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Alshahrani MY, Ebrahim HA, Alqahtani SM, Bayoumy NM, Kamar SS, ShamsEldeen AM, Haidara MA, Al-Ani B, Albawardi A. Metformin Suppresses Thioacetamide-Induced Chronic Kidney Disease in Association with the Upregulation of AMPK and Downregulation of Oxidative Stress and Inflammation as Well as Dyslipidemia and Hypertension. Molecules 2023; 28:2756. [PMID: 36985728 PMCID: PMC10056045 DOI: 10.3390/molecules28062756] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/09/2023] [Accepted: 03/15/2023] [Indexed: 03/22/2023] Open
Abstract
Toxic chemicals such as carbon tetrachloride and thioacetamide (TAA) are reported to induce hepato-nephrotoxicity. The potential protective outcome of the antidiabetic and pleiotropic drug metformin against TAA-induced chronic kidney disease in association with the modulation of AMP-activated protein kinase (AMPK), oxidative stress, inflammation, dyslipidemia, and systemic hypertension has not been investigated before. Therefore, 200 mg/kg TAA was injected (via the intraperitoneal route) in a model group of rats twice a week starting at week 3 for 8 weeks. The control rats were injected with the vehicle for the same period. The metformin-treated group received 200 mg/kg metformin daily for 10 weeks, beginning week 1, and received TAA injections with dosage and timing similar to those of the model group. All rats were culled at week 10. It was observed that TAA induced substantial renal injury, as demonstrated by significant kidney tissue damage and fibrosis, as well as augmented blood and kidney tissue levels of urea, creatinine, inflammation, oxidative stress, dyslipidemia, tissue inhibitor of metalloproteinases-1 (TIMP-1), and hypertension. TAA nephrotoxicity substantially inhibited the renal expression of phosphorylated AMPK. All these markers were significantly protected by metformin administration. In addition, a link between kidney fibrosis and these parameters was observed. Thus, metformin provides profound protection against TAA-induced kidney damage and fibrosis associated with the augmentation of the tissue protective enzyme AMPK and inhibition of oxidative stress, inflammation, the profibrogenic gene TIMP-1, dyslipidemia, and hypertension for a period of 10 weeks in rats.
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Affiliation(s)
- Mohammad Y. Alshahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha 61413, Saudi Arabia
| | - Hasnaa A. Ebrahim
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Saeed M. Alqahtani
- Department of Surgery, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia
| | - Nervana M. Bayoumy
- Department of Physiology, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
| | - Samaa S. Kamar
- Department of Histology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo 11566, Egypt
- Histology Department, Armed Forces College of Medicine, Cairo 11566, Egypt
| | - Asmaa M. ShamsEldeen
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo 11566, Egypt
| | - Mohamed A. Haidara
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo 11566, Egypt
| | - Bahjat Al-Ani
- Department of Physiology, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia
| | - Alia Albawardi
- Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 15551, United Arab Emirates
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Dagorn PG, Buchholz B, Kraus A, Batchuluun B, Bange H, Blockken L, Steinberg GR, Moller DE, Hallakou-Bozec S. A novel direct adenosine monophosphate kinase activator ameliorates disease progression in preclinical models of Autosomal Dominant Polycystic Kidney Disease. Kidney Int 2023; 103:917-929. [PMID: 36804411 DOI: 10.1016/j.kint.2023.01.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 01/13/2023] [Accepted: 01/27/2023] [Indexed: 02/21/2023]
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) mainly results from mutations in the PKD1 gene, which encodes polycystin 1. It is the most common inherited kidney disease and is characterized by a progressive bilateral increase in cyst number and size, often leading to kidney failure. The cellular energy sensor and regulator adenosine monophosphate stimulated protein kinase (AMPK) has been implicated as a promising new therapeutic target. To address this hypothesis, we determined the effects of a potent and selective clinical stage direct allosteric AMPK activator, PXL770, in canine and patient-derived 3D cyst models and an orthologous mouse model of ADPKD. PXL770 induced AMPK activation and dose-dependently reduced cyst growth in principal-like Madin-Darby Canine Kidney cells stimulated with forskolin and kidney epithelial cells derived from patients with ADPKD stimulated with desmopressin. In an inducible, kidney epithelium-specific Pkd1 knockout mouse model, PXL770 produced kidney AMPK pathway engagement, prevented the onset of kidney failure (reducing blood urea by 47%), decreased cystic index by 26% and lowered the kidney weight to body weight ratio by 35% compared to untreated control Pkd1 knockout mice. These effects were accompanied by a reduction of markers of cell proliferation (-48%), macrophage infiltration (-53%) and tissue fibrosis (-37%). Thus, our results show the potential of direct allosteric AMPK activation in the treatment of ADPKD and support the further development of PXL770 for this indication.
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Affiliation(s)
| | - Bjoern Buchholz
- Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Andre Kraus
- Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Battsetseg Batchuluun
- Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine and Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Hester Bange
- Crown Bioscience Netherlands B.V., The Netherlands
| | | | - Gregory R Steinberg
- Centre for Metabolism, Obesity and Diabetes Research, Department of Medicine and Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
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Sourij H, Edlinger R, Prischl FC, Kaser S, Horn S, Antlanger M, Paulweber B, Aberer F, Brix J, Cejka D, Stingl H, Kautzky-Willer A, Schmaldienst S, Clodi M, Rosenkranz A, Mayer G, Oberbauer R, Säemann M. [Diabetic kidney disease (update 2023) : Position paper of the Austrian Diabetes Association and the Austrian Society for Nephrology]. Wien Klin Wochenschr 2023; 135:182-194. [PMID: 37101040 PMCID: PMC10133372 DOI: 10.1007/s00508-022-02147-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/21/2022] [Indexed: 04/28/2023]
Abstract
Epidemiological investigations have shown that approximately 2-3% of all Austrians have diabetes mellitus with renal involvement, leaving 250,000 people in Austria affected. The risk of occurrence and progression of this disease can be attenuated by lifestyle interventions as well as optimization of blood pressure, blood glucose control and special drug classes. The present article represents the joint recommendations of the Austrian Diabetes Association and the Austrian Society of Nephrology for the diagnostic and treatment strategies of diabetic kidney disease.
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Affiliation(s)
- Harald Sourij
- Klinische Abteilung für Endokrinologie und Diabetologie, Trials Unit für Interdisziplinäre Metabolische Medizin, Medizinische Universität Graz, Auenbruggerplatz 15, 8036, Graz, Österreich.
| | - Roland Edlinger
- 3. Medizinische Abteilung mit Stoffwechselerkrankungen und Nephrologie, Klinik Hietzing, Wien, Österreich
| | - Friedrich C Prischl
- Abteilung für Innere Medizin IV, Klinikum Wels-Grieskirchen, Wels, Österreich
| | - Susanne Kaser
- Universitätsklinik für Innere Medizin I, Medizinische Universität Innsbruck, Innsbruck, Österreich
| | - Sabine Horn
- Abteilung für Innere Medizin, LKH Villach, Villach, Österreich
| | - Marlies Antlanger
- Universitätsklinik für Innere Medizin 2, Kepler Universitätsklinikum Linz, Linz, Österreich
| | - Bernhard Paulweber
- Universitätsklinik für Innere Medizin I, Landeskrankenhaus Salzburg, Uniklinikum der PMU, Salzburg, Österreich
| | - Felix Aberer
- Klinische Abteilung für Endokrinologie und Diabetologie, Medizinische Universität Graz, Graz, Österreich
| | - Johanna Brix
- 1. Medizinischen Abteilung mit Diabetologie, Endokrinologie und Nephrologie, Klinik Landstraße, Wien, Österreich
| | - Daniel Cejka
- Abteilung für Innere Medizin 3, Ordensklinikum Linz, Elisabethinen, Linz, Österreich
| | - Harald Stingl
- Abteilung für Innere Medizin, LKH Melk, Melk, Österreich
| | - Alexandra Kautzky-Willer
- Klinische Abteilung für Endokrinologie und Stoffwechsel, Universitätsklinik für Innere Medizin III, Medizinische Universität Wien, Wien, Österreich
| | | | - Martin Clodi
- Abteilung für Innere Medizin, Krankenhaus Barmherzige Brüder Linz, Linz, Österreich
| | - Alexander Rosenkranz
- Klinische Abteilung für Nephrologie, Universitätsklinik für Innere Medizin, Medizinische Universität Graz, Graz, Österreich
| | - Gert Mayer
- Nephrologie und Hypertensiologie, Universitätsklinik für Innere Medizin IV, Medizinische Universität Innsbruck, Innsbruck, Österreich
| | - Rainer Oberbauer
- Klinische Abteilung für Nephrologie und Dialyse, Universitätsklinik für Innere Medizin III, Medizinische Universität Wien, Wien, Österreich
| | - Marcus Säemann
- 6. Medizinische Abteilung mit Nephrologie & Dialyse, Klinik Ottakring, Wien, Österreich
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Hu Y, Lei M, Ke G, Huang X, Peng X, Zhong L, Fu P. Metformin Use and Risk of All-Cause Mortality and Cardiovascular Events in Patients With Chronic Kidney Disease-A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 2020; 11:559446. [PMID: 33117278 PMCID: PMC7575818 DOI: 10.3389/fendo.2020.559446] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 09/15/2020] [Indexed: 02/05/2023] Open
Abstract
Background To evaluate whether metformin use assuredly alters overall all-cause death in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Methods Pubmed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials were systematically searched from inception to Feb. 29, 2020 with no language restriction. All related articles comparing all-cause death of T2DM and CKD patients after metformin use (monotherapy or combination) versus non-metformin treatment were identified. Pooled risk ratios (RR) and 95% confidence intervals (CI) were computed using random-effects models regardless of the heterogeneity quantified by Cochrane χ2 and I2 statistics. Results Totally 13 studies (9 cohort studies [CSs], 3 subanalyses or post-hoc analyses of randomized controlled trials [RCTs], and 1 nested case-control article) involving 303,540 patients were included. Metformin-based treatments relative to any other measure displayed significantly lower risks of all-cause mortality (Pooled RRs 0.71, 95%CI 0.61 to 0.84; I2 = 79.0%) and cardiovascular events (Pooled RRs 0.76, 95%CI 0.60 to 0.97; I2 = 87.0%) in CKD patients at stage G1-3, with substantial heterogeneity. Metformin use was not significantly related with these end points in advanced CKD patients. Conclusions Metformin use is connected with significantly less risks of all-cause mortality and cardiovascular events in patients with T2DM and mild/moderate CKD. However, RCTs with large sample sizes are warranted in the future to assess whether these key benefits extend to later stages of CKD by dose adjustment.
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Affiliation(s)
- Yao Hu
- Department of Medicine Renal Division, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
- Department of Medicine Renal Division, Affiliated Hospital & Clinical Medical College of Chengdu University, Chengdu, China
| | - Min Lei
- Department of Medicine Renal Division, Affiliated Hospital & Clinical Medical College of Chengdu University, Chengdu, China
| | - Guibao Ke
- Department of Medicine Renal Division, Affiliated Hospital & Clinical Medical College of Chengdu University, Chengdu, China
| | - Xin Huang
- Department of Medicine Renal Division, Affiliated Hospital & Clinical Medical College of Chengdu University, Chengdu, China
| | - Xuan Peng
- Department of Medicine Renal Division, Affiliated Hospital & Clinical Medical College of Chengdu University, Chengdu, China
| | - Lihui Zhong
- Department of Medicine Renal Division, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China
| | - Ping Fu
- Department of Medicine Renal Division, West China Hospital, West China School of Medicine, Sichuan University, Kidney Research Institute, Chengdu, China
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Mato Mofo EP, Essop MF, Owira PMO. Citrus fruit-derived flavonoid naringenin and the expression of hepatic organic cation transporter 1 protein in diabetic rats treated with metformin. Basic Clin Pharmacol Toxicol 2020; 127:211-220. [PMID: 32180335 DOI: 10.1111/bcpt.13407] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 03/12/2020] [Indexed: 12/16/2022]
Abstract
Naringenin possesses many pharmacological effects and may modulate metformin disposition. The purpose of this study was to evaluate the role of naringenin on hepatic expression of organic cation transporter 1 (OCT1) protein and its associated effects on metformin-associated hyperlactataemia in diabetes. Forty-nine male Sprague Dawley rats randomly assigned to seven groups (n = 7) were orally treated daily with 3.0 mL/kg body-weight (BW) of distilled water (group 1) or 60 mg/kg BW of naringenin (groups 2 and 5) or 250 mg/kg BW of metformin (groups 3 and 6), respectively, dissolved in distilled water. Similarly, group 7 was given metformin and naringenin. Groups 4, 5, 6 and 7 were administered intraperitoneally with streptozotocin at a single dose of 60 mg/kg BW to induce diabetes. Glucose tolerance tests were performed. The animals were killed after 8 weeks of treatment, blood was collected, and livers excised for further biochemical analysis. Lowered body-weight, increased polydipsia and reduced hepatic glycogen concentrations were observed in diabetic rats compared to controls. Naringenin only significantly decreased plasma lactate levels, while metformin only or with naringenin significantly increased plasma lactate levels in diabetic compared to non-treated diabetic animals. Metformin only but not naringenin significantly increased plasma lactate levels in non-diabetic compared to control rats. Furthermore, naringenin with or without metformin but not metformin only significantly increased hepatic organic cation transporter 1 (OCT1) expression in diabetic compared to non-treated diabetic rats. Contrastingly, metformin only but not naringenin significantly increased hepatic OCT1 expression in non-diabetic rats compared to controls. Diabetic rats treated with metformin exhibited significantly increased plasma metformin concentrations compared to non-diabetic but naringenin significantly dropped this parameter. Conversely, hepatic metformin concentrations were significantly lower in diabetic rats treated with metformin compared to non-diabetic rats but significantly increased when naringenin was added. These results suggest that naringenin ameliorated hyperglycaemia-induced reduction in hepatic OCT1 expression leading to metformin accumulation and increased lactic acid production.
