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Zhang C, Ren W, Lu X, Feng L, Li J, Zhu B. Empagliflozin's role in early tubular protection for type 2 diabetes patients. Mol Med 2024; 30:112. [PMID: 39085830 PMCID: PMC11293177 DOI: 10.1186/s10020-024-00881-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 07/17/2024] [Indexed: 08/02/2024] Open
Abstract
BACKGROUND Patients with type 2 diabetes often face early tubular injury, necessitating effective treatment strategies. This study aimed to evaluate the impact of the SGLT2 inhibitor empagliflozin on early tubular injury biomarkers in type 2 diabetes patients with normoalbuminuria. METHODS A randomized controlled clinical study comprising 54 patients selected based on specific criteria was conducted. Patients were divided into an intervention group (empagliflozin, n = 27) and a control group (n = 27) and treated for 6 weeks. Tubular injury biomarkers KIM-1 and NGAL were assessed pre- and post-treatment. RESULTS Both groups demonstrated comparable baseline characteristics. Post-treatment, fasting and postprandial blood glucose levels decreased similarly in both groups. The intervention group exhibited better improvements in total cholesterol, low-density lipoprotein, and blood uric acid levels. Renal function indicators, including UACR and eGFR, showed greater enhancements in the intervention group. Significant reductions in KIM-1 and NGAL were observed in the intervention group. CONCLUSION Treatment with empagliflozin in type 2 diabetes patients with normoalbuminuria led to a notable decrease in tubular injury biomarkers KIM-1 and NGAL. These findings highlight the potential of SGLT2 inhibitors in early tubular protection, offering a new therapeutic approach.
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Affiliation(s)
- Chuangbiao Zhang
- Department of Endocrinology, First Affiliated Hospital of Jinan University, No. 613 West Huangpu Avenue, Tianhe District, Guangzhou, 510630, Guangdong Province, China
| | - Weiwei Ren
- Department of Endocrinology, Guangzhou Baiyun District Maternal And Child Health Hospital, Guangzhou, 51000, Guangdong Province, China
| | - Xiaohua Lu
- Department of Endocrinology, First Affiliated Hospital of Jinan University, No. 613 West Huangpu Avenue, Tianhe District, Guangzhou, 510630, Guangdong Province, China
| | - Lie Feng
- Department of Endocrinology, First Affiliated Hospital of Jinan University, No. 613 West Huangpu Avenue, Tianhe District, Guangzhou, 510630, Guangdong Province, China
| | - Jiaying Li
- Department of Endocrinology, First Affiliated Hospital of Jinan University, No. 613 West Huangpu Avenue, Tianhe District, Guangzhou, 510630, Guangdong Province, China.
| | - Beibei Zhu
- Endoscopy Center, First Affiliated Hospital of Jinan University, No. 613 West Huangpu Avenue, Tianhe District, Guangzhou, 510630, Guangdong Province, China.
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Sousa LS, Nascimento FDA, Rocha J, Rocha-Parise M. Cardioprotective Effects of Sodium-glucose Cotransporter 2 Inhibitors Regardless of Type 2 Diabetes Mellitus: A Meta-analysis. INTERNATIONAL JOURNAL OF CARDIOVASCULAR SCIENCES 2021. [DOI: 10.36660/ijcs.20200339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Tumminia A, Graziano M, Vinciguerra F, Lomonaco A, Frittita L. Efficacy, renal safety and tolerability of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in elderly patients with type 2 diabetes: A real-world experience. Prim Care Diabetes 2021; 15:283-288. [PMID: 33129749 DOI: 10.1016/j.pcd.2020.10.002] [Citation(s) in RCA: 4] [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: 07/10/2020] [Revised: 09/21/2020] [Accepted: 10/03/2020] [Indexed: 12/11/2022]
Abstract
AIMS To evaluate efficacy, renal safety and tolerability of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in a cohort of patients with type 2 diabetes (T2DM) aged ≥65 years. METHODS We retrospectively evaluated 364 elderly individuals with T2DM starting SGLT2i from June 2015 to June 2018. Patients were divided into 2 subgroups based on median age (70 years). Linear mixed effect models were used to estimate changes in glycated hemoglobin (HbA1c), body mass index (BMI), and glomerular filtration rate (eGFR). SGLT2i discontinuation rate and causes of treatment interruption were also recorded. RESULTS A significantly higher percentage of patients achieved HbA1c <7.5% (46.7% vs. 31.6%, p < 0.01) and <8.0% (68.9% vs. 47.2%, p < 0.01) compared to baseline. Each year of therapy was associated with an average HbA1c decrease of 0.34% (p < 0.01) and BMI loss of 0.71 kg/m2 (p < 0.01), without significant interaction across age classes. In the younger group eGFR increased by 1.02 ml/min/year, while in the older group it declined by 0.42 ml/min/year (p = 0.08). Overall discontinuation rate during the follow-up period was similar across age groups (34.2% vs. 36.1%, long-rank p = 0.26). Genitourinary infections were the most frequent cause of treatment interruption (15.8% vs. 17.2%, p = 0.69) in both study groups, while persistent eGFR decline (4.4%) and orthostatic hypotension (1.7%) were only present in older age class. CONCLUSIONS Efficacy, renal safety and tolerability of SGLT2i were similar in people >70 compared to 65-70 years of age, suggesting that a wider use should not be worried even in the elderly. However, some caution must be paid to the occurrence of persistent eGFR decline and orthostatic hypotension, especially in patients >70 years old.
