renal Effects of Sodium-Glucose Co-Transporter Inhibitors. Am J Cardiol 2019; 124 Suppl 1:S28-S35. [PMID: 31741437 DOI: 10.1016/j.amjcard.2019.10.027] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 08/06/2019] [Indexed: 12/28/2022]
Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitors immediately reduce the glomerular filtration rate (GFR) in patients with type 2 diabetes mellitus. When given chronically, they confer benefit by markedly slowing the rate at which chronic kidney disease progresses and are the first agents to do so since the advent of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Salutary effects on the kidney were first demonstrated in cardiovascular outcomes trials and have now emerged from trials enriched in subjects with type 2 diabetes mellitus and chronic kidney disease. A simple model that unifies the immediate and long-term effects of SGLT2 inhibitors on kidney function is based on the assumption that diabetic hyperfiltration puts the kidney at long-term risk and evidence that hyperfiltration is an immediate response to a reduced signal for tubuloglomerular feedback, which occurs to the extent that SGLT2 activity mediates a primary increase in sodium and fluid reabsorption by the proximal tubule. This model will likely continue to serve as a useful description accounting for the beneficial effect of SGLT2 inhibitors on the diabetic kidney, similar to the hemodynamic explanation for the benefit of ACEIs and ARBs. A more complex model will be required to incorporate positive interactions between SGLT2 and sodium-hydrogen exchanger 3 in the proximal tubule and between sodium-glucose co-transporter 1 (SGLT1) and nitric oxide synthase in the macula densa. The implication of these latter nuances for day-to-day clinical medicine remains to be determined.
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King J, McAdam-Marx C, McCaleb R, Davis D, Bemberg GB, Johnson JT. Cost and Utilization Outcomes After Exclusion of Dipeptidyl Peptidase-4 Inhibitors and Other Diabetes Drug Category Changes in a Self-Funded, State Employee Managed Care Plan. J Manag Care Spec Pharm 2019; 25:646-651. [PMID: 31134855 PMCID: PMC10397906 DOI: 10.18553/jmcp.2019.25.6.646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Dipeptidyl peptidase-4 (DPP-4) inhibitors have repeatedly shown no reduction in the clinical outcomes of cardiovascular death, myocardial infarction, stroke, or all-cause mortality. Because the treatment of diabetes is generally one of the top drug categories by cost to health plans and self-funded employers, it is necessary to evaluate coverage of DPP-4 inhibitors, considering their lack of cardiovascular benefit relative to other treatment options. OBJECTIVE To describe the cost and utilization outcomes of drugs used to treat diabetes after exclusion of DPP-4 inhibitors in a self-funded managed care plan. METHODS This study was a retrospective, descriptive analysis of the cost and utilization outcomes after exclusion of DPP-4 inhibitors. Pharmacy claims data and plan membership were analyzed 6 months before DPP-4 inhibitor exclusion (preperiod: December 1, 2016-May 31, 2017) and 6 months after DPP-4 inhibitor coverage ended for all users (postperiod: September 1, 2017-February 28, 2018). The allowed amount, which is not influenced by overlapping plan copay changes, and utilization per member per month (PMPM) were used to estimate the effect of the DPP-4 inhibitor benefit exclusion on plan costs for the antidiabetic class. RESULTS From preperiod to postperiod, all DPP-4 inhibitor products decreased in utilization by 3.02 claims per 1,000 members per month (PTMPM). Glucagon-like peptide-1 receptor agonists, insulins, sodium-glucose cotransporter-2 inhibitors, and thiazolidinedione claims increased by 0.72, 0.43, 0.30, and 0.48 claims PTMPM, respectively, but there was an absolute decrease of 1.35 claims for antidiabetic medications per 1,000 plan members. However, the days supplied PMPM increased from 2.55 to 2.61 (2.3%) days. Allowed amount PMPM increased by $0.27 from $12.19 in the preperiod to $12.31 in the postperiod (2.2%). However, it is estimated that drug cost inflation accounted for over half of the PMPM increase in allowed costs. CONCLUSIONS The observed increase in the allowed amount PMPM was attributable in similar amounts by an increase in utilization of medications with higher cost per day supplied and higher drug prices. Future research will evaluate patient-level effects of this benefit change in terms of antidiabetic medication utilization and outcomes. DISCLOSURES No outside funding supported this study. Davis, Bemberg, and Johnson currently work for or previously worked for the UAMS Evidence-Based Prescription Drug Program, which advises the Employee Benefits Division (EBD) on pharmacy benefit management. The EBD did not provide any additional funding for this study. McAdam-Marx reports grants from AstraZeneca and Sanofi Aventis outside the submitted work. The other authors have no other relevant information to disclose.