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Affiliation(s)
- Edith P Mato Mofo
- Molecular and Clinical Pharmacology Research Laboratory, Department of Pharmacology, Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - M Faadiel Essop
- Cardio-Metabolic Research Group (CMRG), Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - Peter M O Owira
- Molecular and Clinical Pharmacology Research Laboratory, Department of Pharmacology, Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
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Al-Hwiesh AK, Abdul-Rahman IS, Noor AS, Nasr-El-Deen MA, Abdelrahman A, El-Salamoni TS, Al-Muhanna FA, Al-Otaibi K, Al-Audah N. The Phantom of Metformin-Induced Lactic Acidosis in End-Stage Renal Disease Patients: Time to Reconsider with Peritoneal Dialysis Treatment. Perit Dial Int 2020; 37:56-62. [DOI: 10.3747/pdi.2015.00309] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Accepted: 05/17/2016] [Indexed: 01/22/2023] Open
Abstract
ObjectiveMetformin continues to be the safest and most widely used antidiabetic drug. In spite of its well-known benefits; metformin use in end-stage renal disease (ESRD) patients is still restricted. Little has been reported about the effect of peritoneal dialysis (PD) on metformin clearance and the phantom of lactic acidosis deprives ESRD patients from metformin therapeutic advantages. Peritoneal dialysis is probably a safeguard against lactic acidosis, and it is likely that using this drug would be feasible in this group of patients.Material and methodsThe study was conducted on 83 PD patients with type 2 diabetes mellitus. All patients were on automated PD (APD). Metformin was administered in a dose of 500 - 1,000 mg daily. Patients were monitored for glycemic control. Plasma lactic acid and plasma metformin levels were monitored on a scheduled basis. Peritoneal fluid metformin levels were measured. In addition, the relation between plasma metformin and plasma lactate was studied.ResultsMean fasting blood sugar (FBS) was 10.9 ± 0.5 and 7.8 ± 0.7, and mean hemoglobin A1-C (HgA1C) was 8.2 ± 0.8 and 6.4 ± 1.1 at the beginning and end of the study, respectively (p < 0.001). The mean body mass index (BMI) was 29.1 ± 4.1 and 27.3 ± 4.5 at the beginning and at the end of the study, respectively (p < 0.001). The overall mean plasma lactate level across all blood samples was 1.44 ± 0.6. Plasma levels between 2 and 3 mmol/L were found in 11.8% and levels of 3 - 3.6 mmol/L in 2.4% plasma samples. Hyperlactemia (level > 2 and < 5 mmol/L) was not associated with overt acidemia. None of our patients had lactic acidosis (levels > 5 mmol/L). Age ≥ 60 was a predictor for hyperlactemia. No relationship was found between plasma metformin and lactate levels.ConclusionMetformin may be used with caution in a particular group of ESRD patients who are on APD. Metformin allows better diabetic control with significant reduction of BMI. Information on the relationship between metformin and plasma lactate levels is lacking. Peritoneal dialysis appears to be a safeguard against the development of lactic acidosis in this group of patients.
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Affiliation(s)
| | | | - Abdul-Salam Noor
- Department of Internal Medicine, Queens University, Kingston, Ontario, Canada
| | | | - Abdalla Abdelrahman
- Nephrology Division, King Fahd Hospital of the University, University of Dammam, Saudi Arabia; and Department of Electrical Engineering, Queens University, Kingston, Ontario, Canada
| | | | - Fahd A. Al-Muhanna
- Department of Internal Medicine, Queens University, Kingston, Ontario, Canada
| | - Khalid Al-Otaibi
- Department of Internal Medicine, Queens University, Kingston, Ontario, Canada
| | - Nehad Al-Audah
- Department of Internal Medicine, Queens University, Kingston, Ontario, Canada
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Akhter MS, Uppal P. Toxicity of Metformin and Hypoglycemic Therapies. Adv Chronic Kidney Dis 2020; 27:18-30. [PMID: 32146997 DOI: 10.1053/j.ackd.2019.08.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 08/01/2019] [Indexed: 12/15/2022]
Abstract
Metformin along with other antidiabetic medications provide benefit to patients in the treatment of type 2 diabetes mellitus, but caution is advised in certain scenarios to avoid toxicity in kidney disease. Renal dosing, monitoring of kidney function, and evaluating the risk of developing serious side effects are warranted with some agents. The available literature with regard to incidence of adverse events and toxicity of hypoglycemic therapies is reviewed.
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Integration of immunogenic activation and immunosuppressive reversion using mitochondrial-respiration-inhibited platelet-mimicking nanoparticles. Biomaterials 2019; 232:119699. [PMID: 31891817 DOI: 10.1016/j.biomaterials.2019.119699] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 11/20/2019] [Accepted: 12/16/2019] [Indexed: 12/28/2022]
Abstract
Here, we developed platelet membranes (PM) as nano-carriers to co-encapsulate metformin (Met) and IR780 (PM-IR780-Met NPs). The resulting nano-carrier ensured a longer circulation lifetime and facilitated the greater accumulation of IR780 and Met in tumors owing to the active adhesion between PM and tumor cells. As a photodynamic therapy (PDT) agent, IR780 could effectively kill the tumor by producing toxic reactive singlet oxygen species (ROS), while the introduction of Met inhibited mitochondrial respiration and reduced tumor oxygen consumption, thereby evoking an oxygen-boosted PDT and propelling the immunogenic cell death (ICD)-based immunogenic pathway. Meanwhile, the reversed tumor hypoxia also impeded the myeloid derived suppressor cell (MDSC)-regulated immunosuppressive pathway. Finally, tremendous T cells were recruited and activated, providing a promising platform to eliminate the primary tumors and synchronously opening a new avenue for the effective ablation of tumor metastasis.
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Rhee JJ, Han J, Montez-Rath ME, Kim SH, Cullen MR, Stafford RS, Winkelmayer WC, Chertow GM. Antidiabetic medication use in patients with type 2 diabetes and chronic kidney disease. J Diabetes Complications 2019; 33:107423. [PMID: 31537413 PMCID: PMC6823164 DOI: 10.1016/j.jdiacomp.2019.107423] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 08/19/2019] [Accepted: 08/19/2019] [Indexed: 10/26/2022]
Abstract
AIMS To quantify patterns of conventional and newer antidiabetic medication use in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). METHODS We used data from a large claims and integrated dataset that includes employed and commercially insured patients in the US to select patients who had T2DM and CKD with information on laboratory values and prescriptions for antidiabetic medications from January 1, 2014 to January 1, 2015. We stratified the analyses by sociodemographic variables. RESULTS In a cohort of 38,577 patients with T2DM and CKD, we found wide variation in the treatment of T2DM by CKD stage as well as by several sociodemographic factors. Although metformin was the most commonly prescribed medication, only about half of patients in the cohort and fewer than two-thirds of patients with early stage CKD were prescribed metformin. Approximately 10.6% of patients with CKD stage 4 and 2.1% of the patients with CKD stage 5 were prescribed metformin. Sulfonylureas with active metabolites that accumulate with impaired kidney function were prescribed in more than one-third of patients with CKD stages 3b, 4, and 5. Only 3.4% and 12.3% of patients were prescribed GLP-1 and DPP-4 respectively. CONCLUSIONS Prescriptions for metformin were lower than expected among patients with mild to moderate CKD. Prescriptions for newer antidiabetic medications with known safety and efficacy across the spectrum of CKD remained low. Prescriptions for agents contraindicated in advanced CKD continued to be written in a sizeable fraction of patients.
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Affiliation(s)
- Jinnie J Rhee
- Division of Nephrology, Stanford University School of Medicine, Stanford, CA, United States; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, United States.
| | - Jialin Han
- Division of Nephrology, Stanford University School of Medicine, Stanford, CA, United States
| | - Maria E Montez-Rath
- Division of Nephrology, Stanford University School of Medicine, Stanford, CA, United States
| | - Sun H Kim
- Division of Endocrinology, Gerontology, and Metabolism, Stanford University School of Medicine, Stanford, CA, United States; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, United States
| | - Mark R Cullen
- Division of Primary Care and Population health, Stanford University School of Medicine, Stanford, CA, United States
| | - Randall S Stafford
- Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, United States
| | - Wolfgang C Winkelmayer
- Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Glenn M Chertow
- Division of Nephrology, Stanford University School of Medicine, Stanford, CA, United States; Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, United States
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Zuo H, Tao J, Shi H, He J, Zhou Z, Zhang C. Platelet-mimicking nanoparticles co-loaded with W 18O 49 and metformin alleviate tumor hypoxia for enhanced photodynamic therapy and photothermal therapy. Acta Biomater 2018; 80:296-307. [PMID: 30223092 DOI: 10.1016/j.actbio.2018.09.017] [Citation(s) in RCA: 118] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 08/26/2018] [Accepted: 09/12/2018] [Indexed: 02/03/2023]
Abstract
W18O49-mediated photodynamic therapy (PDT) and photothermal therapy (PTT) are limited by the easily oxidized property and tumor hypoxia. Here, we report the development of platelet membranes as nanocarriers to co-load W18O49 nanoparticles (NPs) and metformin (PM-W18O49-Met NPs). Platelet membranes can protect W18O49 from oxidation and immune evasion, and increase the accumulation of W18O49 in tumor sites via the passive EPR effect and active adhesion between platelets and cancer cells. The introduction of metformin (Met), a typical anti-diabetic drug, can alleviate the tumor hypoxia through reducing oxygen consumption. As a result, ROS and heat generation are both greatly increased, as revealed by ROS/hypoxia imaging in vitro, IR thermal imaging in vivo and PET imaging in vivo. PM-W18O49-Met NPs show the improved therapeutic effects with greatly inhibited tumor growth and induced tumor cell apoptosis. Therefore, our work provides a novel strategy for simultaneous enhanced PDT and PTT, which is promising in bioapplication. STATEMENTE OF SIGNIFICANCE: W18O49-mediated photodynamic therapy and photothermal therapy are limited by the poor delivery of nanoparticles to tumors, the easily oxidized property, and tumor hypoxia environment, which will induce tumor treatment failure. Herein, we report the development of platelet membranes as nanocarriers to co-load W18O49 nanoparticles and metformin (PM-W18O49-Met NPs). Platelet membranes can protect W18O49 from oxidation and immune evasion, and increase the accumulation of W18O49 in tumor sites via the passive EPR effect and active adhesion. Metformin can alleviate the tumor hypoxia through reducing oxygen consumption. Hence, ROS and heat generation are both greatly increased. PM-W18O49-Met NPs show the improved therapeutic effects with greatly inhibited tumor growth and induced apoptosis. Therefore, our work provides a novel strategy in bioapplication.
