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PloS One 2020The association between sodium-glucose cotransporter 2 inhibitors (SGLT2i's) and lower extremity amputation is unclear. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The association between sodium-glucose cotransporter 2 inhibitors (SGLT2i's) and lower extremity amputation is unclear.
PURPOSE
To systematically review randomized control trials (RCTs) and observational studies quantifying risk of lower extremity amputations associated with SGLT2i use.
DATA SOURCES AND STUDY SELECTION
We searched PubMed, EMBASE, Scopus, and the Cochrane Central Register of Controlled Trials from January 2011 to February 2020 for RCTs and observational studies including lower extremity amputation outcomes for individuals with type 2 diabetes mellitus treated with SGLT2i's vs. alternative treatments or placebo.
DATA EXTRACTION AND SYNTHESIS
Two reviewers independently extracted data.
MAIN OUTCOMES AND MEASURES
Our primary outcome was risk of lower limb amputation. Secondary outcomes included peripheral arterial disease, peripheral vascular disease, venous ulcerations, and diabetic foot infections. We also evaluated the risk of bias. We conducted random and fixed effects relative risk meta-analysis of RCTs.
RESULTS
After screening 2,006 studies, 12 RCTs and 18 observational studies were included, of which 7 RCTs and 18 observational studies had at least one event. The random effects meta-analysis of 7 RCTs suggested the absence of a statistically significant association between SGLT2i exposure with evidence of substantial statistical heterogeneity (n = 424/23,716 vs n = 267/18,737 in controls; RR 1.28, CI's 0.93-1.76; I2 = 62.0%; p = 0.12) whereas fixed effects analysis showed an increased risk with statistical heterogeneity (RR 1.27, 1.09-1.48; I2 = 62%; p = 0.003). Subgroup analysis of canagliflozin vs placebo showed a statistically significantly increased risk in a fixed effects meta-analysis (n = 2 RCTs, RR 1.59, 1.26-2.01; I2 = 88%; p = 0.0001) whereas the meta-analysis of dapagliflozin or empagliflozin (n = 2 RCTs each) and a single RCT for ertugliflozin did not show a significantly increased risk. The findings from observational studies were too heterogeneous to be pooled in a meta-analysis and draw meaningful conclusions. Both randomized and observational studies were of generally good methodological quality.
CONCLUSIONS
Overall, there was no consistent evidence of SGLT2i exposure and increased risk of amputation. The increased risk of amputation seen in the large, long-term Canagliflozin Cardiovascular Assessment Study (CANVAS) trial for canagliflozin, and select observational studies, merits continued exploration.
Topics: Amputation, Surgical; Benzhydryl Compounds; Glucosides; Humans; Lower Extremity; Peripheral Arterial Disease; Randomized Controlled Trials as Topic; Risk; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds
PubMed: 32502190
DOI: 10.1371/journal.pone.0234065 -
Lakartidningen Feb 2018
Topics: Algorithms; Anticholesteremic Agents; Blood Glucose; Diabetes Mellitus, Type 2; Glycoside Hydrolase Inhibitors; Humans; Incretins; Insulin; Insulin Resistance; Life Style; Metformin; Practice Guidelines as Topic; Sulfonylurea Compounds
PubMed: 29461581
DOI: No ID Found -
Mayo Clinic Proceedings Aug 2019To compare incident dementia risk among patients who initiated treatment with metformin or sulfonylurea in Veterans Health Affairs (VHA) patients with replication in... (Comparative Study)
Comparative Study
OBJECTIVE
To compare incident dementia risk among patients who initiated treatment with metformin or sulfonylurea in Veterans Health Affairs (VHA) patients with replication in Kaiser Permanente Washington (KPW) patients to determine whether first-choice antidiabetic medications are associated with reduced risk of dementia.
PATIENTS AND METHODS
Cohorts contained 75,187 VHA patients and 10,866 KPW patients, 50 years and older, who initiated monotherapy with metformin or sulfonylurea. Patients were free of dementia diagnoses and any diabetes treatment for 2 years before cohort entry. Variables were extracted from electronic health data from VHA (1999-2015) and KPW (1996-2015), which included diagnosis codes, pharmacy data, laboratory values, and demographic characteristics. Propensity scores and inverse probability of treatment weighting controlled for confounding.