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Affiliation(s)
- Jarrod King
- 1 University of Arkansas for Medical Sciences College of Pharmacy, Little Rock
| | - Carrie McAdam-Marx
- 1 University of Arkansas for Medical Sciences College of Pharmacy, Little Rock
| | - Rachael McCaleb
- 1 University of Arkansas for Medical Sciences College of Pharmacy, Little Rock
| | - Dwight Davis
- 2 Evidence-Based Prescription Drug Program, University of Arkansas for Medical Sciences College of Pharmacy, Little Rock
| | | | - Jill T Johnson
- 2 Evidence-Based Prescription Drug Program, University of Arkansas for Medical Sciences College of Pharmacy, Little Rock
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Zou CY, Liu XK, Sang YQ, Wang B, Liang J. Effects of SGLT2 inhibitors on cardiovascular outcomes and mortality in type 2 diabetes: A meta-analysis. Medicine (Baltimore) 2019; 98:e18245. [PMID: 31804352 PMCID: PMC6919451 DOI: 10.1097/md.0000000000018245] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Optimal glycemic control is required to restrain the increase of cardiovascular events in patients with type 2 diabetes. The effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on cardiovascular events and mortality in those patients are not well established. This meta-analysis was conducted to assess the effects of SGLT2 inhibitors on cardiovascular events and mortality in patients with type 2 diabetes. METHODS We conducted a systematic literature search of Medline, Embase and Cochrane Library and included randomized controlled trials (RCTs) of 3 different SGLT2 inhibitors (canagliflozin, dapagliflozin and empagliflozin) that evaluated the effects on cardiovascular outcomes and mortality in the final meta-analysis. The intervention arm was defined either as SGLT2 inhibitor monotherapy or as SGLT2 inhibitor add-on to other non-SGLT2 inhibitor antidiabetic agents (ADAs). RESULTS Forty-two trials with a total of 61,076 patients with type 2 diabetes were included in the meta-analysis. Compared with the control, SGLT2 inhibitor treatment was associated with a reduction in the incidence of major adverse cardiovascular events (MACEs) (OR = 0.86, 95% CI 0.80-0.93, P < .0001), myocardial infarction (OR = 0.86, 95% CI 0.79-0.94, P = .001), cardiovascular mortality (OR = 0.74, 95% CI 0.67-0.81, P < .0001) and all cause mortality (OR = 0.85, 95% CI 0.79-0.92, P < .0001). However, the risk of ischemic stroke was not reduced after SGLT2 inhibitor treatment in patients with type 2 diabetes (OR = 0.95, 95% CI 0.85-1.07, P = .42). CONCLUSION These data suggest a decreased risk of harm with SGLT2 inhibitor as a class with respect to cardiovascular events and mortality.