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Affiliation(s)
- Andrea Tumminia
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Diabetes, Obesity and Dietetic Center, Garibaldi Hospital, Via Palermo 636, 95122, Catania, Italy.
| | - Marco Graziano
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Diabetes, Obesity and Dietetic Center, Garibaldi Hospital, Via Palermo 636, 95122, Catania, Italy.
| | - Federica Vinciguerra
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Diabetes, Obesity and Dietetic Center, Garibaldi Hospital, Via Palermo 636, 95122, Catania, Italy.
| | - Andrea Lomonaco
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Diabetes, Obesity and Dietetic Center, Garibaldi Hospital, Via Palermo 636, 95122, Catania, Italy.
| | - Lucia Frittita
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Diabetes, Obesity and Dietetic Center, Garibaldi Hospital, Via Palermo 636, 95122, Catania, Italy.
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Okada K, Hoshide S, Kato M, Kanegae H, Ishibashi S, Kario K. Safety and efficacy of empagliflozin in elderly Japanese patients with type 2 diabetes mellitus: A post hoc analysis of data from the SACRA study. J Clin Hypertens (Greenwich) 2020; 23:860-869. [PMID: 33326172 PMCID: PMC8678714 DOI: 10.1111/jch.14131] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/26/2020] [Accepted: 11/29/2020] [Indexed: 12/15/2022]
Affiliation(s)
- Kenta Okada
- Division of Endocrinology and Metabolism Department of Medicine Jichi Medical University School of Medicine Tochigi Japan
| | - Satoshi Hoshide
- Division of Cardiovascular Medicine Department of Medicine Jichi Medical University School of Medicine Tochigi Japan
| | | | - Hiroshi Kanegae
- Division of Cardiovascular Medicine Department of Medicine Jichi Medical University School of Medicine Tochigi Japan
| | - Shun Ishibashi
- Division of Endocrinology and Metabolism Department of Medicine Jichi Medical University School of Medicine Tochigi Japan
| | - Kazuomi Kario
- Division of Cardiovascular Medicine Department of Medicine Jichi Medical University School of Medicine Tochigi Japan
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Pandya N, Hames E, Sandhu S. Challenges and Strategies for Managing Diabetes in the Elderly in Long-Term Care Settings. Diabetes Spectr 2020; 33:236-245. [PMID: 32848345 PMCID: PMC7428662 DOI: 10.2337/ds20-0018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Diabetes affects a large number of patients in the long-term care (LTC) setting, and their care is often complicated because of multimorbidity, diabetes-related complications, disability, dependency on caregivers, and geriatric syndromes, including frailty and cognitive impairment. This population includes patients receiving short-term rehabilitation in skilled nursing facilities, those who are residents in LTC facilities, and those receiving palliative or end-of-life care. An individualized approach to care based on clinical complexity, diabetes trajectory, and patients' preferences and goals is required. Such patients may experience one or more transitions of care and decline in condition. They are also prone to adverse drug events, cardiovascular events, and hypoglycemia. Facility-related challenges include varying staff competencies and practitioner preferences, inconsistent interdisciplinary communication, overly complex medication regimens, and poorly implemented care transitions.
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Affiliation(s)
- Naushira Pandya
- Department of Geriatrics, Nova Southeastern University, Fort Lauderdale, FL
| | - Elizabeth Hames
- Kiran Patel College of Osteopathic Medicine, Fort Lauderdale, FL
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Sertbas M, Guduk O, Guduk O, Yazici Z, Dagci S, Sertbas Y. Current situation analysis of diabetic home care patients. North Clin Istanb 2019; 7:140-145. [PMID: 32259035 PMCID: PMC7117632 DOI: 10.14744/nci.2019.59751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 10/22/2019] [Indexed: 11/20/2022] Open
Abstract
OBJECTIVE Diabetes is one of the primary diagnoses for admission to home health care units. Although there are many studies about elderly diabetic patients, there are not many studies on home care patients with diabetes. The present study aims to analyze the current status of diabetic home care patients with their biochemical data and medications. METHODS This was a retrospective study, including 256 diabetic patients who were following up by the Home Health Unit of Istanbul Provincial Health Directorate Public Hospitals Services-2. In this study, we analyzed the current biochemical data of the patients with their medications. RESULTS In this study, 185 female (72.3%) and 71 male (27.7%) patients were recruited with the mean HbA1c of 8.25±1.77. Among these patients, 65% of them were using oral antidiabetic (OAD), and 58% were using insulin. There were 21 (8.2%) patients who were not receiving any treatment. While patients who were using only oral antidiabetic have better A1c levels (A1c: 7.73±1.45), patients who were insülin using had HbA1c levels as high as the patients who were not using any medication. This may be due to the progression of diabetes, fear of hypoglycemia or insufficient insülin use. While metformin was the most commonly used OAD, with a 38% usage rate. When compared to HbA1c levels, there was no difference between the types of insulin used (p=0.167). CONCLUSION As a result, it is important to plan regular visits and personalized treatment by keeping in mind the benefits to risk ratios in home-care diabetic patients.