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Affiliation(s)
- Huaqin Zuo
- Department of Nuclear Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Jiangsu 210008, PR China; Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Jiangsu 210008, PR China; Department of Hematology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Jiangsu 225001, PR China
| | - Junxian Tao
- Department of Endocrinology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Jiangsu 225001, PR China
| | - Hua Shi
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Jiangsu 210008, PR China
| | - Jian He
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Jiangsu 210008, PR China.
| | - Zhengyang Zhou
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, Jiangsu 210008, PR China.
| | - Chao Zhang
- Collaborative Innovation Center of Chemistry for Life Sciences, College of Engineering and Applied Sciences, Nanjing University, Jiangsu 210093, PR China.
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Qi H, Nielsen PM, Schroeder M, Bertelsen LB, Palm F, Laustsen C. Acute renal metabolic effect of metformin assessed with hyperpolarised MRI in rats. Diabetologia 2018; 61:445-454. [PMID: 28936623 DOI: 10.1007/s00125-017-4445-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 08/04/2017] [Indexed: 01/07/2023]
Abstract
AIMS/HYPOTHESIS Metformin inhibits hepatic mitochondrial glycerol phosphate dehydrogenase, thereby increasing cytosolic lactate and suppressing gluconeogenesis flux in the liver. This inhibition alters cytosolic and mitochondrial reduction-oxidation (redox) potential, which has been reported to protect organ function in several disease states including diabetes. In this study, we investigated the acute metabolic and functional changes induced by metformin in the kidneys of both healthy and insulinopenic Wistar rats used as a model of diabetes. METHODS Diabetes was induced by intravenous injection of streptozotocin, and kidney metabolism in healthy and diabetic animals was investigated 4 weeks thereafter using hyperpolarised 13C-MRI, Clark-type electrodes and biochemical analysis. RESULTS Metformin increased renal blood flow, but did not change total kidney oxygen consumption. In healthy rat kidneys, metformin increased [1-13C]lactate production and reduced mitochondrial [1-13C]pyruvate oxidation (decreased the 13C-bicarbonate/[1-13C]pyruvate ratio) within 30 min of administration. Corresponding alterations to indices of mitochondrial, cytosolic and whole-cell redox potential were observed. Pyruvate oxidation was maintained in the diabetic rats, suggesting that the diabetic state abrogates metabolic reprogramming caused by metformin. CONCLUSIONS/INTERPRETATION This study demonstrates that metformin-induced acute metabolic alterations in healthy kidneys favoured anaerobic metabolism at the expense of aerobic metabolism. The results suggest that metformin directly alters the renal redox state, with elevated renal cytosolic redox states as well as decreased mitochondrial redox state. These findings suggest redox biology as a novel target to eliminate the renal complications associated with metformin treatment in individuals with impaired renal function.
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Affiliation(s)
- Haiyun Qi
- MR Research Centre, Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark
| | - Per M Nielsen
- MR Research Centre, Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark
| | - Marie Schroeder
- MR Research Centre, Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark
| | - Lotte B Bertelsen
- MR Research Centre, Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark
| | - Fredrik Palm
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Christoffer Laustsen
- MR Research Centre, Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark.
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13
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Metformin prescribing in low-income and insured patients with prediabetes. J Am Pharm Assoc (2003) 2017; 57:483-487. [PMID: 28551306 DOI: 10.1016/j.japh.2017.04.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 03/16/2017] [Accepted: 04/06/2017] [Indexed: 11/21/2022]
Abstract
OBJECTIVES To describe prescribing patterns of metformin in low-income and Medicaid-insured patients with prediabetes and to identify common demographic characteristics and comorbid conditions of low-income and Medicaid-insured patients receiving metformin for treatment of prediabetes. DESIGN Retrospective observational study. SETTING AND PARTICIPANTS Patients (18-60 years old) who were enrolled in South Carolina Medicaid and diagnosed with prediabetes between January 2009 and December 2013. MAIN OUTCOME MEASURES Metformin prescribing to treat prediabetes identified from pharmacy claims. RESULTS Among 7102 patients who met the study criteria, 7.4% (n = 520) were prescribed metformin for prediabetes. Nearly 45% (n = 238) of eligible patients prescribed metformin initiated treatment within 30 days after diagnosis of prediabetes. Twenty-five percent of those prescribed metformin took 280 days or longer to initiate treatment after diagnosis of prediabetes. Older age, black race, managed care plan, comorbid hypertension and obesity, and longer enrollment period significantly increased the likelihood of metformin prescribing to treat prediabetes. CONCLUSION Prevalence of metformin prescription to treat prediabetes is less than 8% in low-income and Medicaid-insured patients. Sociodemographic characteristics and comorbid conditions influenced metformin prescribing in the low-income population.
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14
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Mary A, Hartemann A, Liabeuf S, Aubert CE, Kemel S, Salem JE, Cluzel P, Lenglet A, Massy ZA, Lalau JD, Mentaverri R, Bourron O, Kamel S. Association between metformin use and below-the-knee arterial calcification score in type 2 diabetic patients. Cardiovasc Diabetol 2017; 16:24. [PMID: 28202017 PMCID: PMC5311847 DOI: 10.1186/s12933-017-0509-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 02/05/2017] [Indexed: 12/14/2022] Open
Abstract
Background Vascular calcification (VC) is common in type 2 diabetes, and is associated with cardiovascular complications. Recent preclinical data suggest that metformin inhibits VC both in vitro and in animal models. However, metformin’s effects in patients with diabetic VC have not previously been characterized. The present study investigated the association between metformin use and lower-limb arterial calcification in patients with type 2 diabetes and high cardiovascular risk. Methods The DIACART cross-sectional cohort study included 198 patients with type 2 diabetes but without severe chronic kidney disease. Below-the-knee calcification scores were assessed by computed tomography and supplemented by colour duplex ultrasonography. Data on anti-diabetic drugs were carefully collected from the patients’ medical records and during patient interviews. Biochemical and clinical data were studied as potential confounding factors. Results Metformin-treated patients had a significantly lower calcification score than metformin-free patients (mean ± standard deviation: 2033 ± 4514 and 4684 ± 9291, respectively; p = 0.01). A univariate analysis showed that metformin was associated with a significantly lower prevalence of severe below-the-knee arterial calcification (p = 0.02). VC was not significantly associated with the use of other antidiabetic drugs, including sulfonylureas, insulin, gliptin, and glucagon like peptide-1 analogues. A multivariate logistic regression analysis indicated that the association between metformin use and calcification score (odds ratio [95% confidence interval] = 0.33 [0.11–0.98]; p = 0.045) was independent of age, gender, tobacco use, renal function, previous cardiovascular disease, diabetes duration, neuropathy, retinopathy, HbA1c levels, and inflammation. Conclusions In patients with type 2 diabetes, metformin use was independently associated with a lower below-the-knee arterial calcification score. This association may contribute to metformin’s well-known vascular protective effect. Further prospective investigations of metformin’s potential ability to inhibit VC in patients with and without type 2 diabetes are now needed to confirm these results.
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Affiliation(s)
- Aurélien Mary
- INSERM U-1088, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications, 80025, Amiens, France. .,Amiens University Medical Center, Pharmacy, 80054, Amiens, France. .,Universite de Picardie Jules Verne, UFR Pharmacie, 80025, Amiens, France.
| | - Agnes Hartemann
- Pitié Salpêtrière Hospital, Diabetology, 75005, Paris, France.,Universite Paris-Sorbonne, UMPC - Paris 06, 75005, Paris, Île-de-France, France.,INSERM UMR_S 1138, Centre de recherche des Cordeliers, 75006, Paris, France.,Institute of Cardiometabolism and Nutrition, Paris, France
| | - Sophie Liabeuf
- INSERM U-1088, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications, 80025, Amiens, France.,Universite de Picardie Jules Verne, UFR Pharmacie, 80025, Amiens, France.,Amiens University Hospital, Clinical Research Centre, Division of Clinical Pharmacology, 80054, Amiens, France
| | - Carole Elodie Aubert
- INSERM UMR_S 1138, Centre de recherche des Cordeliers, 75006, Paris, France.,Bern University Hospital, University of Bern, General Internal Medicine, 3012, Bern, Switzerland
| | - Salim Kemel
- Universite Paris-Sorbonne, UMPC - Paris 06, 75005, Paris, Île-de-France, France.,Pitié Salpêtrière Hospital, Cardiovascular and Interventional Radiology, 75005, Paris, France.,FRANCE2Biomedical Imaging Lab, 75006, Paris, France
| | - Joe Elie Salem
- Universite Paris-Sorbonne, UMPC - Paris 06, 75005, Paris, Île-de-France, France.,Institute of Cardiometabolism and Nutrition, Paris, France.,Pitié Salpêtrière Hospital, Pharmacology, 75005, Paris, France.,Pitié Salpêtrière Hospital, Clinical Investigation Center, CIC-1421, 75005, Paris, France
| | - Philippe Cluzel
- Universite Paris-Sorbonne, UMPC - Paris 06, 75005, Paris, Île-de-France, France.,Pitié Salpêtrière Hospital, Cardiovascular and Interventional Radiology, 75005, Paris, France.,FRANCE2Biomedical Imaging Lab, 75006, Paris, France
| | - Aurélie Lenglet
- INSERM U-1088, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications, 80025, Amiens, France.,Amiens University Medical Center, Pharmacy, 80054, Amiens, France.,Universite de Picardie Jules Verne, UFR Pharmacie, 80025, Amiens, France
| | - Ziad A Massy
- Ambroise Paré Hospital, Nephrology, 92104, Boulogne-Billancourt, France.,Universite Versailles Saint-Quentin-en-Yvelines, Paris-Ile-de-France-Ouest, 78000, Versailles, France.,INSERM U-1018, Research Centre in Epidemiology and Population Health (CESP) Team 5, 94807, Villejuif, France
| | - Jean-Daniel Lalau
- INSERM U-1088, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications, 80025, Amiens, France.,Amiens University Medical Center, Endocrinology and Nutrition, 80054, Amiens, France.,Universite de Picardie Jules Verne, UFR Médecine, 80025, Amiens, France
| | - Romuald Mentaverri
- INSERM U-1088, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications, 80025, Amiens, France.,Universite de Picardie Jules Verne, UFR Pharmacie, 80025, Amiens, France.,Amiens University Hospital, Bone and Endocrine Biology, 80054, Amiens, France
| | - Olivier Bourron
- Pitié Salpêtrière Hospital, Diabetology, 75005, Paris, France.,Universite Paris-Sorbonne, UMPC - Paris 06, 75005, Paris, Île-de-France, France.,INSERM UMR_S 1138, Centre de recherche des Cordeliers, 75006, Paris, France.,Institute of Cardiometabolism and Nutrition, Paris, France
| | - Saïd Kamel
- INSERM U-1088, Pathophysiological Mechanisms and Consequences of Cardiovascular Calcifications, 80025, Amiens, France. .,Universite de Picardie Jules Verne, UFR Pharmacie, 80025, Amiens, France. .,Amiens University Hospital, Biochemistry, 80054, Amiens, France.
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15
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Yokoyama S, Tsuji H, Hiraoka S, Nishihara M. Investigation of Risk Factors Affecting Lactate Levels in Japanese Patients Treated with Metformin. Biol Pharm Bull 2017; 39:2022-2027. [PMID: 27904044 DOI: 10.1248/bpb.b16-00517] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Metformin is a biguanaide antidiabetic drug used worldwide, and its effectiveness and benefits have already been established. However, the safety of high doses of metformin in Japanese patients, especially in elderly patients with a decreased renal function, remains unclear. Among the side effects of metformin, lactate acidosis is the most problematic due to a high mortality rate. Therefore, we assessed plasma lactate levels in metformin-treated patients to identify independent risk factors for hyperlactemia. 290 outpatients receiving various doses of metformin at our hospital were enrolled between March and July 2014. Serum electrolytes, Cre (creatinine), BUN (blood urea nitrogen), UA (uric acid), HbA1c (hemoglobin A1c), and lactate levels were investigated. Lactate levels did not significantly differ between the elderly (≥75 years) and non-elderly (<75 years) groups. Patients in the elderly group had a significantly lower daily metformin dose and estimated glomerular filtration rate (eGFR), compared with the non-elderly group (both p<0.005). Between with and without hyperlactemia groups, no significant differences were observed in either Cre or age. On the other hand, patients with hyperlactemia had a significantly higher dose of metformin than those without hyperlactemia (p<0.05). In this study, we found that old age and mildly impaired kidney function were not associated with increased lactate levels, and that a higher dose of metformin may be an independent risk factor for elevated lactate levels in Japanese patients.