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Affiliation(s)
- Cai-Yan Zou
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University; Affiliated to Medical School of Southeast University
| | - Xue-Kui Liu
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University; Affiliated to Medical School of Southeast University
| | - Yi-Quan Sang
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University; Affiliated to Medical School of Southeast University
| | - Ben Wang
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University; Affiliated to Medical School of Southeast University
| | - Jun Liang
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University; Affiliated to Medical School of Southeast University
- Xuzhou Institute of Medical Science, Xuzhou Institute of Diabetes, Xuzhou, Jiangsu, China
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Ninčević V, Omanović Kolarić T, Roguljić H, Kizivat T, Smolić M, Bilić Ćurčić I. Renal Benefits of SGLT 2 Inhibitors and GLP-1 Receptor Agonists: Evidence Supporting a Paradigm Shift in the Medical Management of Type 2 Diabetes. Int J Mol Sci 2019; 20:5831. [PMID: 31757028 PMCID: PMC6928920 DOI: 10.3390/ijms20235831] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/13/2019] [Accepted: 11/18/2019] [Indexed: 01/09/2023] Open
Abstract
Diabetic nephropathy (DN) is one of the most perilous side effects of diabetes mellitus type 1 and type 2 (T1DM and T2DM).). It is known that sodium/glucose cotransporter 2 inhibitors (SGLT 2i) and glucagone like peptide-1 receptor agonists (GLP-1 RAs) have renoprotective effects, but the molecular mechanisms are still unknown. In clinical trials GLP-1 analogs exerted important impact on renal composite outcomes, primarily on macroalbuminuria, possibly through suppression of inflammation-related pathways, however enhancement of natriuresis and diuresis is also one of possible mechanisms of nephroprotection. Dapagliflozin, canagliflozin, and empagliflozin are SGLT2i drugs, useful in reducing hyperglycemia and in their potential renoprotective mechanisms, which include blood pressure control, body weight loss, intraglomerular pressure reduction, and a decrease in urinary proximal tubular injury biomarkers. In this review we have discussed the potential synergistic and/or additive effects of GLP 1 RA and SGLT2 inhibitors on the primary onset and progression of kidney disease, and the potential implications on current guidelines of diabetes type 2 management.
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Affiliation(s)
- Vjera Ninčević
- Department of Pharmacology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia; (V.N.); (T.O.K.); (H.R.)
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Crkvena 21, 31000 Osijek, Croatia
| | - Tea Omanović Kolarić
- Department of Pharmacology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia; (V.N.); (T.O.K.); (H.R.)
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Crkvena 21, 31000 Osijek, Croatia
| | - Hrvoje Roguljić
- Department of Pharmacology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia; (V.N.); (T.O.K.); (H.R.)
- Department for Cardiovascular Disease, University Hospital Osijek, 4, 31000 Osijek, Croatia
| | - Tomislav Kizivat
- Clinical Institute of Nuclear Medicine and Radiation Protection, University Hospital Osijek, 31000 Osijek, Croatia;
- Department for Nuclear Medicine and Oncology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek; J. Huttlera 4, 31000 Osijek, Croatia
| | - Martina Smolić
- Department of Pharmacology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia; (V.N.); (T.O.K.); (H.R.)
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Crkvena 21, 31000 Osijek, Croatia
| | - Ines Bilić Ćurčić
- Department of Pharmacology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, 31000 Osijek, Croatia; (V.N.); (T.O.K.); (H.R.)
- Department of Diabetes, Endocrinology and Metabolism Disorders, University Hospital Osijek, 31000 Osijek, Croatia
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Kalra J, Mangali SB, Dasari D, Bhat A, Goyal S, Dhar I, Sriram D, Dhar A. SGLT1 inhibition boon or bane for diabetes-associated cardiomyopathy. Fundam Clin Pharmacol 2019; 34:173-188. [PMID: 31698522 DOI: 10.1111/fcp.12516] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 09/18/2019] [Accepted: 10/14/2019] [Indexed: 12/29/2022]
Abstract
Chronic hyperglycaemia is a peculiar feature of diabetes mellitus (DM). Sequential metabolic abnormalities accompanying glucotoxicity are some of its implications. Glucotoxicity most likely corresponds to the vascular intricacy and metabolic alterations, such as increased oxidation of free fatty acids and reduced glucose oxidation. More than half of those with diabetes also develop cardiac abnormalities due to unknown causes, posing a major threat to the currently available marketed preparations which are being used for treating these cardiac complications. Even though impairment in cardiac functioning is the principal cause of death in individuals with type 2 diabetes (T2D), reducing plasma glucose levels has little effect on cardiovascular disease (CVD) risk. In vitro and in vivo studies have demonstrated that inhibitors of sodium glucose transporter (SGLT) represent a putative therapeutic intervention for these pathological conditions. Several clinical trials have reported the efficacy of SGLT inhibitors as a novel and potent antidiabetic agent which along with its antihyperglycaemic activity possesses the potential of effectively treating its associated cardiac abnormalities. Thus, hereby, the present review highlights the role of SGLT inhibitors as a successful drug candidate for correcting the shifts in deregulation of cardiac energy substrate metabolism together with its role in treating diabetes-related cardiac perturbations.