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Affiliation(s)
- Meltem Sertbas
- Department of Internal Medicine, Health Sciences University Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey
| | - Ozlem Guduk
- Department of Internal Medicine, Health Sciences University Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey
| | - Ozden Guduk
- Health Institutes of Turkey, Istanbul, Turkey
| | - Zeynep Yazici
- Department of Cardiology, Siyami Ersek Training and Research Hospital, Istanbul, Turkey
| | - Selma Dagci
- Department of Internal Medicine, Health Sciences University, Umraniye Training and Research Hospital, Istanbul, Turkey
| | - Yasar Sertbas
- Department of Internal Medicine, Health Sciences University Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkey
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Lamos EM, Hedrington M, Davis SN. An update on the safety and efficacy of oral antidiabetic drugs: DPP-4 inhibitors and SGLT-2 inhibitors. Expert Opin Drug Saf 2019; 18:691-701. [DOI: 10.1080/14740338.2019.1626823] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- Elizabeth Mary Lamos
- Division of Endocrinology, Diabetes and Metabolism, University of Maryland School of Medicine, Baltimore,
MD, USA
| | - Maka Hedrington
- Division of Endocrinology, Diabetes and Metabolism, University of Maryland School of Medicine, Baltimore,
MD, USA
| | - Stephen N Davis
- Department of Medicine, University of Maryland Medical Center, Baltimore,
MD, USA
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Abstract
INTRODUCTION Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are recommended after metformin for a large spectrum of patients with type 2 diabetes, because of a favorable benefit/risk profile despite a variety of adverse events. AREAS COVERED This narrative review discusses the safety profile of SGLT2is: initial concerns (cardiovascular safety, acute renal failure, hypoglycemia, urinary and genital infections, volume depletion, bladder cancer), further concerns (euglycemic ketoacidosis, bone fractures) and more recent concerns (lower limb amputation, Fournier's gangrene). EXPERT OPINION Overall, the safety profile of SGLT2is is good. The only increased adverse event that was consistently reported in clinical trials and observational studies is genital mycotic infections, with only a borderline increase in urinary tract infections. Among clinical trials, only the CANVAS program reported an unexpected increase in bone fractures and peripheral amputations. A variety of rare adverse events have been described as case reports, including ketoacidosis, amputations and Fournier gangrene, which led to specific warnings by regulatory agencies. Identifying predisposing patient's characteristics and/or precipitating clinical conditions would help prevent the most severe complications. These adverse events should not mask the overall cardiovascular and renal benefit of SGLT2is, especially in patients with type 2 diabetes at high cardiovascular risk.
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Affiliation(s)
- André J Scheen
- a Division of Clinical Pharmacology , Center for Interdisciplinary Research on Medicines (CIRM), Liège University , Liège , Belgium.,b Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine , CHU Liège , Liège , Belgium
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Meneilly GS, Knip A, Miller DB, Sherifali D, Tessier D, Zahedi A. Diabetes in Older People. Can J Diabetes 2018; 42 Suppl 1:S283-S295. [PMID: 29650107 DOI: 10.1016/j.jcjd.2017.10.021] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Indexed: 12/15/2022]
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Gómez-Huelgas R, Gómez Peralta F, Rodríguez Mañas L, Formiga F, Puig Domingo M, Mediavilla Bravo JJ, Miranda C, Ena J. [Treatment of type 2 diabetes mellitus in elderly patients]. Rev Esp Geriatr Gerontol 2018; 53:89-99. [PMID: 29439834 DOI: 10.1016/j.regg.2017.12.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 12/18/2017] [Indexed: 06/08/2023]
Abstract
The prevalence of type 2 diabetes mellitus (DM2) increases markedly with age. Antidiabetic treatment and the objectives of glycaemic control in elderly patients with DM2 should be individualised according to their biopsychosocial characteristics. In elderly patients for whom the benefits of intensive antidiabetic treatment are limited, the basic objectives should be to improve the quality of life, preserve functionality and avoid adverse effects, especially hypoglycaemia. Treatment of DM2 in the elderly was the subject of a consensus document published in 2012 and endorsed by several Spanish scientific societies. Since then, new therapeutic groups and evidence have emerged that warrant an update to this consensus document. The present document focuses on the therapeutic aspects of DM2 in elderly patients, understood as being older than 75 years or frail.
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Affiliation(s)
- R Gómez-Huelgas
- Servicio de Medicina Interna, Hospital Regional Universitario de Málaga, Málaga, España; Instituto de Investigación Biomédica de Málaga (IBIMA); CIBER de Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III; Sociedad Española de Medicina Interna (SEMI).