RESULTS
Veterans Health Affairs patients were 60.8±6.8 years of age on average, and KPW patients were 63.1±9.5 years of age. In the VHA sample, 72,769 (96.8%) were male; and in the KPW sample, 5480 (50.4%). After adjusting for confounding, metformin initiation was associated with a significantly (P=.02) lower risk of dementia in VHA (hazard ratio, 0.9; 95% CI, 0.9-1.0), with a similar point estimate in KPW (hazard ratio, 0.9; 95% CI, 0.7-1.1). Metformin was not associated with dementia risk in patients 75 years and older.
CONCLUSION
Existing epidemiological studies of metformin and incident dementia have been inconsistent. Using a similar study design in 2 patient populations that differed in clinical and demographic characteristics, our results provide robust evidence that metformin use is associated with a modestly lower risk of incident dementia.
Topics: Age Factors; Aged; Databases, Factual; Dementia; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hospitals, Veterans; Humans; Incidence; Male; Metformin; Middle Aged; Prognosis; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Sex Factors; Sulfonylurea Compounds; United States
PubMed: 31378227
DOI: 10.1016/j.mayocp.2019.01.004 -
Trends in Endocrinology and Metabolism:... Aug 2017Sulfonylureas are the most commonly used second-line drug class for treating type 2 diabetes mellitus (T2DM). While the cardiovascular safety of sulfonylureas has been... (Review)
Review
Sulfonylureas are the most commonly used second-line drug class for treating type 2 diabetes mellitus (T2DM). While the cardiovascular safety of sulfonylureas has been examined in several trials and nonrandomized studies, little is known of their specific effects on sudden cardiac arrest (SCA) and related serious arrhythmic outcomes. This knowledge gap is striking, because persons with DM are at increased risk of SCA. In this review, we explore the influence of sulfonylureas on the risk of serious arrhythmias, with specific foci on ischemic preconditioning, cardiac excitability, and serious hypoglycemia as putative mechanisms. Elucidating the relationship between individual sulfonylureas and serious arrhythmias is critical, especially as the diabetes epidemic intensifies and SCA incidence increases in persons with diabetes.
Topics: Animals; Arrhythmias, Cardiac; Death, Sudden, Cardiac; Diabetes Mellitus, Type 2; Heart Rate; Humans; Hypoglycemic Agents; Incidence; Ischemic Preconditioning, Myocardial; Sulfonylurea Compounds
PubMed: 28545784
DOI: 10.1016/j.tem.2017.04.003 -
Acta Medica Portuguesa Sep 1989With near optimal metabolic control, in diabetes mellitus, hypoglycaemia has become a very important problem. Its main causes are excessive insulin or sulfonylurea... (Review)
Review
With near optimal metabolic control, in diabetes mellitus, hypoglycaemia has become a very important problem. Its main causes are excessive insulin or sulfonylurea dosages, omission of meals, unprogrammed physical exercise or disturbances of the neurohormonal counterregulatory mechanisms.
Topics: Diabetes Mellitus; Humans; Hypoglycemia; Insulin; Sulfonylurea Compounds
PubMed: 2694771
DOI: No ID Found -
Journal of Translational Medicine Sep 2023Previous studies have assessed the association between antidiabetic drugs and stroke risk, but the results are inconsistent. Mendelian randomization (MR) was used to...
BACKGROUND
Previous studies have assessed the association between antidiabetic drugs and stroke risk, but the results are inconsistent. Mendelian randomization (MR) was used to assess effects of antidiabetic drugs on stroke risk.
METHODS
We selected blood glucose-lowering variants in genes encoding antidiabetic drugs targets from genome-wide association studies (GWAS). A two-sample MR and Colocalization analyses were applied to examine associations between antidiabetic drugs and the risk of stroke. For antidiabetic agents that had effect on stroke risk, an independent blood glucose GWAS summary data was used for further verification.