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Affiliation(s)
- Jaspreet Kalra
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Suresh Babu Mangali
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Deepika Dasari
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Audesh Bhat
- Centre for Molecular Biology, Central University of Jammu, Jammu, 181143, India
| | - Srashti Goyal
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Indu Dhar
- Department of Clinical Science, University of Bergen, Bergen, 5009, Norway
| | - Dharamrajan Sriram
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
| | - Arti Dhar
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet, Hyderabad,, Andhra Pradesh, 500078, India
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Bailey CJ, Del Prato S, Wei C, Reyner D, Saraiva G. Durability of glycaemic control with dapagliflozin, an SGLT2 inhibitor, compared with saxagliptin, a DPP4 inhibitor, in patients with inadequately controlled type 2 diabetes. Diabetes Obes Metab 2019; 21:2564-2569. [PMID: 31364269 PMCID: PMC6851837 DOI: 10.1111/dom.13841] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 07/10/2019] [Accepted: 07/25/2019] [Indexed: 01/13/2023]
Abstract
Dapagliflozin is associated with greater reductions in HbA1c and weight than saxagliptin in management of type 2 diabetes mellitus (T2DM). The present post hoc analyses compared the durability of these effects over short- and long-term follow-up in patients with T2DM who were inadequately controlled with metformin (≥1500 mg/day) and who were receiving either dapagliflozin (10 mg/day) or saxagliptin (5 mg/day). Failure of glycaemiccontrol was assessed using the slope of the change in HbA1c from baseline-over-time regression line (coefficient of failure [CoF]). CoF was compared directly (dapagliflozin vs saxagliptin) over the short term (NCT01606007, 24 weeks) and indirectly (placebo-adjusted) over the long term (NCT00528879 and NCT00121667, 102 weeks). A low CoF value indicated greater durability. CoF was lower for dapagliflozin versus saxagliptin over 18-24 weeks (-1.38%/year; 95% CI, -2.41 to -0.35; P = .009) and 20-102 weeks (-0.37%/year; 95% CI, -0.73 to -0.02; P = .04). Fewer dapagliflozin-treated patients versus saxagliptin-treated patients required rescue medication or discontinued the study because of failure to achieve glycaemic control at 24 weeks (3.4% vs 9.4%; P = .0191). In patients with T2DM who were inadequately controlled with metformin, dapagliflozin was associated with greater durability of glycaemic control than saxagliptin over 18-24 and 20-102 weeks.
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Affiliation(s)
| | - Stefano Del Prato
- Section of Metabolic Diseases and Diabetes, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Cheryl Wei
- AstraZeneca, R&D Bio Pharmaceuticals, Late CVRMGaithersburgMaryland
| | - Daniel Reyner
- AstraZeneca, R&D Bio Pharmaceuticals, Late CVRMGaithersburgMaryland
| | - Gabriela Saraiva
- AstraZeneca, R&D Bio Pharmaceuticals, Late CVRMGaithersburgMaryland
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Hollander P, Hill J, Johnson J, Wei Jiang Z, Golm G, Huyck S, Terra SG, Mancuso JP, Engel SS, Lauring B, Liu J. Results of VERTIS SU extension study: safety and efficacy of ertugliflozin treatment over 104 weeks compared to glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin. Curr Med Res Opin 2019; 35:1335-1343. [PMID: 30760125 DOI: 10.1080/03007995.2019.1583450] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Objective: To assess the safety and efficacy of ertugliflozin over 104 weeks in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin. Methods: In this double-blind, multicenter, randomized, phase III study (VERTIS SU; NCT01999218), adults with T2DM and glycated hemoglobin (HbA1c) 7.0-9.0% on metformin ≥1500 mg/day received ertugliflozin 5 mg or 15 mg, or glimepiride. The primary efficacy time point was Week 52; double-blinded treatment continued until Week 104. Results: Baseline characteristics of randomized, treated patients (n = 1315) were similar across groups (mean age 58.2 years, HbA1c 7.8%); 76.4% completed the study; 61.6% completed on study medication. Mean glimepiride dose at 104 weeks was 3.5 mg/day. At Week 104, least squares mean change from baseline in HbA1c (95% confidence intervals) were -0.3% (-0.4, -0.2), -0.4% (-0.5, -0.3) and -0.4% (-0.5, -0.3) for ertugliflozin 5 mg, 15 mg, and glimepiride, respectively. Ertugliflozin provided sustained reductions in body weight and systolic blood pressure (SBP) over 104 weeks. The incidence of adverse events (AEs) and serious AEs was similar across groups. The incidence of symptomatic hypoglycemia was 3.8%, 6.4% and 22.1% in the ertugliflozin 5 mg, 15 mg, and glimepiride groups, respectively. Genital mycotic infections were reported in 5.3%, 2.6% and 0% of men, respectively, and 9.2%, 12.3% and 1.4% of women, respectively. The incidence of urinary tract infection and hypovolemia AEs was similar across groups. Conclusions: Ertugliflozin was well tolerated and provided clinically meaningful glycemic control and durable reductions in body weight and SBP over 104 weeks.