| | - F Gómez Peralta
- Unidad de Endocrinología y Nutrición, Hospital General de Segovia, Segovia, España; Sociedad Española de Diabetes (SED)
| | - L Rodríguez Mañas
- Servicio de Geriatría, Hospital Universitario de Getafe, Madrid, España; CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III; Sociedad Española de Medicina Geriátrica (SEMEG)
| | - F Formiga
- Unidad de Geriatría, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Barcelona, España; Sociedad Española de Geriatría y Gerontología (SEGG)
| | - M Puig Domingo
- Servicio de Endocrinología y Nutrición, Hospital Germans Trias i Pujol, Badalona, Barcelona, España; Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, Barcelona, España; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III; Sociedad Española de Endocrinología y Nutrición (SEEN)
| | - J J Mediavilla Bravo
- Centro de Salud Burgos Rural, Burgos, España; Sociedad Española de Medicina General (SEMERGEN)
| | - C Miranda
- Centro de Salud Buenavista, Toledo, España; Sociedad Española de Médicos Generales y de Familia (SEMG)
| | - J Ena
- Servicio de Medicina Interna, Hospital Marina Baixa, La Vila Joiosa, Alicante, España; Sociedad Española de Medicina Interna (SEMI)
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Gómez-Huelgas R, Gómez Peralta F, Rodríguez Mañas L, Formiga F, Puig Domingo M, Mediavilla Bravo JJ, Miranda C, Ena J. Treatment of type 2 diabetes mellitus in elderly patients. Rev Clin Esp 2018; 218:74-88. [PMID: 29366502 DOI: 10.1016/j.rce.2017.12.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 12/03/2017] [Indexed: 02/06/2023]
Abstract
The prevalence of type 2 diabetes mellitus (DM2) increases markedly with age. Antidiabetic treatment and the objectives of glycaemic control in elderly patients with DM2 should be individualised according to their biopsychosocial characteristics. In elderly patients for whom the benefits of intensive antidiabetic treatment are limited, the basic objectives should be to improve the quality of life, preserve functionality and avoid adverse effects, especially hypoglycaemia. Treatment of DM2 in the elderly was the subject of a consensus document published in 2012 and endorsed by several Spanish scientific societies. Since then, new therapeutic groups and evidence have emerged that warrant an update to this consensus document. The present document focuses on the therapeutic aspects of DM2 in elderly patients, understood as being older than 75 years or frail.
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Affiliation(s)
- R Gómez-Huelgas
- Servicio de Medicina Interna, Hospital Regional Universitario de Málaga, Málaga, España; Instituto de Investigación Biomédica de Málaga (IBIMA); CIBER de Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III; Sociedad Española de Medicina Interna (SEMI).
| | - F Gómez Peralta
- Unidad de Endocrinología y Nutrición, Hospital General de Segovia, Segovia, España; Sociedad Española de Diabetes (SED)
| | - L Rodríguez Mañas
- Servicio de Geriatría, Hospital Universitario de Getafe, Madrid, España; CIBER de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III; Sociedad Española de Medicina Geriátrica (SEMEG)
| | - F Formiga
- Unidad de Geriatría, Hospital Universitari de Bellvitge, ĹHospitalet de Llobregat, Barcelona, España; Sociedad Española de Geriatría y Gerontología (SEGG)
| | - M Puig Domingo
- Servicio de Endocrinología y Nutrición, Hospital Germans Trias i Pujol, Badalona, Barcelona, España; Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, Barcelona, España; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III; Sociedad Española de Endocrinología y Nutrición (SEEN)
| | - J J Mediavilla Bravo
- Centro de Salud Burgos Rural, Burgos, España; Sociedad Española de Medicina General (SEMERGEN)
| | - C Miranda
- Centro de Salud Buenavista, Toledo, España; Sociedad Española de Médicos Generales y de Familia (SEMG)
| | - J Ena
- Servicio de Medicina Interna, Hospital Marina Baixa, La Vila Joiosa, Alicante, España; Sociedad Española de Medicina Interna (SEMI)
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Advances in Managing Type 2 Diabetes in the Elderly: A Focus on Inpatient Care and Transitions of Care. Am J Ther 2018. [DOI: 10.1097/mjt.0000000000000667] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Kambara T, Shibata R, Osanai H, Nakashima Y, Asano H, Sakai K, Murohara T, Ajioka M. Use of sodium-glucose cotransporter 2 inhibitors in older patients with type 2 diabetes mellitus. Geriatr Gerontol Int 2017; 18:108-114. [PMID: 28861952 DOI: 10.1111/ggi.13149] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Revised: 06/18/2017] [Accepted: 06/27/2017] [Indexed: 12/19/2022]
Abstract
AIM Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic agents that act on the proximal renal tubules to lower blood glucose levels by inhibiting glucose reabsorption and promoting urinary glucose excretion. The present study assessed the long-term use of SGLT2 inhibitors in older patients with diabetes. METHODS A total of 117 older patients with type 2 diabetes who were given SGLT2 inhibitors were enrolled from April 2014 to March 2016. RESULTS The mean age of the patients was 73.7 ± 10.0 years. During the follow-up period (mean 289.3 days), there was no event associated with oral administration of SGLT2 inhibitors. These drugs significantly lowered fasting blood glucose and glycosylated hemoglobin levels at 6 months, and did not affect the creatinine level, blood urea nitrogen/creatinine ratio or estimated glomerular filtration rate during treatment. Although the treatment significantly increased hemoglobin and hematocrit levels, it did not affect the ultrasonographically determined diameter of the inferior vena cava, and no signs of intravascular collapse were observed. Changes in brain natriuretic peptide levels during the follow-up period were assessed in 78 patients with a brain natriuretic peptide level exceeding the normal upper limit before treatment with SGLT2 inhibitors. The brain natriuretic peptide levels significantly decreased after 6 months of treatment. CONCLUSIONS In older Japanese patients with diabetes, treatment with SGLT2 inhibitors for 6 months exerted a favorable hypoglycemic effect, while no sign of dehydration was observed. Geriatr Gerontol Int 2018; 18: 108-114.
