Comparative Study

Authors: Natalie McCormick, Chio Yokose, Na Lu...

IMPORTANCE

Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) are a revolutionary treatment for type 2 diabetes (T2D) with cardiovascular, kidney, and serum urate-lowering benefits.

OBJECTIVE

To compare risk of incident gout and rate of recurrent flares between patients with T2D initiating SGLT2i vs sulfonylurea, most common second-line glucose-lowering therapy, when added to metformin monotherapy.

DESIGN, SETTING, AND PARTICIPANTS

This sequential, propensity score-matched, new-user comparative effectiveness study using target trial emulation framework included adults with T2D receiving metformin monotherapy in a Canadian general population database from January 1, 2014, to June 30, 2022.

EXPOSURES

Initiation of SGLT2i vs sulfonylurea.

MAIN OUTCOMES AND MEASURES

The primary outcome was incident gout diagnosis, ascertained by emergency department (ED), hospital, outpatient, and medication dispensing records. Secondary outcomes were gout-primary hospitalizations and ED visits and major adverse cardiovascular events (MACE), as well as recurrent flare rates among prevalent gout patients. Heart failure (HF) hospitalization was assessed as positive control outcome and osteoarthritis encounters as negative control. For target trial emulations, we used Cox proportional hazards and Poisson regressions with 1:1 propensity score matching (primary analysis) and overlap weighting (sensitivity analysis). The analysis was conducted from September to December, 2023.

RESULTS

Among 34 604 propensity score matched adults with T2D initiating SGLT2i or sulfonylurea (20 816 [60%] male, mean [SD] age, 60 [12.4] years), incidence of gout was lower among SGLT2i initiators (4.27 events per 1000 person-years) than sulfonylurea initiators (6.91 events per 1000 person-years), with a hazard ratio (HR) of 0.62 (95% CI, 0.48-0.80) and a rate difference (RD) of -2.64 (95% CI, -3.99 to -1.29) per 1000 person-years. Associations persisted regardless of sex, age, or baseline diuretic use. SGLT2i use was also associated with fewer recurrent flares among gout patients (rate ratio, 0.67; 95% CI, 0.55-0.82; and RD, -20.9; 95% CI, -31.9 to -10.0 per 1000 person-years). HR and RD for MACE associated with SGLT2i use were 0.87 (95% CI, 0.77-0.98) and -3.58 (95% CI, -6.19 to -0.96) per 1000 person-years. For control outcomes, SGLT2i users had lower risk of HF (HR, 0.53; 95% CI, 0.38-0.76), as expected, with no difference in osteoarthritis (HR, 1.11; 95% CI, 0.94-1.34). Results were similar when applying propensity score overlap weighting.

CONCLUSIONS

In this population-based cohort study, the gout and cardiovascular benefits associated with SGLT2i in these target trial emulations may guide selection of glucose-lowering therapy in patients with T2D, at risk for or already with gout.

Topics: Humans; Diabetes Mellitus, Type 2; Sodium-Glucose Transporter 2 Inhibitors; Gout; Male; Female; Middle Aged; Sulfonylurea Compounds; Metformin; Hypoglycemic Agents; Aged; Propensity Score; Canada

PubMed: 38619822
DOI: 10.1001/jamainternmed.2024.0376

Authors: Yahui Zhu, Mao Li, Hongfen Wang...

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

Review

Authors: A Fagulha

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

Authors: Anne M Hendriks, Dennis Schrijnders, Nanne Kleefstra...

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

Review

Authors: Jingqian Su, Jingran Xu, Shan Hu...

Diabetes, a metabolic disease caused by abnormally high levels of blood glucose, has a high prevalence rate worldwide and causes a series of complications, including coronary heart disease, stroke, peripheral vascular disease, end-stage renal disease, and retinopathy. Small-molecule compounds have been developed as drugs for the treatment of diabetes because of their oral advantages. Insulin secretagogues are a class of small-molecule drugs used to treat diabetes, and include sulfonylureas, non-sulfonylureas, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase 4 inhibitors, and other novel small-molecule insulin secretagogues. However, many small-molecule compounds cause different side effects, posing huge challenges to drug monotherapy and drug selection. Therefore, the use of different small-molecule drugs must be improved. This article reviews the mechanism, advantages, limitations, and potential risks of small-molecule insulin secretagogues to provide future research directions on small-molecule drugs for the treatment of diabetes.

Topics: Humans; Hypoglycemic Agents; Animals; Insulin; Diabetes Mellitus; Sulfonylurea Compounds; Dipeptidyl-Peptidase IV Inhibitors; Secretagogues; Insulin Secretion; Blood Glucose; Glucagon-Like Peptide-1 Receptor; Diabetes Mellitus, Type 2; Insulin Secretagogues; Glucagon-Like Peptide-1 Receptor Agonists

PubMed: 39059347
DOI: 10.1016/j.biopha.2024.117179

Comparative Study

Authors: Jeffrey F Scherrer, Joanne Salas, James S Floyd...

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

Authors: Ying Fu, Jing-Yi Wang, Dong Zhang...

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

Review

Authors: Charles E Leonard, Sean Hennessy, Xu Han...

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

Meta-Analysis Review

Authors: J A Hirst, A J Farmer, A Dyar...

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

Comparative Study

Authors: Matteo Franchi, Giacomo Pellegrini, Angelo Avogaro...

INTRODUCTION

We aimed to compare the effectiveness and cost-effectiveness profiles of glucagon-like peptide-1 receptor agonist (GLP-1-RA), sodium-glucose cotransporter 2 inhibitor (SGLT2i), and dipeptidyl peptidase-4 inhibitor (DPP-4i) compared with sulfonylureas and glinides (SU).

RESEARCH DESIGN AND METHODS

Population-based retrospective cohort study based on linked regional healthcare utilization databases. The cohort included all residents in Lombardy aged ≥40 years, treated with metformin in 2014, who started a second-line treatment between 2015 and 2018 with SU, GLP-1-RA, SGLT2i, or DPP-4i. For each cohort member who started SU, one patient who began other second-line treatments was randomly selected and matched for sex, age, Multisource Comorbidity Score, and previous duration of metformin treatment. Cohort members were followed up until December 31, 2022. The association between second-line treatment and clinical outcomes was assessed using Cox proportional hazards models. The incremental cost-effectiveness ratios (ICERs) were calculated and compared between newer diabetes drugs and SU.

RESULTS

Overall, 22 867 patients with diabetes were included in the cohort, among which 10 577, 8125, 2893 and 1272 started a second-line treatment with SU, DPP-4i, SGLT2i and GLP-1-RA, respectively. Among these, 1208 patients for each group were included in the matched cohort. As compared with SU, those treated with DPP-4i, SGLT2i and GLP-1-RA were associated to a risk reduction for hospitalization for major adverse cardiovascular events (MACE) of 22% (95% CI 3% to 37%), 29% (95% CI 12% to 44%) and 41% (95% CI 26% to 53%), respectively. The ICER values indicated an average gain of €96.2 and €75.7 each month free from MACE for patients on DPP-4i and SGLT2i, respectively.

CONCLUSIONS

Newer diabetes drugs are more effective and cost-effective second-line options for the treatment of type 2 diabetes than SUs.

Topics: Humans; Diabetes Mellitus, Type 2; Male; Cost-Benefit Analysis; Female; Sulfonylurea Compounds; Retrospective Studies; Hypoglycemic Agents; Middle Aged; Aged; Dipeptidyl-Peptidase IV Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Follow-Up Studies; Treatment Outcome; Adult; Blood Glucose

PubMed: 38802266
DOI: 10.1136/bmjdrc-2023-003991