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Affiliation(s)
| | - Julie Hill
- b Merck & Co. Inc. , Kenilworth , NJ , USA
| | | | | | | | | | | | | | | | - Brett Lauring
- f formerly of Merck & Co. Inc. , Kenilworth , NJ , USA
- g Currently at Takeda Pharmaceuticals , Cambridge , MA , USA
| | - Jie Liu
- b Merck & Co. Inc. , Kenilworth , NJ , USA
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Dicembrini I, Nreu B, Mannucci E, Monami M. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors and cancer: A meta-analysis of randomized controlled trials. Diabetes Obes Metab 2019; 21:1871-1877. [PMID: 30972917 DOI: 10.1111/dom.13745] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 04/04/2019] [Accepted: 04/09/2019] [Indexed: 12/25/2022]
Abstract
AIM The aim of this meta-analysis of randomized trials was to assess the effects of SGLT-2i on the overall incidence of malignancies and on different types of cancer, summerizing the results of trials with a duration of at least 1 year. This was done in light of the effect of SGLT-2 inhibitors (SGLT-2is) that has been highlighted by some studies, showing an increased incidence of bladder cancer, particularly with use of empagliflozin. MATERIALS AND METHODS A Medline and Embase search for "Canaglifozin", "Dapaglifozin", "Empaglifozin", "Ertuglifozin", "Ipraglifozin", Tofoglifozin" or "Luseoglifozin" was performed, identifying randomized trials with a duration of more than 52 weeks up to 1 December 2018 that compared SGLT-2is with placebo or active comparators. The outcomes considered were all types of cancer and several site-specific cancers (ie, breast, pulmonary, gastrointestinal, hepatic, pancreatic, skin, prostate and bladder). Mantel-Haenszel odds ratios with 95% Confidence Intervals (MH-OR, 95% CI) were calculated for all outcomes. RESULTS A total of 27 trials fulfilled the inclusion criteria. Retrieved trials had enrolled 27 744 and 20 441 patients in SGLT-2 inhibitor and comparator groups, respectively. No difference was observed in the incidence of all malignancies between patients allocated to SGLT-2i and comparators (MH-OR 0.98[0.77-1.24]). The incidence of bladder cancer, and of any other type of cancer, was not significantly increased by treatment with any SGLT-2i. CONCLUSIONS Available data from randomized trials do not suggest a detrimental effect of SGLT-2is on the incidence of malignancies in general, or in bladder cancer in particular.