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Affiliation(s)
- Takahiro Kambara
- Department of Cardiovascular Medicine, Tosei General Hospital, Seto, Japan
| | - Rei Shibata
- Department of Advanced Cardiovascular Therapeutics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroyuki Osanai
- Department of Cardiovascular Medicine, Tosei General Hospital, Seto, Japan
| | | | - Hiroshi Asano
- Department of Cardiovascular Medicine, Tosei General Hospital, Seto, Japan
| | - Kazuyoshi Sakai
- Department of Cardiovascular Medicine, Tosei General Hospital, Seto, Japan
| | - Toyoaki Murohara
- Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masayoshi Ajioka
- Department of Cardiovascular Medicine, Tosei General Hospital, Seto, Japan
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Bundhun PK, Janoo G, Huang F. Adverse drug events observed in patients with type 2 diabetes mellitus treated with 100 mg versus 300 mg canagliflozin: a systematic review and meta-analysis of published randomized controlled trials. BMC Pharmacol Toxicol 2017; 18:19. [PMID: 28411624 PMCID: PMC5392384 DOI: 10.1186/s40360-017-0126-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Accepted: 02/28/2017] [Indexed: 12/15/2022] Open
Abstract
Background Nowadays, canagliflozin monotherapy, or in combination with other oral hypoglycemic agents (OHAs), is often administered in patients who are treated for type 2 diabetes mellitus (T2DM). Therefore, we aimed to systematically compare the adverse drugs events (AEs) which were associated with 100 mg versus 300 mg canagliflozin respectively, using a large number of randomized patients with T2DM which were obtained from published trials. Methods Randomized controlled trials (RCTs) comparing 100 mg versus 300 mg canagliflozin in patients who were treated for T2DM were searched from electronic databases. AEs reported during a follow up period ranging from 12 to 104 weeks were considered as the clinical endpoints in this analysis. We calculated odds ratios (OR) with 95% confidence intervals (CIs) and the analyses were carried out by RevMan 5 · 3 software. Results Ten trials involving a total number of 5394 patients (2604 patients who were treated with 100 mg canagliflozin and 2790 patients who were treated with 300 mg canagliflozin) were included. The current results showed that serious AEs were not significantly higher in patients who were treated by 300 mg canagliflozin, with OR: 1.01, 95% CI: 0.79–1.29; P = 0.93. Also, a similar rate of death was observed in patients who were treated by either 100 or 300 mg canagliflozin with OR: 1.13, 95% CI: 0.43–2.94; P = 0.80. Urinary tract infections, postural dizziness and hypoglycemia were also similarly manifested, with OR: 0.93, 95% CI: 0.70–1.23; P = 0.61, OR: 1.51, 95% CI: 0.42–5.37; P = 0.53 and OR: 0.96, 95% CI: 0.81–1.13; P = 0.60 respectively. However, drug discontinuation due to AEs significantly favored 100 mg canagliflozin only during this unequal follow-up period with OR: 1.35, 95% CI: 1.06–1.72; P = 0.01, but it was not significantly different when trials with similar follow-up periods were analyzed. Conclusion 300 mg canagliflozin was not associated with significantly higher adverse events compared to 100 mg canagliflozin in those patients who were treated for T2DM. However, because this result was partly affected by other anti-diabetic medications which were included in the treatment regimen, further studies based on patients who were treated strictly on canagliflozin monotherapy should be recommended to completely solve this issue.
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Affiliation(s)
- Pravesh Kumar Bundhun
- Institute of Cardiovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China
| | - Girish Janoo
- Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China
| | - Feng Huang
- Institute of Cardiovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China.
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16
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Xiong W, Xiao MY, Zhang M, Chang F. Efficacy and safety of canagliflozin in patients with type 2 diabetes: A meta-analysis of randomized controlled trials. Medicine (Baltimore) 2016; 95:e5473. [PMID: 27902600 PMCID: PMC5134817 DOI: 10.1097/md.0000000000005473] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2016] [Revised: 10/31/2016] [Accepted: 11/01/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Canagliflozin is a new SGLT2 inhibitor which has been approved as an adjunct to diet and exercise for the treatment of adults with type 2 diabetes (T2D) mellitus in more than 30 countries. To evaluate the efficacy and safety of canagliflozin in patients with T2D, we carried out a meta-analysis of phase III clinical trials to offer an additional evidence of the efficacy and safety of canagliflozin for evidence-based clinical practice, strictly restricting the treatment durations to 26 weeks (core period) and 52 weeks (extension period). METHODS Randomized controlled trials (RCTs) published in English were searched in PubMed, Embase, and the Cochrane Library database (before April 2016). The studies reporting the efficacy and safety of canagliflozin in patients with T2DM were considered. Two authors separately performed data extraction. The differences were discussed and resolved. Pooled weighted mean differences (WMDs) or relative risks and 95% confidence intervals (CIs) were computed by using either fixed- or random-effects models. RESULTS At the end of the selection process, 7 RCTs were collected and included in the present analysis. Placebo-subtracted WMDs (%) of glycosylated hemoglobin (HbA1c) were -0.63 (95% CI: -0.77, -0.49) and -0.80 (95% CI: -0.98, -0.62) for canagliflozin 100 and 300 mg, respectively, from baseline to week 26. At week 26, canagliflozin 100 and 300 mg significantly reduced the body weight from baseline when compared with that of placebo, with a WMD of -2.23 and -3.00 in percent changes (P < 0.001 for both). The fasting and postmeal glucose, blood pressure (BP), and triglycerides were also reduced. These reductions were sustained over 52 weeks but had no significant differences between the 100 and 300 mg doses. The overall safety of canagliflozin was good, with the exception of high incidence of genital mycotic infections and osmotic diuresis-related adverse events. CONCLUSION Canagliflozin was found to reduce HbA1c, fasting and postmeal glucose, body weight, BP, and triglycerides, and it was generally well tolerated in patients with T2DM.