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Affiliation(s)
- Shota Yokoyama
- Department of Pharmacy, Mazda Hospital of Mazda Motor Corporation
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16
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George J, Bipi PK, Gomathy S, Gracious N, Kumar S, Mohandas MK. Lactate levels and risk of lactic acidosis with metformin in diabetic kidney disease patients. SAUDI JOURNAL OF KIDNEY DISEASES AND TRANSPLANTATION 2017; 28:1356-1361. [DOI: 10.4103/1319-2442.220870] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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17
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Laustsen C. Hyperpolarized 13C Magnetic Resonance Treatment Response Monitoring: A New Paradigm for Multiorgan Metabolic Assessment of Pharmacological Interventions? Diabetes 2016; 65:3529-3531. [PMID: 27879402 DOI: 10.2337/dbi16-0055] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Christoffer Laustsen
- MR Research Centre, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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18
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Lin TT, Wu CC, Yang YH, Lin LY, Lin JL, Chen PC, Hwang JJ. Anti-Hyperglycemic Agents and New-Onset Acute Myocardial Infarction in Diabetic Patients with End-Stage Renal Disease Undergoing Dialysis. PLoS One 2016; 11:e0160436. [PMID: 27513562 PMCID: PMC4981426 DOI: 10.1371/journal.pone.0160436] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Accepted: 07/19/2016] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Diabetes and chronic kidney disease (CKD) are a high-stakes combination for cardiovascular disease. Patients with decreased kidney function and end-stage renal disease (ESRD) have increased risk of hypoglycemia when attaining better glycemic control, leading to higher risk of myocardial infarction (MI). For these patients, which kinds of anti-hyperglycemic agents would be associated with higher risk of MI is not clear. METHODS We identified patients from a nation-wide database called Registry for Catastrophic Illness, which encompassed almost 100% of the patients receiving dialysis therapy in Taiwan from 1995 to 2008. Patients with diabetes and ESRD were selected as the study cohort. Propensity score adjustment and Cox's proportional hazards regression model were used to estimate the hazard ratios (HRs) for new-onset MI. RESULTS Among 15,161 patients, 39% received insulin, 40% received sulfonylureas, 18% received meglitinides and 3% received thiazolidinedione (TZD). After a median follow-up of 1,357 days, the incidence of MI was significant increase in patients taking sulfonylureas (HR = 1.523, 95% confidence interval [CI] = 1.331-1.744), meglitinides (HR = 1.251, 95% CI = 1.048-1.494) and TZD (HR = 1.515, 95% CI = 1.071-2.145) by using patients receiving insulin therapy as the reference group. The risk of MI remains higher in other three groups in subgroup analyses. CONCLUSIONS In conclusion, among diabetic patients with ESRD undergoing dialysis, the use of sulfonylureas, meglitinides and TZD are associated with higher risk of new-onset MI as compared with insulin.
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Affiliation(s)
- Ting-Tse Lin
- Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan
- Institute of Biomedical Engineering, National Chiao-Tung University, Hsinchu, Taiwan
| | - Chih-Chen Wu
- Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan
| | - Yao-Hsu Yang
- Department for Traditional Chinese Medicine, Chang Gung Memorial Hospital Chia-Yi, Taiwan
- Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health, Taipei, Taiwan
- Center of Excellence for Chang Gung Research Datalink, Chang Gung Memorial Hospital, Chiayi, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Lian-Yu Lin
- Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Jiunn-Lee Lin
- Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Pau-Chung Chen
- Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health, Taipei, Taiwan
| | - Juey-Jen Hwang
- Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
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Visconti L, Cernaro V, Ferrara D, Costantino G, Aloisi C, Amico L, Chirico V, Santoro D, Noto A, David A, Buemi M, Lacquaniti A. Metformin-related lactic acidosis: is it a myth or an underestimated reality? Ren Fail 2016; 38:1560-1565. [DOI: 10.1080/0886022x.2016.1216723] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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20
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Cucchiari D, Podestà MA, Merizzoli E, Calvetta A, Morenghi E, Angelini C, Ponticelli C, Badalamenti S. Dose-related effects of metformin on acid-base balance and renal function in patients with diabetes who develop acute renal failure: a cross-sectional study. Acta Diabetol 2016; 53:551-8. [PMID: 26821225 DOI: 10.1007/s00592-016-0836-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 01/01/2016] [Indexed: 12/21/2022]
Abstract
AIMS The role of metformin in the development of lactic acidosis (LA) in the setting of acute renal failure (ARF) is debated. Moreover, recent experiments suggested that metformin can also be nephrotoxic, but little clinical data exist about this topic. We sought to investigate these possible associations in a large cohort of patients with diabetes who developed ARF. METHODS We analyzed data from patients with diabetes admitted to our emergency department between 2007 and 2011 with ARF and a previously normal renal function (n = 126). We compared acid-base balance and renal function of patients taking metformin (n = 74) with patients not taking it (n = 52). RESULTS Patients taking metformin had decreased pH (7.31 ± 0.16 vs 7.39 ± 0.11, p = 0.008) and higher lactates (4.54 ± 4.30 vs 1.71 ± 1.14 mmol/L, p < 0.001). Both acidosis (pH < 7.35) and LA (lactates >5 mmol/L and pH < 7.35) were more frequently observed in this group (p = 0.0491 and p < 0.001, respectively). Multivariate analysis ruled out the role of some possible confounders, especially decreased renal function. The influence of metformin on pH and lactates grew significantly with higher doses of the drug (p = 0.259 and p = 0.092 for <1 g/day, p = 0.289 and p < 0.001 for 1-2 g/day, p = 0.009 and p < 0.001 for 2-3 g/day, for pH and lactates, respectively). Metformin influenced creatinine levels in a dose-related manner as well (p = 0.925 for <1 g/day, p = 0.033 for 1-2 g/day, p < 0.001 for 2-3 g/day). CONCLUSIONS In patients with diabetes who were admitted to our emergency department with ARF, the use of metformin was associated in a dose-related fashion with both LA and worse renal function.
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Affiliation(s)
- David Cucchiari
- Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, MI, Italy.
| | - Manuel Alfredo Podestà
- Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, MI, Italy
| | - Elisa Merizzoli
- Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, MI, Italy
| | - Albania Calvetta
- Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, MI, Italy
| | - Emanuela Morenghi
- Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, MI, Italy
| | - Claudio Angelini
- Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, MI, Italy
| | - Claudio Ponticelli
- Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, MI, Italy
| | - Salvatore Badalamenti
- Nephrology and Dialysis Unit, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, MI, Italy
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21
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Pecoits-Filho R, Abensur H, Betônico CCR, Machado AD, Parente EB, Queiroz M, Salles JEN, Titan S, Vencio S. Interactions between kidney disease and diabetes: dangerous liaisons. Diabetol Metab Syndr 2016; 8:50. [PMID: 27471550 PMCID: PMC4964290 DOI: 10.1186/s13098-016-0159-z] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 07/10/2016] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (DM) globally affects 18-20 % of adults over the age of 65 years. Diabetic kidney disease (DKD) is one of the most frequent and dangerous complications of DM2, affecting about one-third of the patients with DM2. In addition to the pancreas, adipocytes, liver, and intestines, the kidneys also play an important role in glycemic control, particularly due to renal contribution to gluconeogenesis and tubular reabsorption of glucose. METHODS In this review article, based on a report of discussions from an interdisciplinary group of experts in the areas of endocrinology, diabetology and nephrology, we detail the relationship between diabetes and kidney disease, addressing the care in the diagnosis, the difficulties in achieving glycemic control and possible treatments that can be applied according to the different degrees of impairment. DISCUSSION Glucose homeostasis is extremely altered in patients with DKD, who are exposed to a high risk of both hyperglycemia and hypoglycemia. Both high and low glycemic levels are associated with increased morbidity and shortened survival in this group of patients. Factors that are associated with an increased risk of hypoglycemia in DKD patients include decreased renal gluconeogenesis, deranged metabolic pathways (including altered metabolism of medications) and decreased insulin clearance. On the other hand, decrease glucose filtration and excretion, and inflammation-induce insulin resistance are predisposing factors to hyperglycemic episodes. CONCLUSION Appropriate glycaemic monitoring and control tailored for diabetic patients is required to avoid hypoglycaemia and other glycaemic disarrays in patients with DM2 and kidney disease. Understanding the renal physiology and pathophysiology of DKD has become essential to all specialties treating diabetic patients. Disseminating this knowledge and detailing the evidence will be important to initiate breakthrough research and to encourage proper treatment of this group of patients.
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Affiliation(s)
- Roberto Pecoits-Filho
- School of Medicine, Pontificia Universidade Católica do Paraná, Imaculada Conceição, 1155, Curitiba, PR 80215-901 Brazil
| | - Hugo Abensur
- School of Medicine, University of São Paulo, São Paulo, Brazil
| | - Carolina C. R. Betônico
- Hospital Regional de Presidente Prudente, Universidade do Oeste Paulista, Presidente Prudente, São Paulo, Brazil
| | | | | | - Márcia Queiroz
- School of Medicine, University of São Paulo, São Paulo, Brazil
| | | | - Silvia Titan
- School of Medicine, University of São Paulo, São Paulo, Brazil
| | - Sergio Vencio
- Institute of Pharmaceutical Sciences, Goiania, Brazil
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Muller C, Dimitrov Y, Imhoff O, Richter S, Ott J, Krummel T, Bazin-Kara D, Chantrel F, Hannedouche T. Oral antidiabetics use among diabetic type 2 patients with chronic kidney disease. Do nephrologists take account of recommendations? J Diabetes Complications 2016; 30:675-80. [PMID: 26900098 DOI: 10.1016/j.jdiacomp.2016.01.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Revised: 01/12/2016] [Accepted: 01/20/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND There is an increasing prevalence of diabetes type 2 and chronic kidney disease, challenging appropriate prescribing of oral anti-diabetic drugs (OADs). METHODS We have described the practice patterns of 13 nephrologists in 4 centers, in a cohort of 301 consecutive adult type 2 diabetic patients. Among oral anti-diabetic prescriptions, we have detailed drugs dosage for each subject, with 3 different formulae for estimating glomerular filtration rate (GFR) and its adequation according to the latest ERBP recommendations (2015). As individuals were mostly obese in this work, we also compare adequacy rates using both standard indexed CKD-EPI formula and CKD-EPI formula de-indexed from body surface area. RESULTS Using the CKD-EPI formula as the reference method for estimating GFR, 53.5% of patients were outside the recommendations, mostly for metformin (30% of the whole cohort) and for sitagliptin (17.9% of the whole cohort). With Cockcroft and Gault formula, 38.2% of persons were outside recommendations and 45.9% (p<0.001) with CKD-EPI de-indexed. Among individuals consulting a nephrologist for the first time (n=90), 61.1% were outside recommendations (p=0.1). Among those persons under diabetologist supervision (n=103), 63.1% were outside recommendations (p=0.09), and were taking significantly more often metformin and insulin. CONCLUSION We have found a substantial number of inadequate OAD prescriptions in type 2 diabetic patients with chronic kidney disease. The proportion of individuals outside guidelines was strongly affected by the method used for estimating GFR and by the type of practice, i.e., specialists versus general practitioners.