RESULTS
Genetic proxies for sulfonylureas targets were associated with reduced risk of any stroke (OR=0.062, 95% CI 0.013-0.295, P=4.65×10) and any ischemic stroke (OR=0.055, 95% CI 0.010-0.289, P=6.25×10), but not with intracranial hemorrhage. Colocalization supported shared casual variants for blood glucose with any stroke and any ischemic stroke within the encoding genes for sulfonylureas targets (KCNJ11 and ABCC8) (posterior probability>0.7). Furthermore, genetic variants in the targets of insulin/insulin analogues, glucagon-like peptide-1 analogues, thiazolidinediones, and metformin were not associated with the risk of any stroke, any ischemic stroke and intracranial hemorrhage. The association was consistent in the analysis of sulfonylureas with stroke risk using an independent blood glucose GWAS summary data.
CONCLUSIONS
Our findings showed that genetic proxies for sulfonylureas targets by lowering blood glucose were associated with a lower risk of any stroke and any ischemic stroke. The study might be of great significance to guide the selection of glucose-lowering drugs in individuals at high risk of stroke.
Topics: Humans; Hypoglycemic Agents; Blood Glucose; Genome-Wide Association Study; Risk Factors; Sulfonylurea Compounds; Insulin; Stroke; Ischemic Stroke; Intracranial Hemorrhages
PubMed: 37777789
DOI: 10.1186/s12967-023-04565-x -
Molecules (Basel, Switzerland) Sep 2017A series of novel sulfonylurea benzothiazolines was designed by splicing active groups and bioisosterism. A solvent-free synthetic route was developed for the...
A series of novel sulfonylurea benzothiazolines was designed by splicing active groups and bioisosterism. A solvent-free synthetic route was developed for the sulfonylurea benzothiazoline derivatives via the cyclization and carbamylation. All compounds were characterized by IR, ¹H-NMR, C-NMR, HRMS. The biological activity tests indicated the compounds could protect maize against the injury caused by chlorsulfuron to some extent. The molecular docking result showed that the new compound competed with chlorsulfuron to bind with the herbicide target enzyme active site to attain detoxification.
Topics: Benzothiazoles; Molecular Structure; Proton Magnetic Resonance Spectroscopy; Solvents; Sulfonamides; Sulfonylurea Compounds; Triazines
PubMed: 28937640
DOI: 10.3390/molecules22101601 -
European Journal of Pharmacology Oct 2019Type 2 diabetes mellitus (T2DM) is associated with a higher risk of cancer and cancer-related mortality. Increased blood glucose and insulin levels in T2DM patients may...
Type 2 diabetes mellitus (T2DM) is associated with a higher risk of cancer and cancer-related mortality. Increased blood glucose and insulin levels in T2DM patients may be, at least in part, responsible for this effect. Indeed, lowering glucose and/or insulin levels pharmacologically appears to reduce cancer risk and progression, as has been demonstrated for the biguanide metformin in observational studies. Studies investigating the influence of sulfonylurea derivatives (SUs) on cancer risk have provided conflicting results, partly due to comparisons with metformin. Furthermore, little attention has been paid to within-class differences in systemic and off-target effects of the SUs. The aim of this systematic review is to discuss the available preclinical and clinical evidence on how the different SUs influence cancer development and risk. Databases including PubMed, Cochrane, Database of Abstracts on Reviews and Effectiveness, and trial registries were systematically searched for available clinical and preclinical evidence on within-class differences of SUs and cancer risk. The overall preclinical and clinical evidence suggest that the influence of SUs on cancer risk in T2DM patients differs between the various SUs. Potential mechanisms include differing affinities for the sulfonylurea receptors and thus differential systemic insulin exposure and off-target anti-cancer effects mediated for example through potassium transporters and drug export pumps. Preclinical evidence supports potential anti-cancer effects of SUs, which are of interest for further studies and potentially repurposing of SUs. At this time, the evidence on differences in cancer risk between SUs is not strong enough to guide clinical decision making.