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Affiliation(s)
- Ilaria Dicembrini
- Department of Diabetology, Careggi Teaching Hospital, University of Florence, Florence, Italy
| | - Besmir Nreu
- Department of Diabetology, Careggi Teaching Hospital, University of Florence, Florence, Italy
| | - Edoardo Mannucci
- Department of Diabetology, Careggi Teaching Hospital, University of Florence, Florence, Italy
| | - Matteo Monami
- Department of Diabetology, Careggi Teaching Hospital, University of Florence, Florence, Italy
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Dicembrini I, Tomberli B, Nreu B, Baldereschi GI, Fanelli F, Mannucci E, Monami M. Peripheral artery disease and amputations with Sodium-Glucose co-Transporter-2 (SGLT-2) inhibitors: A meta-analysis of randomized controlled trials. Diabetes Res Clin Pract 2019; 153:138-144. [PMID: 31150722 DOI: 10.1016/j.diabres.2019.05.028] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 05/02/2019] [Accepted: 05/22/2019] [Indexed: 12/25/2022]
Abstract
BACKGROUND Concerns have been raised on the risk of lower limb amputations with SGLT-2 inhibitors. Aim of the present metanalysis is the assessment of the effect of SGLT-2inhibitors on peripheral artery disease and lower limb amputations in randomized controlled trials performed in patients with type 2 diabetes. METHODS A Medline and Embase search for "Canaglifozin" OR "Dapaglifozin" OR "Empaglifozin" OR "Ertuglifozin" OR "Ipraglifozin" OR Tofoglifozin" OR "Luseoglifozin" was performed, collecting randomized clinical trials (duration > 12 weeks) up to December 1st, 2018, comparing SGLT-2i at approved dose with placebo or other active comparators different from SGLT-2 inhibitors. Furthermore, unpublished studies were searched in the www.clinicaltrials.gov register. Separate analyses were performed for individual molecules of the class. In addition, a separate analysis was performed for placebo-controlled trials. Mantel-Haenszel odds ratio with 95% Confidence Interval (MH-OR) was calculated for all outcomes defined above. RESULTS A total of 27 trials fulfilling the inclusion criteria was identified. The overall incidence of peripheral artery disease was increased with SGLT-2 inhibitors (MH-OR: 1.26 [1.04, 1.52]). The increase of risk was statistically significant only with canagliflozin. MH-OR for amputation in the three cardiovascular safety trials with SGLT-2 inhibitors was 1.22 [0.59-2.52]. CONCLUSIONS At present, there is no reason to believe that empagliflozin or dapagliflozin increase the risk of either peripheral artery disease of lower limb amputations. Canagliflozin could be associated with a specific risk, which needs to be further investigated.
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Affiliation(s)
| | - Benedetta Tomberli
- Cardiothoracovascular Department, Careggi Hospital and University of Florence, Italy
| | - Besmir Nreu
- Diabetology, Careggi Hospital and University of Florence, Italy
| | | | - Fabrizio Fanelli
- Vascular Interventional Radiology Department, Careggi Hospital and University of Florence, Italy
| | | | - Matteo Monami
- Diabetology, Careggi Hospital and University of Florence, Italy.
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Weir MR. Renal effects of sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes and renal impairment. Postgrad Med 2019; 131:367-375. [PMID: 31132013 DOI: 10.1080/00325481.2019.1624582] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In patients with type 2 diabetes (T2D), microvascular changes in the kidney often result in diabetic kidney disease (DKD), the progression of which is associated with an increased risk of cardiovascular (CV) and all-cause mortality. Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are a newer class of oral glucose-lowering therapies that were associated with significant reductions in the risk of major adverse CV events, CV death, and hospitalization for heart failure compared with placebo in CV outcomes trials (CVOTs) of patients with T2D and established CV disease or varying levels of CV risk. In addition, SGLT-2is reduced the risks of clinically relevant renal outcomes in these large randomized studies, indicating the potential for renoprotective effects in patients with T2D and DKD. This review discussed the non-glycemic effects of SGLT-2is in patients with T2D and renal impairment, including reductions in systolic and diastolic blood pressure, decreases in albuminuria and plasma uric acid, changes in estimated glomerular filtration rate, and minimal changes in electrolytes. Potential mechanisms for the renoprotective effects of SGLT-2is observed in CVOTs were considered, including the likely incremental benefits of SGLT-2is when added to renin-aldosterone-angiotensin system inhibitors (RAASis). The possibility of extending the use of SGLT-2is to patients with non-DKD was also discussed. Although the exact mechanisms by which SGLT-2is improve renal outcomes are not fully understood, they are likely to be multifactorial and additive when these drugs are used in combination with RAASis in patients with DKD.