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Affiliation(s)
- Clotilde Muller
- Strasbourg Civil Hospital, Nephrology department, 1 place de l'hôpital, 67000, Strasbourg, France; School of Medicine, University of Strasbourg, Rue Kirschleger, 67000, Strasbourg, France; UMR 1109, Laboratoire Immunologie et Rhumatologie, Strasbourg, France.
| | - Yves Dimitrov
- Haguenau Hospital, Nephrology department, 64 Avenue du Pr Leriche, 67500, Haguenau, France
| | - Olivier Imhoff
- Clinique Ste Anne, Nephrology department, Rue Philippe Thyss, 67085, Strasbourg, France
| | - Sarah Richter
- Clinique Ste Anne, Nephrology department, Rue Philippe Thyss, 67085, Strasbourg, France
| | - Julien Ott
- Haguenau Hospital, Nephrology department, 64 Avenue du Pr Leriche, 67500, Haguenau, France
| | - Thierry Krummel
- Strasbourg Civil Hospital, Nephrology department, 1 place de l'hôpital, 67000, Strasbourg, France
| | - Dorothée Bazin-Kara
- Strasbourg Civil Hospital, Nephrology department, 1 place de l'hôpital, 67000, Strasbourg, France
| | - Francois Chantrel
- Mulhouse Hospital, Nephrology department, 20 Avenue du Dr René Laennec, 68100, Mulhouse, France
| | - Thierry Hannedouche
- Strasbourg Civil Hospital, Nephrology department, 1 place de l'hôpital, 67000, Strasbourg, France; School of Medicine, University of Strasbourg, Rue Kirschleger, 67000, Strasbourg, France
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Sourij H, Edlinger R, Prischl F, Auinger M, Kautzky-Willer A, Säemann MD, Prager R, Clodi M, Schernthaner G, Mayer G, Oberbauer R, Rosenkranz AR. Diabetische Nierenerkrankung – Update 2016. Wien Klin Wochenschr 2016; 128 Suppl 2:S85-96. [DOI: 10.1007/s00508-016-0992-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Roussel R, Lorraine J, Rodriguez A, Salaun-Martin C. Overview of Data Concerning the Safe Use of Antihyperglycemic Medications in Type 2 Diabetes Mellitus and Chronic Kidney Disease. Adv Ther 2015; 32:1029-64. [PMID: 26581749 DOI: 10.1007/s12325-015-0261-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Indexed: 12/26/2022]
Abstract
INTRODUCTION It can be a challenge to manage glycemic control in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD), due to both patient and medication issues. Although most antihyperglycemic medications can be used in mild kidney disease, many medications are either not advised or require dose adjustments in more advanced CKD. This review summarizes product label information, pharmacokinetic and clinical studies, and clinical guidelines relevant to use of antihyperglycemic medications in CKD. METHODS Product labels and guidelines from North America and Europe, as well as pharmacokinetic and clinical studies of diabetes medication use in CKD were identified through Medline and PubMed searches, up to February 2015. Available data are summarized and correlations between treatment recommendations and available research are discussed, as are glycemic targets for patients with CKD. RESULTS Newer medications have significantly more data available than older medications regarding use in CKD, although larger clinical studies are still lacking for some drugs. As CKD advances, dose adjustment is needed for many medications [numerous dipeptidyl peptidase-4 inhibitors, some insulins, sodium glucose co-transporter 2 (SGLT2) inhibitors], although not for others (thiazolidinediones, meglitinides). Some medications are not recommended for use in more advanced CKD (metformin, SGLT2 inhibitors, some glucagon-like protein-1 receptor agonists) for safety or efficacy reasons. There is not always good alignment between label recommendations, pharmacokinetic or clinical studies, and guideline recommendations for use of these drugs in CKD. In particular, controversy remains about the use of metformin in moderate CKD and appropriate use of liraglutide and sulfonylureas in advanced CKD. CONCLUSION Considerable variability exists with respect to recommendations and clinical data for the many antihyperglycemic drugs used in patients with T2DM and CKD. FUNDING Eli Lilly and Company.
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Affiliation(s)
- Ronan Roussel
- Division of Endocrinology Diabetes and Nutrition, DHU FIRE, Groupe Hospitalier Bichat-Claude Bernard, AP-HP, Paris, France.
- INSERM U 1138, Cordeliers Research Center, Paris, France.
- University Paris Diderot-Paris 7, Paris, France.
| | | | | | - Carole Salaun-Martin
- Eli Lilly, Neuilly Cedex, France
- Division of Endocrinology Diabetes and Nutrition, Hopital Max Fourestier, Nanterre, France
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Hung SC, Chang YK, Liu JS, Kuo KL, Chen YH, Hsu CC, Tarng DC. Metformin use and mortality in patients with advanced chronic kidney disease: national, retrospective, observational, cohort study. Lancet Diabetes Endocrinol 2015; 3:605-14. [PMID: 26094107 DOI: 10.1016/s2213-8587(15)00123-0] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Revised: 04/15/2015] [Accepted: 04/17/2015] [Indexed: 01/06/2023]
Abstract
BACKGROUND Metformin is recommended as a first-line treatment for patients with type 2 diabetes. However, use of this drug has been contraindicated in individuals with impaired kidney function because of the perceived risk of lactic acidosis. Evidence now supports cautious use of metformin in people with mild-to-moderate chronic kidney disease. However, studies examining the use of metformin in patients with advanced chronic kidney disease are lacking. We aimed to assess the safety of metformin in patients with type 2 diabetes and advanced (approximately stage 5) chronic kidney disease. METHODS We did a retrospective, observational, cohort study of patients with type 2 diabetes who were enrolled prospectively in Taiwan's national health insurance research database between Jan 1, 2000, and June 30, 2009, and had follow-up data until Dec 31, 2009. We included individuals with a serum creatinine concentration greater than 530 μmol/L, which is approximately equivalent to stage 5 chronic kidney disease. From a consecutive sample of 12 350 patients with type 2 diabetes and chronic kidney disease, 1005 used metformin and 11 345 were non-users. We matched users and non-users of metformin by propensity score in a 1:3 ratio. Our primary outcome was all-cause mortality. FINDINGS 813 metformin users were matched by propensity score to 2439 non-users. The two groups of patients did not differ significantly by 30 baseline clinical and socioeconomic variables. Median follow-up in the matched cohort was 2·1 years (range 0·3-9·8). All-cause mortality was reported in 434 (53%) of 813 metformin users and in 1012 (41%) of 2439 non-users. After multivariate adjustment, metformin use was an independent risk factor for mortality (adjusted hazard ratio 1·35, 95% CI 1·20-1·51; p<0·0001). The increased mortality risk was dose-dependent and was consistent across all subgroup analyses. However, metformin use compared with no use was associated with a higher but non-significant risk of metabolic acidosis (1·6 vs 1·3 events per 100 patient-years; adjusted hazard ratio 1·30, 95% CI 0·88-1·93; p=0·19). INTERPRETATION Use of metformin in people with type 2 diabetes and a serum creatinine concentration greater than 530 μmol/L is associated with a significantly increased risk of all-cause mortality compared with non-users. Metformin use should not be encouraged in this patient group. FUNDING Taipei Tzu Chi Hospital, Taipei Veterans General Hospital, Foundation for Poison Control, National Health Research Institutes, Ministry of Science and Technology of Taiwan.
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Affiliation(s)
- Szu-Chun Hung
- Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Yu-Kang Chang
- Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan
| | - Jia-Sin Liu
- Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan
| | - Ko-Lin Kuo
- Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Yu-Hsin Chen
- Division of Nephrology, Department of Internal Medicine, Taipei City Hospital Yang-Ming Branch, Taipei, Taiwan
| | - Chih-Cheng Hsu
- Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan; Department of Health Services Administration, China Medical University, Taichung, Taiwan.
| | - Der-Cherng Tarng
- Institutes of Physiology and Clinical Medicine, National Yang-Ming University, and Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
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Udell JA, Bhatt DL, Braunwald E, Cavender MA, Mosenzon O, Steg PG, Davidson JA, Nicolau JC, Corbalan R, Hirshberg B, Frederich R, Im K, Umez-Eronini AA, He P, McGuire DK, Leiter LA, Raz I, Scirica BM. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes and moderate or severe renal impairment: observations from the SAVOR-TIMI 53 Trial. Diabetes Care 2015; 38:696-705. [PMID: 25552421 DOI: 10.2337/dc14-1850] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The glycemic management of patients with type 2 diabetes mellitus (T2DM) and renal impairment is challenging, with few treatment options. We investigated the effect of saxagliptin in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial according to baseline renal function. RESEARCH DESIGN AND METHODS Patients with T2DM at risk for cardiovascular events were stratified as having normal or mildly impaired renal function (estimated glomerular filtration rate [eGFR] >50 mL/min/1.73 m(2); n = 13,916), moderate renal impairment (eGFR 30-50 mL/min/1.73 m(2); n = 2,240), or severe renal impairment (eGFR <30 mL/min/1.73 m(2); n = 336) and randomized to receive saxagliptin or placebo. The primary end point was cardiovascular death, myocardial infarction, or ischemic stroke. RESULTS After a median duration of 2 years, saxagliptin neither increased nor decreased the risk of the primary and secondary composite end points compared with placebo, irrespective of renal function (all P for interactions ≥ 0.19). Overall, the risk of hospitalization for heart failure among the three eGFR groups of patients was 2.2% (referent), 7.4% (adjusted hazard ratio [HR] 2.38 [95% CI 1.95-2.91], P < 0.001), and 13.0% (adjusted HR 4.59 [95% CI 3.28-6.28], P < 0.001), respectively. The relative risk of hospitalization for heart failure with saxagliptin was similar (P for interaction = 0.43) in patients with eGFR >50 mL/min/1.73 m(2) (HR 1.23 [95% CI 0.99-1.55]), eGFR 30-50 mL/min/1.73 m(2) (HR 1.46 [95% CI 1.07-2.00]), and in patients with eGFR <30 (HR 0.94 [95% CI 0.52-1.71]). Patients with renal impairment achieved reductions in microalbuminuria with saxagliptin (P = 0.041) that were similar to those of the overall trial population. CONCLUSIONS Saxagliptin did not affect the risk of ischemic cardiovascular events, increased the risk of heart failure hospitalization, and reduced progressive albuminuria, irrespective of baseline renal function.
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Affiliation(s)
- Jacob A Udell
- Cardiovascular Division, Women's College Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Deepak L Bhatt
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Eugene Braunwald
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Matthew A Cavender
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Ofri Mosenzon
- Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Ph Gabriel Steg
- Département Hospitalo-Universitaire-Fibrosis Inflammation Remodelling, INSERM U-1148, Université Paris-Diderot, and Hôpital Bichat, AP-HP, Paris, France Imperial College, Royal Brompton Hospital, London, U.K
| | - Jaime A Davidson
- Division of Endocrinology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Jose C Nicolau
- Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil
| | - Ramon Corbalan
- Cardiovascular Division, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | | | - KyungAh Im
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Amarachi A Umez-Eronini
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Ping He
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Darren K McGuire
- Division of Cardiovascular Medicine, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Lawrence A Leiter
- Division of Endocrinology and Metabolism, Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Itamar Raz
- Diabetes Unit, Division of Internal Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Benjamin M Scirica
- TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
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Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2015; 58:429-42. [PMID: 25583541 DOI: 10.1007/s00125-014-3460-0] [Citation(s) in RCA: 509] [Impact Index Per Article: 50.9] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 10/20/2014] [Indexed: 12/15/2022]
Affiliation(s)
- Silvio E Inzucchi
- Section of Endocrinology, Yale University School of Medicine, Yale-New Haven Hospital, New Haven, CT, USA
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Molitch ME, Adler AI, Flyvbjerg A, Nelson RG, So WY, Wanner C, Kasiske BL, Wheeler DC, de Zeeuw D, Mogensen CE. Diabetic kidney disease: a clinical update from Kidney Disease: Improving Global Outcomes. Kidney Int 2015; 87:20-30. [PMID: 24786708 PMCID: PMC4214898 DOI: 10.1038/ki.2014.128] [Citation(s) in RCA: 190] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 02/19/2014] [Accepted: 02/20/2014] [Indexed: 12/24/2022]
Abstract
The incidence and prevalence of diabetes mellitus (DM) continue to grow markedly throughout the world, due primarily to the increase in type 2 DM (T2DM). Although improvements in DM and hypertension management have reduced the proportion of diabetic individuals who develop chronic kidney disease (CKD) and progress to end-stage renal disease (ESRD), the sheer increase in people developing DM will have a major impact on dialysis and transplant needs. This KDIGO conference addressed a number of controversial areas in the management of DM patients with CKD, including aspects of screening for CKD with measurements of albuminuria and estimated glomerular filtration rate (eGFR); defining treatment outcomes; glycemic management in both those developing CKD and those with ESRD; hypertension goals and management, including blockers of the renin-angiotensin-aldosterone system; and lipid management.