Topics: Animals; Carcinogenesis; Humans; Neoplasms; Risk; Sulfonylurea Compounds
PubMed: 31408647
DOI: 10.1016/j.ejphar.2019.172598 -
Diabetologia May 2013Sulfonylureas are widely prescribed glucose-lowering medications for diabetes, but the extent to which they improve glycaemia is poorly documented. This systematic... (Meta-Analysis)
Meta-Analysis Review
AIMS/HYPOTHESIS
Sulfonylureas are widely prescribed glucose-lowering medications for diabetes, but the extent to which they improve glycaemia is poorly documented. This systematic review evaluates how sulfonylurea treatment affects glycaemic control.
METHODS
Medline, EMBASE, the Cochrane Library and clinical trials registries were searched to identify double-blinded randomised controlled trials of fixed-dose sulfonylurea monotherapy or sulfonylurea added on to other glucose-lowering treatments. The primary outcome assessed was change in HbA1c, and secondary outcomes were adverse events, insulin dose and change in body weight.
RESULTS
Thirty-one trials with a median duration of 16 weeks were included in the meta-analysis. Sulfonylurea monotherapy (nine trials) lowered HbA1c by 1.51% (17 mmol/mol) more than placebo (95% CI, 1.25, 1.78). Sulfonylureas added to oral diabetes treatment (four trials) lowered HbA1c by 1.62% (18 mmol/mol; 95% CI 1.0, 2.24) compared with the other treatment, and sulfonylurea added to insulin (17 trials) lowered HbA1c by 0.46% (6 mmol/mol; 95% CI 0.24, 0.69) and lowered insulin dose. Higher sulfonylurea doses did not reduce HbA1c more than lower doses. Sulfonylurea treatment resulted in more hypoglycaemic events (RR 2.41, 95% CI 1.41, 4.10) but did not significantly affect the number of other adverse events. Trial length, sulfonylurea type and duration of diabetes contributed to heterogeneity.
CONCLUSIONS/INTERPRETATION
Sulfonylurea monotherapy lowered HbA1c level more than previously reported, and we found no evidence that increasing sulfonylurea doses resulted in lower HbA1c. HbA1c is a surrogate endpoint, and we were unable to examine long-term endpoints in these predominately short-term trials, but sulfonylureas appear to be associated with an increased risk of hypoglycaemic events.
Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Evidence-Based Medicine; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Randomized Controlled Trials as Topic; Sulfonylurea Compounds
PubMed: 23494446
DOI: 10.1007/s00125-013-2856-6 -
International Journal of Molecular... Aug 2022New quinazoline-sulfonylurea hybrids were prepared and examined for their in vivo anti-hyperglycemic activities in STZ-induced hyperglycemic rats using glibenclamide as...
Design, Synthesis, Molecular Modeling and Anti-Hyperglycemic Evaluation of Quinazoline-Sulfonylurea Hybrids as Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) and Sulfonylurea Receptor (SUR) Agonists.
New quinazoline-sulfonylurea hybrids were prepared and examined for their in vivo anti-hyperglycemic activities in STZ-induced hyperglycemic rats using glibenclamide as a reference drug. Compounds VI-6-a, V, IV-4, VI-4-c, IV-6, VI-2-a, IV-1, and IV-2 were more potent than the reference glibenclamide. They induced significant reduction in the blood glucose levels of diabetic rats: 78.2, 73.9, 71.4, 67.3, 62, 60.7, 58.4, and 55.9%, respectively, while the reference glibenclamide had 55.4%. Compounds IV-1, VI-2-a, IV-2, V, and IV-6 showed more prolonged antidiabetic activity than glibenclamide. Moreover, molecular docking and pharmacokinetic studies were performed to examine binding modes of the prepared compounds against peroxisome proliferator-activated receptor gamma (PPARγ). The highest active compounds exhibited good binding affinity with high free energy of binding against PPARγ. In silico absorption, distribution, metabolism, elimination and toxicity (ADMET) studies were performed to investigate pharmacokinetics and safety of the synthesized compounds. They showed considerable human intestinal absorption with low toxicity profile.
Topics: Animals; Diabetes Mellitus, Experimental; Glyburide; Humans; Hypoglycemic Agents; Molecular Docking Simulation; PPAR gamma; Quinazolines; Rats; Sulfonylurea Compounds; Sulfonylurea Receptors
PubMed: 36077003
DOI: 10.3390/ijms23179605