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Affiliation(s)
- Matthew R Weir
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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Chen Z, Li G. Sodium-Glucose Co-Transporter 2 Inhibitors Compared with Sulfonylureas in Patients with Type 2 Diabetes Inadequately Controlled on Metformin: A Meta-Analysis of Randomized Controlled Trials. Clin Drug Investig 2019; 39:521-531. [PMID: 31041606 DOI: 10.1007/s40261-019-00781-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND OBJECTIVE When metformin is insufficient for patients with type 2 diabetes mellitus (T2DM), the optimal adjunctive therapy is unclear. This meta-analysis was to compare the efficacy and safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors with sulfonylureas (SUs) as second-line therapy in patients with T2DM inadequately controlled on metformin. METHODS We systematically searched PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for randomized controlled trials comparing SGLT2 inhibitors with SUs as add-on to metformin. Our primary endpoints were glycemic control, hypoglycemia, and change in weight. We assessed pooled data using a random-effects model. RESULTS Five trials involving 4300 participants were included in our meta-analysis. Compared with SUs, SGLT2 inhibitors led to no significant reduction in changes in HbA1c (mean difference [MD] - 0.06; 95% confidence interval [CI] [- 0.12, 0.08]), but less hypoglycemia as add-on to metformin (odds ratio [OR] 0.12; 95% CI [0.07, 0.21]). SGLT2 inhibitors led to a reduction in weight by about 3.5 kg; however, SUs caused a gain in weight by about 1 kg (MD - 4.39; 95% CI [- 4.64, - 4.14]). SGLT2 inhibitors also showed a reduction in blood pressure, but increased the incidence of genital tract infections compared with SUs. Interestingly, subgroup analysis by duration of interventions showed that reduction of HbA1c from baseline was similar between the two groups at 12-52 weeks, but SGLT2 inhibitors led to a greater reduction in HbA1c at 104-208 weeks. CONCLUSIONS Despite similar glycemic efficacy in a relatively short term, SGLT2 inhibitors are more effective in the longer term than SUs as add-on to metformin. In addition, SGLT2 inhibitors produce less hypoglycemic events and lead to greater reductions in weight and blood pressure compared with SUs.
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Affiliation(s)
- Ze Chen
- School of Medicine, Wuhan University, No. 115 Donghu Road, Wuhan, 430071, Hubei, China.
| | - Gerui Li
- School of Medicine, Wuhan University, No. 115 Donghu Road, Wuhan, 430071, Hubei, China
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Ku EJ, Lee DH, Jeon HJ, Oh TK. Empagliflozin versus dapagliflozin in patients with type 2 diabetes inadequately controlled with metformin, glimepiride and dipeptidyl peptide 4 inhibitors: A 52-week prospective observational study. Diabetes Res Clin Pract 2019; 151:65-73. [PMID: 30954510 DOI: 10.1016/j.diabres.2019.04.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 02/26/2019] [Accepted: 04/01/2019] [Indexed: 02/06/2023]
Abstract
AIMS To directly compare the effectiveness and safety between two distinct sodium-glucose co-transporter 2 (SGLT2) inhibitors, empagliflozin and dapagliflozin, as part of a quadruple oral antidiabetic agents (OADs) in patients with inadequately controlled type 2 diabetes (T2D). METHODS This study was an open-labeled, prospective, 52-week study conducted in T2D patients with glycated hemoglobin (HbA1c) ranging 7.5-12.0% with metformin, glimepiride and dipeptidyl peptidase-4 inhibitors. Patients were divided into either empagliflozin (25 mg/day) or dapagliflozin (10 mg/day). The outcome measures included changes in HbA1c, fasting plasma glucose (FPG), and cardiometabolic variables and the safety profiles. RESULTS In total, 350 patients were enrolled with empagliflozin (n = 176) and dapagliflozin (n = 174), respectively. After 52 weeks, both groups showed significant reductions in HbA1c and FPG, but the reduction was greater in the empagliflozin group (P < 0.001). Both groups showed significantly decreased blood pressure and body weight and high-density lipoprotein cholesterol levels were increased in the empagliflozin (between groups, P = 0.035). Both groups showed similar safety profiles. CONCLUSIONS Our study demonstrated that SGLT2 inhibitors can be effectively used as a fourth OAD in T2D patients who are treated with three other OADs. More specifically, empagliflozin was more effective in reducing HbA1c and improving other cardiometabolic parameters than dapagliflozin. Clinical Trial Number NCT03748810 (ClinicalTrials.gov).
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Affiliation(s)
- Eu Jeong Ku
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea; Department of Internal Medicine, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Dong-Hwa Lee
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea; Department of Internal Medicine, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Hyun Jeong Jeon
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea; Department of Internal Medicine, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Tae Keun Oh
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea; Department of Internal Medicine, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea.
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