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Affiliation(s)
| | - Amanda I. Adler
- Institute of Metabolic Science, Addenbrooke’s Hospitals, Cambridge, United Kingdom
| | | | - Robert G. Nelson
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, United States
| | - Wing-Yee So
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, People’s Republic of China
| | | | | | | | - Dick de Zeeuw
- University Medical Center Groningen, Groningen, The Netherlands
| | - Carl E. Mogensen
- Aarhus University Hospital and Aarhus University, Aarhus, Denmark
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Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015; 38:140-9. [PMID: 25538310 DOI: 10.2337/dc14-2441] [Citation(s) in RCA: 1893] [Impact Index Per Article: 189.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Silvio E Inzucchi
- Section of Endocrinology, Yale University School of Medicine, Yale-New Haven Hospital, New Haven, CT
| | | | - John B Buse
- Division of Endocrinology, University of North Carolina School of Medicine, Chapel Hill, NC
| | - Michaela Diamant
- Diabetes Center/Department of Internal Medicine, VU University Medical Center, Amsterdam, the Netherlands
| | - Ele Ferrannini
- Department of Medicine, University of Pisa School of Medicine, Pisa, Italy
| | - Michael Nauck
- Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany
| | - Anne L Peters
- Division of Endocrinology, Keck School of Medicine of the University of Southern California, Los Angeles, CA
| | - Apostolos Tsapas
- Second Medical Department, Aristotle University Thessaloniki, Thessaloniki, Greece
| | - Richard Wender
- American Cancer Society, Atlanta, GA Department of Family and Community Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA
| | - David R Matthews
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, U.K. National Institute for Health Research (NIHR), Oxford Biomedical Research Centre, Oxford, U.K. Harris Manchester College, University of Oxford, Oxford, U.K
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Abstract
Table 3 provides an overview of the oral antihyperglycemic drugs reviewed in this article. A 2011 meta-analysis by Bennett and colleagues found low or insufficient quality of evidence favoring an initial choice of metformin, SUs, glinides, TZDs, or (table see text) DPP-4 inhibitors (alpha-glucosidase inhibitors, bromocriptine mesylate, and SGLT2 inhibitors were not included in this meta-analysis) with regard to the outcomes measures of all-cause mortality, cardiovascular events and mortality, and incidence of microvascular disease (retinopathy, nephropathy, and neuropathy) in previously healthy individuals with newly diagnosed T2DM. Likewise, the Bennett and colleagues meta-analysis judged these drugs to be of roughly equal efficacy with regard to reduction of HbA1c (1%–1.6%) from the pretreatment baseline. The ADOPT clinical trial of 3 different and, at the time, popular, oral monotherapies for T2DM provides support for the consensus recommendation of metformin as first-line therapy. The ADOPT trial showed slightly superior HbA1c reduction for rosiglitazone compared with metformin, which was in turn superior to glyburide. However, significant adverse events, including edema, weight gain, and fractures, were more common in the rosiglitazone-treated patients. The implication of this trial is that the combination of low cost, low risk, minimal adverse effects, and efficacy of metformin justifies use of this agent as the cornerstone of oral drug treatment of T2DM. Judicious use of metformin in groups formerly thought to be at high risk for lactic acidosis (ie, those with CHF, chronic kidney disease [eGFR >30 mL/min/1.73 m2], and the elderly) may be associated with mortality benefit rather than increased risk. Secondary and tertiary add-on drug therapy should be individualized based on cost, personal preferences, and overall treatment goals, taking into account the wishes and priorities of the patient.
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Affiliation(s)
- Stephen A Brietzke
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Missouri-Columbia, DC043 UMHC, 1 Hospital Drive, Columbia, MO 65212, USA.
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Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA 2014; 312:2668-75. [PMID: 25536258 PMCID: PMC4427053 DOI: 10.1001/jama.2014.15298] [Citation(s) in RCA: 421] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
IMPORTANCE Metformin is widely viewed as the best initial pharmacological option to lower glucose concentrations in patients with type 2 diabetes mellitus. However, the drug is contraindicated in many individuals with impaired kidney function because of concerns of lactic acidosis. OBJECTIVE To assess the risk of lactic acidosis associated with metformin use in individuals with impaired kidney function. EVIDENCE ACQUISITION In July 2014, we searched the MEDLINE and Cochrane databases for English-language articles pertaining to metformin, kidney disease, and lactic acidosis in humans between 1950 and June 2014. We excluded reviews, letters, editorials, case reports, small case series, and manuscripts that did not directly pertain to the topic area or that met other exclusion criteria. Of an original 818 articles, 65 were included in this review, including pharmacokinetic/metabolic studies, large case series, retrospective studies, meta-analyses, and a clinical trial. RESULTS Although metformin is renally cleared, drug levels generally remain within the therapeutic range and lactate concentrations are not substantially increased when used in patients with mild to moderate chronic kidney disease (estimated glomerular filtration rates, 30-60 mL/min per 1.73 m2). The overall incidence of lactic acidosis in metformin users varies across studies from approximately 3 per 100,000 person-years to 10 per 100,000 person-years and is generally indistinguishable from the background rate in the overall population with diabetes. Data suggesting an increased risk of lactic acidosis in metformin-treated patients with chronic kidney disease are limited, and no randomized controlled trials have been conducted to test the safety of metformin in patients with significantly impaired kidney function. Population-based studies demonstrate that metformin may be prescribed counter to prevailing guidelines suggesting a renal risk in up to 1 in 4 patients with type 2 diabetes mellitus--use which, in most reports, has not been associated with increased rates of lactic acidosis. Observational studies suggest a potential benefit from metformin on macrovascular outcomes, even in patients with prevalent renal contraindications for its use. CONCLUSIONS AND RELEVANCE Available evidence supports cautious expansion of metformin use in patients with mild to moderate chronic kidney disease, as defined by estimated glomerular filtration rate, with appropriate dosage reductions and careful follow-up of kidney function.
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Affiliation(s)
- Silvio E Inzucchi
- Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut
| | - Kasia J Lipska
- Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut
| | - Helen Mayo
- Health Sciences Digital Library and Learning Center, University of Texas Southwestern Medical Center, Dallas
| | - Clifford J Bailey
- School of Life & Health Sciences, Aston University, Birmingham, United Kingdom
| | - Darren K McGuire
- Division of Cardiology, University of Texas Southwestern Medical Center, Dallas
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Ioannidis I. Diabetes treatment in patients with renal disease: Is the landscape clear enough? World J Diabetes 2014; 5:651-658. [PMID: 25317242 PMCID: PMC4138588 DOI: 10.4239/wjd.v5.i5.651] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2013] [Revised: 03/31/2014] [Accepted: 07/18/2014] [Indexed: 02/05/2023] Open
Abstract
Diabetes is the most important risk factors for chronic kidney disease (CKD). The risk of CKD attributable to diabetes continues to rise worldwide. Diabetic patients with CKD need complicated treatment for their metabolic disorders as well as for related comorbidities. They have to treat, often intensively, hypertension, dyslipidaemia, bone disease, anaemia, and frequently established cardiovascular disease. The treatment of hypoglycaemia in diabetic persons with CKD must tie their individual goals of glycaemia (usually less tight glycaemic control) and knowledge on the pharmacokinetics and pharmacodynamics of drugs available to a person with kidney disease. The problem is complicated from the fact that in many efficacy studies patients with CKD are excluded so data of safety and efficacy for these patients are missing. This results in fear of use by lack of evidence. Metformin is globally accepted as the first choice in practically all therapeutic algorithms for diabetic subjects. The advantages of metformin are low risk of hypoglycaemia, modest weight loss, effectiveness and low cost. Data of UKPDS indicate that treatment based on metformin results in less total as well cardiovascular mortality. Metformin remains the drug of choice for patients with diabetes and CKD provided that their estimate Glomerular Filtration Rate (eGFR) remains above 30 mL/min per square meter. For diabetic patients with eGFR between 30-60 mL/min per square meter more frequent monitoring of renal function and dose reduction of metformin is needed. The use of sulfonylureas, glinides and insulin carry a higher risk of hypoglycemia in these patients and must be very careful. Lower doses and slower titration of the dose is needed. Is better to avoid sulfonylureas with active hepatic metabolites, which are renally excreted. Very useful drugs for this group of patients emerge dipeptidyl peptidase 4 inhibitors. These drugs do not cause hypoglycemia and most of them (linagliptin is an exception) require dose reduction in various stages of renal disease.
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Venos ES, Sigal RJ. My patient's diabetic kidney disease has progressed to stage 4; should I discontinue metformin? Can J Diabetes 2014; 38:296-9. [PMID: 25284696 DOI: 10.1016/j.jcjd.2014.07.225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Revised: 07/30/2014] [Accepted: 07/31/2014] [Indexed: 11/17/2022]
Affiliation(s)
- Erik S Venos
- Division of Endocrinology, Departments of Medicine and Community Health Sciences, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
| | - Ronald J Sigal
- Division of Endocrinology, Departments of Medicine and Community Health Sciences, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Cardiac Sciences and Institute of Public Health, Faculties of Medicine and Kinesiology, University of Calgary, Calgary, Alberta, Canada
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Adam WR, O'Brien RC. A justification for less restrictive guidelines on the use of metformin in stable chronic renal failure. Diabet Med 2014; 31:1032-8. [PMID: 24909998 DOI: 10.1111/dme.12515] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Accepted: 06/03/2014] [Indexed: 11/30/2022]
Abstract
AIM The aim was to justify less restrictive use of metformin in stable chronic renal failure, because a literature review reveals metformin is associated with a significantly lower incidence of cardiovascular events and mortality compared with other hypoglycaemic agents, and metformin-associated lactic acidosis is rare and causation uncertain. Studies on intentional metformin overdose and metformin bioavailability, renal clearance and plasma metformin in renal impairment provide evidence in support of a less restrictive use of metformin. METHODS In metformin overdose (n = 22), lactic acidosis was not inevitable with a plasma metformin > 40 mg/l (therapeutic level c. 1 mg/l): Severe lactic acidosis (pH ≤ 7.21, plasma lactate ≥ 11 mmol/l, n = 8) did not occur unless plasma metformin was > 40 mg/l. Plasma lactate was a more consistent predictor of pH than plasma metformin, with plasma lactate ≤ 4.7 being associated with a pH ≥ 7.34. A likely 'safe' plasma lactate is < 3.5 mmol/l and plasma metformin < 10 mg/l. RESULTS Plasma metformin can be predicted from estimated glomerular filtration rate and metformin dose. Reported plasma metformin in renal failure was always less than predicted plasma metformin. Predicted plasma metformin (mg/l), with an estimated glomerular filtration rate of 30 ml/min and metformin 2000 mg/day was 6.8; an estimated glomerular filtration rate of 20 ml/min and metformin 1500 mg/day was 5.1; an estimated glomerular filtration rate of 10 ml/min and metformin 500 mg/day was 4.4. CONCLUSION Metformin accumulates in renal failure and, although accumulation does not always lead to lactic acidosis, dose modification to achieve a predicted plasma metformin < 10 mg/l is suggested. As plasma metformin is not routinely available, plasma lactate should be useful in monitoring the use of metformin in renal failure.
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Affiliation(s)
- W R Adam
- Rural Health Academic Centre, Shepparton
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Eppenga WL, Lalmohamed A, Geerts AF, Derijks HJ, Wensing M, Egberts A, De Smet PAGM, de Vries F. Risk of lactic acidosis or elevated lactate concentrations in metformin users with renal impairment: a population-based cohort study. Diabetes Care 2014; 37:2218-24. [PMID: 24842984 DOI: 10.2337/dc13-3023] [Citation(s) in RCA: 105] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The objective of this study was to determine whether treatment with metformin in patients with renal impairment is associated with a higher risk of lactic acidosis or elevated lactate concentrations compared with users of a noninsulin antidiabetic drug (NIAD) who had never used metformin. RESEARCH DESIGN AND METHODS A cohort of 223,968 metformin users and 34,571 diabetic patients who had never used metformin were identified from the Clinical Practice Research Datalink (CPRD).The primary outcome was defined as either a CPRD READ code lactic acidosis or a record of a plasma lactate concentration >5 mmol/L. The associations between renal impairment, dose of metformin, and the risk of lactic acidosis or elevated lactate concentrations were determined with time-dependent Cox models and expressed as hazard ratios (HRs). RESULTS The crude incidence of lactic acidosis or elevated lactate concentrations in current metformin users was 7.4 per 100,000 person-years (vs. 2.2 per 100,000 person-years in nonusers). Compared with nonusers, risk of lactic acidosis or elevated lactate concentrations in current metformin users was significantly associated with a renal function <60 mL/min/1.73 m(2) (adjusted HR 6.37 [95% CI 1.48-27.5]). The increased risk among patients with impaired renal function was further increased in users of ≥730 g of metformin in the preceding year (adjusted HR 11.8 [95% CI 2.27-61.5]) and in users of a recent high daily dose (>2 g) of metformin (adjusted HR 13.0 [95% CI 2.36-72.0]). CONCLUSIONS Our study is consistent with current recommendations that the renal function of metformin users should be adequately monitored and that the dose of metformin should be adjusted, if necessary, if renal function falls below 60 mL/min/1.73 m(2).