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Abstract
Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycemia by increasing urinary glucose excretion. They have been evaluated in patients with type 2 diabetes treated with diet/exercise, metformin, dual oral therapy or insulin. Three agents are available in Europe and the USA (canagliflozin, dapagliflozin, empagliflozin) and others are commercialized in Japan or in clinical development. SGLT2 inhibitors reduce glycated hemoglobin, with a minimal risk of hypoglycemia. They exert favorable effects beyond glucose control with consistent body weight, blood pressure, and serum uric acid reductions. Empagliflozin showed remarkable reductions in cardiovascular/all-cause mortality and in hospitalization for heart failure in patients with previous cardiovascular disease. Positive renal outcomes were also shown with empagliflozin. Mostly reported adverse events are genital mycotic infections, while urinary tract infections and events linked to volume depletion are rather rare. Concern about a risk of ketoacidosis and bone fractures has been recently raised, which deserves caution and further evaluation.
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Affiliation(s)
- André J Scheen
- Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.
- Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium.
- Department of Medicine, CHU Sart Tilman (B35), B-4000, Liege 1, Belgium.
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Marín-Peñalver JJ, Martín-Timón I, Sevillano-Collantes C, del Cañizo-Gómez FJ. Update on the treatment of type 2 diabetes mellitus. World J Diabetes 2016; 7:354-95. [PMID: 27660695 PMCID: PMC5027002 DOI: 10.4239/wjd.v7.i17.354] [Citation(s) in RCA: 366] [Impact Index Per Article: 40.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 07/02/2016] [Accepted: 07/20/2016] [Indexed: 02/05/2023] Open
Abstract
To achieve good metabolic control in diabetes and keep long term, a combination of changes in lifestyle and pharmacological treatment is necessary. Achieving near-normal glycated hemoglobin significantly, decreases risk of macrovascular and microvascular complications. At present there are different treatments, both oral and injectable, available for the treatment of type 2 diabetes mellitus (T2DM). Treatment algorithms designed to reduce the development or progression of the complications of diabetes emphasizes the need for good glycaemic control. The aim of this review is to perform an update on the benefits and limitations of different drugs, both current and future, for the treatment of T2DM. Initial intervention should focus on lifestyle changes. Moreover, changes in lifestyle have proven to be beneficial, but for many patients is a complication keep long term. Physicians should be familiar with the different types of existing drugs for the treatment of diabetes and select the most effective, safe and better tolerated by patients. Metformin remains the first choice of treatment for most patients. Other alternative or second-line treatment options should be individualized depending on the characteristics of each patient. This article reviews the treatments available for patients with T2DM, with an emphasis on agents introduced within the last decade.
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19
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Glycemic Control Outcomes After Canagliflozin Initiation: Observations in a Medicare and Commercial Managed Care Population in Clinical Practice. Clin Ther 2016; 38:2046-2057.e2. [DOI: 10.1016/j.clinthera.2016.07.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Revised: 07/12/2016] [Accepted: 07/13/2016] [Indexed: 11/23/2022]
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21
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Abstract
INTRODUCTION Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) offer a new opportunity for the management of type 2 diabetes mellitus. These agents reduce hyperglycemia by decreasing the renal glucose threshold and thereby increasing urinary glucose excretion. Subsequent reduction of glucotoxicity improves beta-cell sensitivity to glucose and tissue insulin sensitivity. AREAS COVERED This article analyzes the efficacy and safety data of canagliflozin, dapagliflozin and empagliflozin in randomized controlled trials of 24 - 104 weeks duration, compared with placebo or an active comparator, in patients treated with diet/exercise, metformin, dual oral therapy or insulin. EXPERT OPINION SGLT2 inhibitors significantly and consistently reduce glycated hemoglobin, with a minimal risk of hypoglycemia. The improvement of glucose control is similar or slightly better compared with metformin, sulfonylureas or sitagliptin, with the add-on value of significant reductions in body weight and blood pressure. However, caution is recommended in fragile elderly patients and patients with chronic kidney disease. An increased risk of genital mycotic infections is observed, but urinary tract infections are rare. Concern about an unexpected risk of euglycemic ketoacidosis has been recently reported. A possible renal protection deserves further attention. A remarkable reduction in cardiovascular mortality was reported in EMPA-REG OUTCOME with empagliflozin.