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Affiliation(s)
- Willemijn L Eppenga
- Scientific Institute for Quality of Healthcare, Radboud University Nijmegen Medical Center, Nijmegen, the NetherlandsHospital Pharmacy 'ZANOB', 's-Hertogenbosch, the Netherlands
| | - Arief Lalmohamed
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the NetherlandsDepartment of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Arjen F Geerts
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the Netherlands
| | - Hieronymus J Derijks
- Hospital Pharmacy 'ZANOB', 's-Hertogenbosch, the NetherlandsDivision of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the Netherlands
| | - Michel Wensing
- Scientific Institute for Quality of Healthcare, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Antoine Egberts
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the NetherlandsDepartment of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Peter A G M De Smet
- Scientific Institute for Quality of Healthcare, Radboud University Nijmegen Medical Center, Nijmegen, the NetherlandsDepartment of Clinical Pharmacy, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands
| | - Frank de Vries
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the NetherlandsDepartment of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, the NetherlandsCare and Public Health Research Institute (CAPHRI), Maastricht, the Netherlands
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Ramirez G, Morrison AD, Bittle PA. Clinical practice considerations and review of the literature for the Use of DPP-4 inhibitors in patients with type 2 diabetes and chronic kidney disease. Endocr Pract 2014; 19:1025-34. [PMID: 23757605 DOI: 10.4158/ep12306.ra] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVE Many commonly prescribed agents for the treatment of type 2 diabetes (T2DM) have important restrictions on use in patients with renal impairment. Prescribing information and published data on dipeptidyl peptidase-4 (DPP-4) inhibitors indicate that these agents are suitable for use in this patient population. However, a recent database analysis indicated prevalent underrecognition of renal impairment and limited awareness of prescription considerations associated with DPP-4 inhibitor use in patients with renal impairment. Thus, this article reviews recent literature on the safety, efficacy, pharmacokinetics, and clinical use of DPP-4 inhibitors in patients with renal impairment and T2DM. METHODS PubMed searches were conducted for literature describing the use of DPP-4 inhibitors in patients with renal impairment. RESULTS Most DPP-4 inhibitors are characterized by significant renal clearance. As a result, pharmacokinetics are measurably affected by the presence of renal impairment; plasma exposure of DPP-4 inhibitors and their metabolites may increase by up to sevenfold in severe impairment/end-stage renal disease. The exception in this case is linagliptin, which is eliminated predominantly via the hepatobiliary system. Our search identified several studies that evaluated specific doses of DPP-4 inhibitors in patients with renal impairment and reported positive safety and efficacy results. CONCLUSIONS Overall, DPP-4 inhibitors are an effective means of controlling blood glucose in patients with T2DM and renal impairment. Considering the restrictions associated with many other antihyperglycemic agents when used in patients with renal impairment, DPP-4 inhibitors should be a considered as a treatment option in this patient population.
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Naunton M, Kyle G, Owoka F, Naunton-Boom K. Pharmacist review prevents evolving metformin-associated lactic acidosis. J Clin Pharm Ther 2014; 39:567-70. [DOI: 10.1111/jcpt.12187] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Accepted: 06/02/2014] [Indexed: 01/05/2023]
Affiliation(s)
- M. Naunton
- Faculty of Health; Discipline of Pharmacy; University of Canberra; Bruce ACT Australia
| | - G. Kyle
- Faculty of Health; Discipline of Pharmacy; University of Canberra; Bruce ACT Australia
| | - F. Owoka
- Faculty of Health; Discipline of Pharmacy; University of Canberra; Bruce ACT Australia
| | - K. Naunton-Boom
- Faculty of Health; Discipline of Pharmacy; University of Canberra; Bruce ACT Australia
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Penfornis A, Blicklé JF, Fiquet B, Quéré S, Dejager S. How are patients with type 2 diabetes and renal disease monitored and managed? Insights from the observational OREDIA study. Vasc Health Risk Manag 2014; 10:341-52. [PMID: 24966684 PMCID: PMC4063863 DOI: 10.2147/vhrm.s60312] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background and aim Chronic kidney disease (CKD) is frequent in type 2 diabetes mellitus (T2DM), and therapeutic management of diabetes is more challenging in patients with renal impairment (RI). The place of metformin is of particular interest since most scientific societies now recommend using half the dosage in moderate RI and abstaining from use in severe RI, while the classic contraindication with RI has not been removed from the label. This study aimed to assess the therapeutic management, in particular the use of metformin, of T2DM patients with CKD in real life. Methods This was a French cross-sectional observational study: 3,704 patients with T2DM diagnosed for over 1 year and pharmacologically treated were recruited in two cohorts (two-thirds were considered to have renal disease [CKD patients] and one-third were not [non-CKD patients]) by 968 physicians (81% general practitioners) in 2012. Results CKD versus non-CKD patients were significantly older with longer diabetes history, more diabetic complications, and less strict glycemic control (mean glycated hemoglobin [HbA1c] 7.5% versus 7.1%; 25% of CKD patients had HbA1c ≥8% versus 15% of non-CKD patients). Fifteen percent of CKD patients had severe RI, and 66% moderate RI. Therapeutic management of T2DM was clearly distinct in CKD, with less use of metformin (62% versus 86%) but at similar mean daily doses (~2 g/d). Of patients with severe RI, 33% were still treated with metformin, at similar doses. For other oral anti-diabetics, a distinct pattern of use was seen across renal function (RF): use of sulfonylureas (32%, 31%, and 20% in normal RF, moderate RI, and severe RI, respectively) and DPP4-i (dipeptidyl peptidase-4 inhibitors) (41%, 36%, and 25%, respectively) decreased with RF, while that of glinides increased (8%, 14%, and 18%, respectively). CKD patients were more frequently treated with insulin (40% versus 16% of non-CKD patients), and use of insulin increased with deterioration of RF (19%, 39%, and 61% of patients with normal RF, moderate RI, and severe RI, respectively). Treatment was modified at the end of the study-visit in 34% of CKD patients, primarily to stop or reduce metformin. However, metformin was stopped in only 40% of the severe RI patients. Conclusion Despite a fairly good detection of CKD in patients with T2DM, RI was insufficiently taken into account for adjusting anti-diabetic treatment.
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Affiliation(s)
- Alfred Penfornis
- Department of Endocrinology-Metabolism and Diabetology-Nutrition, Jean Minjoz Hospital, University of Franche-Comté, Besançon, France
| | - Jean Frédéric Blicklé
- Department of Internal Medicine and Diabetology, Strasbourg University Hospital, Strasbourg, France
| | - Béatrice Fiquet
- Clinical Affairs, Novartis Pharma SAS, Rueil-Malmaison, France
| | - Stéphane Quéré
- BioStatistics, Novartis Pharma SAS, Rueil-Malmaison, France
| | - Sylvie Dejager
- Clinical Affairs, Novartis Pharma SAS, Rueil-Malmaison, France
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39
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Abstract
Metformin has traditionally been regarded as contraindicated in chronic kidney disease (CKD), though guidelines in recent years have been relaxed to permit therapy if the glomerular filtration rate (GFR) is > 30 mL/min. The main problem is the perceived risk of lactic acidosis (LA). Epidemiological evidence suggests that this fear is disproportionate. Lactic acidosis is a rare complication to type 2 diabetes mellitus (T2DM), with an incidence of 6/100,000 patient-years. The risk is not increased in metformin-treated patients. Metformin possesses a number of clinical effects independent of glucose reduction, including weight loss, which are beneficial to patients. The risk of death and cardiovascular disease is reduced by about a third in non-CKD patients. Since metformin intoxication undoubtedly causes LA, and metformin is renally excreted, inappropriate dosage of metformin will increase the risk of LA. It is suggested that introduction of metformin therapy to more advanced stages of CKD may bring therapeutic benefits that outweigh the possible risks.
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Affiliation(s)
- James Heaf
- Department of Nephrology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
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40
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Lalau JD, Arnouts P, Sharif A, De Broe ME. Metformin and other antidiabetic agents in renal failure patients. Kidney Int 2014; 87:308-22. [PMID: 24599253 DOI: 10.1038/ki.2014.19] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 11/21/2013] [Accepted: 12/12/2013] [Indexed: 12/11/2022]
Abstract
This review mainly focuses on metformin, and considers oral antidiabetic therapy in kidney transplant patients and the potential benefits and risks of antidiabetic agents other than metformin in patients with chronic kidney disease (CKD). In view of the debate concerning lactic acidosis associated with metformin, this review tries to solve a paradox: metformin should be prescribed more widely because of its beneficial effects, but also less widely because of the increasing prevalence of contraindications to metformin, such as reduced renal function. Lactic acidosis appears either as part of a number of clinical syndromes (i.e., unrelated to metformin), induced by metformin (involving an analysis of the drug's pharmacokinetics and mechanisms of action), or associated with metformin (a more complex situation, as lactic acidosis in a metformin-treated patient is not necessarily accompanied by metformin accumulation, nor does metformin accumulation necessarily lead to lactic acidosis). A critical analysis of guidelines and literature data on metformin therapy in patients with CKD is presented. Following the present focus on metformin, new paradoxical issues can be drawn up, in particular: (i) metformin is rarely the sole cause of lactic acidosis; (ii) lactic acidosis in patients receiving metformin therapy is erroneously still considered a single medical entity, as several different scenarios can be defined, with contrasting prognoses. The prognosis for severe lactic acidosis seems even better in metformin-treated patients than in non-metformin users.
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Affiliation(s)
- Jean-Daniel Lalau
- 1] Service d'Endocrinologie et de Nutrition, Centre Hospitalier Universitaire, Amiens, France [2] Unité INSERM U-1088, Université de Picardie Jules Verne, Amiens, France
| | - Paul Arnouts
- Department of Nephrology-Diabetology-Endocrinology, AZ Turnhout, Turnhout, Belgium
| | - Adnan Sharif
- Department of Nephrology and Transplantation, Renal Institute of Birmingham, Queen Elizabeth Hospital, Birmingham, UK
| | - Marc E De Broe
- Laboratory of Pathophysiology, University of Antwerp, Wilrijk, Belgium
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Drug-related problems in patients with benign prostatic hyperplasia: a cross sectional retrospective study. PLoS One 2014; 9:e86215. [PMID: 24475089 PMCID: PMC3903504 DOI: 10.1371/journal.pone.0086215] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2013] [Accepted: 12/07/2013] [Indexed: 11/19/2022] Open
Abstract
Benign Prostatic Hyperplasia (BPH) patients are at risk of acquiring drug-related problems (DRPs), as it is present in the majority of aging men. To date, DRPs among BPH patients have not been well studied. We conducted this retrospective study in a tertiary hospital in Malaysia from January 2009 to June 2012 with the aim of identifying the factors associated with DRPs among BPH patients. The Pharmaceutical Care Network Europe Classification Version (PCNE) 5.01 was used as a tool to classify DRPs. We enrolled 203 patients from 259 hospital admissions. A total of 390 DRPs were found and there was an average of 1.5±1.3 problems per hospitalization. 76.1% of hospital admissions included at least one DRP. The most common DRP categories encountered were drug choice problems (45.9%), drug interactions (24.9%), and dosing problems (13.3%). Factors such as advanced age (p = 0.005), a hospital stay of more than 6 days (p = 0.001), polydrug treatments (p<0.001), multiple comorbidities (p<0.001), and comorbid cardiovascular disease (p = 0.011), diabetes mellitus(p = 0.001), hypertension (p<0.001) and renal impairment (p = 0.011) were significantly associated with the occurrence of DRPs. These data indicated that the prevalence of DRPs is high among BPH patients. The identification of different subtypes of DRPs and the factors associated with DRPs may facilitate risk reduction for BPH patients.