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Affiliation(s)
- André J Scheen
- a Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM) , University of Liège , Liège , Belgium.,b Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine , CHU Liège , Liège B-4000 , Belgium
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22
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Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs 2015; 75:33-59. [PMID: 25488697 DOI: 10.1007/s40265-014-0337-y] [Citation(s) in RCA: 381] [Impact Index Per Article: 38.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Inhibitors of sodium-glucose co-transporter type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus (T2DM). Several compounds are already available in many countries (dapagliflozin, canagliflozin, empagliflozin and ipragliflozin) and some others are in a late phase of development. The available SGLT2 inhibitors share similar pharmacokinetic characteristics, with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites, the absence of clinically relevant drug-drug interactions and a low renal elimination as parent drug. SGLT2 co-transporters are responsible for reabsorption of most (90 %) of the glucose filtered by the kidneys. The pharmacological inhibition of SGLT2 co-transporters reduces hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. The amount of glucose excreted in the urine depends on both the level of hyperglycaemia and the glomerular filtration rate. Results of numerous placebo-controlled randomised clinical trials of 12-104 weeks duration have shown significant reductions in glycated haemoglobin (HbA1c), resulting in a significant increase in the proportion of patients reaching HbA1c targets, and a significant lowering of fasting plasma glucose when SGLT2 inhibitors were administered as monotherapy or in addition to other glucose-lowering therapies including insulin in patients with T2DM. In head-to-head trials of up to 2 years, SGLT2 inhibitors exerted similar glucose-lowering activity to metformin, sulphonylureas or sitagliptin. The durability of the glucose-lowering effect of SGLT2 inhibitors appears to be better; however, this remains to be more extensively investigated. The risk of hypoglycaemia was much lower with SGLT2 inhibitors than with sulphonylureas and was similarly low as that reported with metformin, pioglitazone or sitagliptin. Increased renal glucose elimination also assists weight loss and could help to reduce blood pressure. Both effects were very consistent across the trials and they represent some advantages for SGLT2 inhibitors when compared with other oral glucose-lowering agents. The pharmacodynamic response to SGLT2 inhibitors declines with increasing severity of renal impairment, and prescribing information for each SGLT2 inhibitor should be consulted regarding dosage adjustments or restrictions in moderate to severe renal dysfunction. Caution is also recommended in the elderly population because of a higher risk of renal impairment, orthostatic hypotension and dehydration, even if the absence of hypoglycaemia represents an obvious advantage in this population. The overall effect of SGLT2 inhibitors on the risk of cardiovascular disease is unknown and will be evaluated in several ongoing prospective placebo-controlled trials with cardiovascular outcomes. The impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy also deserve more attention. SGLT2 inhibitors are generally well-tolerated. The most frequently reported adverse events are female genital mycotic infections, while urinary tract infections are less commonly observed and generally benign. In conclusion, with their unique mechanism of action that is independent of insulin secretion and action, SGLT2 inhibitors are a useful addition to the therapeutic options available for the management of T2DM at any stage in the natural history of the disease. Although SGLT2 inhibitors have already been extensively investigated, further studies should even better delineate the best place of these new glucose-lowering agents in the already rich armamentarium for the management of T2DM.
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Abstract
The prevalence of obesity is increasing in the elderly population. The primary goal of obesity therapy in elderly is the improvement of metabolic complications and the prevention of severe functional limitations. Clinical studies could demonstrate that the combination of nutritional intervention and physical exercise is of advantage to improve the functional status. Study evidence about the efficacy and safety of medication for weight reduction in elderly is limited, and the risks of bariatric surgery outweigh the possible benefits. The test battery of the comprehensive geriatric assessment is an important tool to determine body composition, nutritional status as well as functional and cognitive capacities of the elderly patient. These results are of central importance for the treatment plan and goals.
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Affiliation(s)
- Monika Lechleitner
- a Department of Internal Medicine, Hospital Hochzirl, A-6170 Zirl, Austria
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Ponticelli C, Sala G, Glassock RJ. Drug management in the elderly adult with chronic kidney disease: a review for the primary care physician. Mayo Clin Proc 2015; 90:633-45. [PMID: 25771152 DOI: 10.1016/j.mayocp.2015.01.016] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Revised: 01/17/2015] [Accepted: 01/21/2015] [Indexed: 12/23/2022]
Abstract
With advancing age, the functional reserve of many organs tends to decrease. In particular, the lean body mass, the levels of serum albumin, the blood flow to the liver, and the glomerular filtration rate are reduced in elderly individuals and can be further impaired by the concomitant presence of acute or chronic kidney disease. Moreover, patients with kidney disease are often affected by comorbid processes and are prescribed multiple medications. The aging process also modifies some drug interactions, including the affinity of some drugs for their receptor, the number of receptors, and the cell responses upon receptor activation. Therefore, older patients with kidney disease are particularly susceptible to the risks of adverse drug reactions. Planning a pharmacological regimen in such patients is confounded by the paucity of information available on the pharmacokinetic and pharmacodynamic profiles of a large number of drugs commonly used in this group of patients. Finally, many aged patients suffer from unintentional poor compliance. In this review, the problems physicians face in designing safe and effective medication management in elderly individuals are discussed, paying attention to those more frequently used, which may be potentially harmful in patients with kidney disease. The risks of overdosing and underdosing are outlined, and some recommendations to reduce the risk of adverse drug reactions are provided. A review of the literature covering the field of drug management in older patients with kidney disease was performed by selecting those articles published between January 1, 1990, and December 1, 2014, using PubMed as a search engine with the keywords elderly, kidney disease, drugs, drug interaction, and renal function.