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Gómez-Huelgas R, Martínez-Castelao A, Artola S, Górriz JL, Menéndez E. [Treatment of type 2 diabetes mellitus in patients with chronic kidney disease. Grupo de Trabajo para el Documento de Consenso sobre el tratamiento de la diabetes tipo 2 en el paciente con enfermedad renal crónica]. Med Clin (Barc) 2013; 142:85.e1-10. [PMID: 24268912 DOI: 10.1016/j.medcli.2013.10.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2013] [Revised: 10/21/2013] [Accepted: 10/24/2013] [Indexed: 02/06/2023]
Abstract
Chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) are highly prevalent chronic diseases, which represent an important public health problem and require a multidisciplinary management. T2DM is the main cause of CKD and it also causes a significant comorbidity with regard to non-diabetic nephropathy. Patients with diabetes and kidney disease represent a special risk group as they have higher morbi-mortality as well as higher risk of hypoglycemia than diabetic individuals with a normal kidney function. Treatment of T2DM in patients with CKD is controversial because of the scarcity of available evidence. The current consensus report aims to ease the appropriate selection and dosage of antidiabetic treatments as well as the establishment of safety objectives of glycemic control in patients with CKD.
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Affiliation(s)
| | - Alberto Martínez-Castelao
- Sociedad Española de Nefrología (SEN), Grupo Español de Estudio de la Nefropatía Diabética (GEENDIAB), España
| | - Sara Artola
- Red de Grupos de Estudio de la Diabetes en Atención Primaria (redGDPS), España
| | - José Luis Górriz
- Sociedad Española de Nefrología (SEN), Grupo Español de Estudio de la Nefropatía Diabética (GEENDIAB), España
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Bonsignore A, Pozzi F, Fraternali Orcioni G, Ventura F, Palmiere C. Fatal metformin overdose: case report and postmortem biochemistry contribution. Int J Legal Med 2013; 128:483-92. [PMID: 24202696 DOI: 10.1007/s00414-013-0927-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Accepted: 10/10/2013] [Indexed: 12/18/2022]
Abstract
Metformin is an oral antihyperglycemic agent used in the management of type 2 diabetes mellitus. Lactic acidosis from metformin overdose is a rare complication of metformin therapy and occurs infrequently with therapeutic use. Fatal cases, both accidental and intentional, are extremely rare in clinical practice. Metformin is eliminated by the kidneys, and impaired renal function can result in an increased plasma concentration of the drug. In this report, we describe an autopsy case involving a 70-year-old woman suffering from diabetes mellitus and impaired renal function who received metformin treatment. Metformin concentrations in the peripheral blood collected during hospitalization and femoral blood collected during autopsy were 42 and 47.3 µg/ml, respectively. Lactic acidosis (29.10 mmol/l) was objectified during hospitalization. Furthermore, postmortem biochemistry allowed ketoacidosis to be diagnosed (blood β-hydroxybutyrate, 10,500 µmol/l). Death was attributed to lactic acidosis due to metformin intoxication. Increased plasma concentrations of the drug were attributed to severely impaired renal function. The case emphasizes the usefulness of performing exhaustive toxicology and postmortem biochemistry towards the more complete understanding of the pathophysiological mechanisms that may be involved in the death process.
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Duong JK, Kumar SS, Kirkpatrick CM, Greenup LC, Arora M, Lee TC, Timmins P, Graham GG, Furlong TJ, Greenfield JR, Williams KM, Day RO. Population pharmacokinetics of metformin in healthy subjects and patients with type 2 diabetes mellitus: simulation of doses according to renal function. Clin Pharmacokinet 2013; 52:373-84. [PMID: 23475568 DOI: 10.1007/s40262-013-0046-9] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND OBJECTIVE Metformin is contraindicated in patients with renal impairment; however, there is poor adherence to current dosing guidelines. In addition, the pharmacokinetics of metformin in patients with significant renal impairment are not well described. The aims of this study were to investigate factors influencing the pharmacokinetic variability, including variant transporters, between healthy subjects and patients with type 2 diabetes mellitus (T2DM) and to simulate doses of metformin at varying stages of renal function. METHODS Plasma concentrations of metformin were pooled from three studies: patients with T2DM (study A; n = 120), healthy Caucasian subjects (study B; n = 16) and healthy Malaysian subjects (study C; n = 169). A population pharmacokinetic model of metformin was developed using NONMEM(®) version VI for both the immediate-release (IR) formulation and the extended-release (XR) formulation of metformin. Total body weight (TBW), lean body weight (LBW), creatinine clearance (CLCR; estimated using TBW and LBW) and 57 single-nucleotide polymorphisms (SNPs) of metformin transporters (OCT1, OCT2, OCT3, MATE1 and PMAT) were investigated as potential covariates. A nonparametric bootstrap (n = 1,000) was used to evaluate the final model. This model was used to simulate 1,000 concentration-time profiles for doses of metformin at each stage of renal impairment to ensure metformin concentrations do not exceed 5 mg/l, the proposed upper limit. RESULTS Creatinine clearance and TBW were clinically and statistically significant covariates with the apparent clearance and volume of distribution of metformin, respectively. None of the 57 SNPs in transporters of metformin were significant covariates. In contrast to previous studies, there was no effect on the pharmacokinetics of metformin in patients carrying the reduced function OCT1 allele (R61C, G401S, 420del or G465R). Dosing simulations revealed that the maximum daily doses in relation to creatinine clearance to prescribe to patients are 500 mg (15 ml/min), 1,000 mg (30 ml/min), 2,000 mg (60 ml/min) and 3,000 mg (120 ml/min), for both the IR and XR formulations. CONCLUSION The population model enabled doses of metformin to be simulated for each stage of renal function, to ensure the concentrations of metformin do not exceed 5 mg/l. However, the plasma concentrations of metformin at these dosage levels are still quite variable and monitoring metformin concentrations may be of value in individualising dosage. This study provides confirmatory data that metformin can be used, with appropriate dosage adjustment, in patients with renal impairment.
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Affiliation(s)
- Janna K Duong
- School of Medical Sciences, University of New South Wales, Kensington, Sydney, NSW, Australia
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Affiliation(s)
- W G Herrington
- Oxford Kidney Unit, Churchill Hospital, Oxford University Hospitals NHS Trust, Headington, Oxford OX3 7LJ, UK.
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46
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Lu WR, Defilippi J, Braun A. Unleash metformin: reconsideration of the contraindication in patients with renal impairment. Ann Pharmacother 2013; 47:1488-97. [PMID: 24259604 DOI: 10.1177/1060028013505428] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE To evaluate the expanded use of metformin in renal impairment. DATA SOURCES The MEDLINE database via PubMed, Web of Science, and Cumulative Index to Nursing and Allied Health were searched in August 2013 and included studies from 1950 onward. STUDY SELECTION AND DATA EXTRACTION The search included comparative trials, observational cohort studies, and meta-analyses using the terms diabetes mellitus, metformin, renal insufficiency, and acidosis, lactic. DATA SYNTHESIS One randomized controlled trial, 1 meta-analysis, 1 case-control, and 3 prospective-cohort studies, representing about 150 000 patients, revealed that metformin is safe in patients with stable mild-moderate renal impairment. The incidence of lactic acidosis is low and similar to sulfonylureas. In addition, reduced risks of cardiovascular disease, all-cause mortality, or any acidosis/serious infection were seen with metformin use in mild-to-moderate renal impairment. CONCLUSIONS Data over the past decade refute the historical contraindication in patients with renal impairment and suggest that the risk of metformin-associated lactic acidosis is low in stable mild-to-moderate renal impairment and similar to the risk with other type 2 diabetes mellitus (DM2) medications with no renal impairment restrictions. Because of its unique impact on microvascular and macrovascular complications, it is advantageous to utilize metformin as the cornerstone in DM2 treatment for as long as possible, including in those patients with mild to moderate stages of renal impairment with no additional contraindications. A dosage reduction is recommended if estimated glomerular filtration rate (eGFR) is between 30 and 45 mL/min/1.73 m(2) and discontinuation if eGFR is <30 mL/min/1.73 m(2).
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Affiliation(s)
- Wenya R Lu
- Central Texas Veterans Health Care System, Temple, TX, USA
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Solini A, Penno G, Bonora E, Fondelli C, Orsi E, Trevisan R, Vedovato M, Cavalot F, Cignarelli M, Morano S, Ferrannini E, Pugliese G. Age, Renal Dysfunction, Cardiovascular Disease, and Antihyperglycemic Treatment in Type 2 Diabetes Mellitus: Findings from the Renal Insufficiency and Cardiovascular Events Italian Multicenter Study. J Am Geriatr Soc 2013; 61:1253-61. [DOI: 10.1111/jgs.12381] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Anna Solini
- Department of Clinical and Experimental Medicine; University of Pisa; Pisa Italy
| | - Giuseppe Penno
- Department of Endocrinology and Metabolism; University of Pisa; Pisa Italy
| | - Enzo Bonora
- Division of Endocrinology and Metabolic Diseases; University of Verona; Verona Italy
| | | | - Emanuela Orsi
- Endocrinology and Diabetes Unit; Fondazione IRCCS “Cà Granda-Ospedale Maggiore Policlinico”; Milan Italy
| | | | - Monica Vedovato
- Department of Clinical and Experimental Medicine; University of Padua; Padua Italy
| | - Franco Cavalot
- Unit of Internal Medicine; University of Turin; Turin Italy
| | - Mauro Cignarelli
- Unit of Endocrinology and Metabolic Diseases; University of Foggia; Foggia Italy
| | - Susanna Morano
- Department of Internal Medicine and Medical Specialties; “La Sapienza” University, Rome; Rome Italy
| | - Ele Ferrannini
- Department of Clinical and Experimental Medicine; University of Pisa; Pisa Italy
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine; “La Sapienza” University, Rome; Rome Italy
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Abstract
Metformin as a biguanid drug entered to the market 50 years ago and now is generally recommended as the first-line treatment in type 2 diabetes, especially in overweight patients, however in recent years new indications for its use have emerged . It improves peripheral and liver sensitivity to insulin, reduces basal hepatic glucose production, increases insulin-stimulated uptake and utilization of glucose by peripheral tissues, decreases hunger and causes weight reduction.Recently, much attention has been made toward the possible kidney protective efficacy of metformin. Recent studies have proven that metformin, possesses antioxidant properties, too.
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Affiliation(s)
- Running Hamid Nasri
- Department of Nephrology, Division of Nephropathology, Isfahan University of Medical Sciences, Isfahan, Iran.
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49
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The Role of Metformin in Metformin-Associated Lactic Acidosis (MALA): Case Series and Formulation of a Model of Pathogenesis. Drug Saf 2013; 36:733-46. [DOI: 10.1007/s40264-013-0038-6] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Scheen AJ, Paquot N. Metformin revisited: a critical review of the benefit-risk balance in at-risk patients with type 2 diabetes. DIABETES & METABOLISM 2013; 39:179-90. [PMID: 23528671 DOI: 10.1016/j.diabet.2013.02.006] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Accepted: 02/12/2013] [Indexed: 12/18/2022]
Abstract
Metformin is unanimously considered a first-line glucose-lowering agent. Theoretically, however, it cannot be prescribed in a large proportion of patients with type 2 diabetes because of numerous contraindications that could lead to an increased risk of lactic acidosis. Various observational data from real-life have shown that many diabetic patients considered to be at risk still receive metformin and often without appropriate dose adjustment, yet apparently with no harm done and particularly no increased risk of lactic acidosis. More interestingly, recent data have suggested that type 2 diabetes patients considered at risk because of the presence of traditional contraindications may still derive benefit from metformin therapy with reductions in morbidity and mortality compared with other glucose-lowering agents, especially sulphonylureas. The present review analyzes the benefit-risk balance of metformin therapy in special populations, namely, patients with stable coronary artery disease, acute coronary syndrome or myocardial infarction, congestive heart failure, renal impairment or chronic kidney disease, hepatic dysfunction and chronic respiratory insufficiency, all conditions that could in theory increase the risk of lactic acidosis. Special attention is also paid to elderly patients with type 2 diabetes, a population that is growing rapidly, as older patients can accumulate several comorbidities classically considered contraindications to the use of metformin. A review of the recent scientific literature suggests that reassessment of the contraindications of metformin is now urgently needed to prevent physicians from prescribing the most popular glucose-lowering therapy in everyday clinical practice outside of the official recommendations.
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Affiliation(s)
- A J Scheen
- Division of Diabetes, Nutrition and Metabolic Disorders and Division of Clinical Pharmacology, Department of Medicine, CHU Sart-Tilman (B35), University of Liège, 4000 Liège, Belgium.
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