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Affiliation(s)
- Claudio Ponticelli
- Nephrology and Dialysis Unit, Humanitas Clinical Research Center, Rozzano, Milano, Italy.
| | - Gabriele Sala
- Nephrology and Dialysis Unit, Humanitas Clinical Research Center, Rozzano, Milano, Italy
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Amblee A. Patient profiling in diabetes and role of canagliflozin. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2014; 7:367-77. [PMID: 25540592 PMCID: PMC4270036 DOI: 10.2147/52761.s0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background Physicians attempt to achieve glycemic goals in patients with type 2 diabetes mellitus (T2DM) through various means, including glucose-lowering medications. There is interindividual variability in response to medications, which can be partially explained by the presence of genetic polymorphisms that affect drug metabolism. Pharmacogenomics studies the hereditary basis of interpatient variations in drug response and aims to identify subgroups of patients whose drug management could be tailored accordingly. The aim of this review is to explore patient profiling in the management of T2DM with a focus on the sodium glucose transporter inhibitor canagliflozin. Methods The PubMed database was searched using the terms “pharmacogenomics” and “diabetes” through May 31, 2014. Published articles and abstracts presented at national/international meetings were considered. Results and conclusion Genome-wide association studies have opened the door for patient profiling and research into genetic variants in multifactorial T2DM. Clinically, it may be possible to tailor the type of medication used based on the presence or absence of the various genetic variants. However, the polymorphisms studied may only explain some of the variability in response to T2DM drugs and needs further validation to ensure its authenticity. There are still unidentified factors which appear to play a role in the interindividual variability seen in clinical practice. The potential exists for pharmacogenomics to promote efficacious, safe, and cost-effective individualized diabetes management. Pharmacogenomics is still in its early stages, and the idea of defining patients genetically to predict individual responses to drugs and obtain safe and effective T2DM management is promising, in spite of existing barriers. Currently, clinical profiling of patients with T2DM and using an individualized approach with most drugs, including canagliflozin, based on comorbid conditions still remains the most accepted approach for the management of T2DM.
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Affiliation(s)
- Ambika Amblee
- Division of Endocrinology, John H Stroger Jr Hospital of Cook County, Chicago, IL, USA ; Rush University Medical Center, Chicago, IL, USA
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26
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Du YF, Ou HY, Beverly EA, Chiu CJ. Achieving glycemic control in elderly patients with type 2 diabetes: a critical comparison of current options. Clin Interv Aging 2014; 9:1963-80. [PMID: 25429208 PMCID: PMC4241951 DOI: 10.2147/cia.s53482] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The prevalence of type 2 diabetes mellitus (T2DM) is increasing in the elderly. Because of the unique characteristics of elderly people with T2DM, therapeutic strategy and focus should be tailored to suit this population. This article reviews the guidelines and studies related to older people with T2DM worldwide. A few important themes are generalized: 1) the functional and cognitive status is critical for older people with T2DM considering their life expectancy compared to younger counterparts; 2) both severe hypoglycemia and persistent hyperglycemia are deleterious to older adults with T2DM, and both conditions should be avoided when determining therapeutic goals; 3) recently developed guidelines emphasize the avoidance of hypoglycemic episodes in older people, even in the absence of symptoms. In addition, we raise the concern of glycemic variability, and discuss the rationale for the selection of current options in managing this patient population.
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Affiliation(s)
- Ye-Fong Du
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Horng-Yih Ou
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Elizabeth A Beverly
- Department of Social Medicine, Ohio University Heritage College of Osteopathic Medicine, Athens, OH, USA
| | - Ching-Ju Chiu
- Institute of Gerontology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Haas B, Eckstein N, Pfeifer V, Mayer P, Hass MDS. Efficacy, safety and regulatory status of SGLT2 inhibitors: focus on canagliflozin. Nutr Diabetes 2014; 4:e143. [PMID: 25365416 PMCID: PMC4259905 DOI: 10.1038/nutd.2014.40] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 09/16/2014] [Accepted: 09/24/2014] [Indexed: 02/06/2023] Open
Abstract
Prevalence of diabetes mellitus is inc6reasing, with a burden of 382 million patients worldwide at present (more than the entire US population). The International Diabetes Federation anticipates an increase up to 592 million patients by 2035. Another major problem arises from the fact that just 50% of patients with type 2 diabetes mellitus are at target glycaemic control with currently available medications. Therefore, a clear need for new therapies that aim to optimize glycaemic control becomes evident. Renal sodium-linked glucose transporter 2 inhibitors are new antidiabetic drugs with an insulin-independent mechanism of action. They pose one remarkable advantage compared with already established antidiabetics: increasing urinary glucose excretion without inducing hypoglycaemia, thereby promoting body weight reduction due to loss of ~300 kcal per day. This review focuses on canagliflozin, which was the first successful compound of this class to be approved by both the US Food and Drug Administration and the European Medicines Agency in 2013. Clinical trials showed promising results: enhancing glycaemic control was paralleled by reducing body weight and systolic and diastolic blood pressure. Nevertheless, some safety concerns remain, such as genital mycotic infections, urinary tract infections and cardiovascular risks in vulnerable patients, which will be closely monitored in several post-authorization safety studies.
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Affiliation(s)
- B Haas
- Federal Institute for Drugs and Medical Devices, Bonn, Germany
| | - N Eckstein
- Federal Institute for Drugs and Medical Devices, Bonn, Germany
- Applied Pharmacy, University of Applied Sciences Kaiserslautern, Campus Pirmasens, Carl-Schurz-Str. 10–16, Pirmasens, Germany
| | - V Pfeifer
- Federal Institute for Drugs and Medical Devices, Bonn, Germany
| | - P Mayer
- Federal Institute for Drugs and Medical Devices, Bonn, Germany
| | - M D S Hass
- Federal Institute for Drugs and Medical Devices, Bonn, Germany
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