Sulphonylureas versus metformin and the risk of ventricular arrhythmias among people with type 2 diabetes: A population‐based cohort study

Abstract

Aim To determine whether the use of sulphonylurea monotherapy, compared with metformin monotherapy, is associated with an increased risk of ventricular arrhythmia (VA) among patients initiating pharmacotherapy for type 2 diabetes. Research Design and Methods We conducted a population‐based cohort study using electronic health data extracted from the UK's Clinical Practice Research Datalink Aurum. Using the active comparator, new‐user cohort design, we compared rates of VA among patients aged 18 years or older using sulphonylurea monotherapy with those using metformin monotherapy as their initial pharmacological treatment for type 2 diabetes from April 1998 to December 2019. We used a Cox proportional hazards model with inverse probability of treatment weighting by propensity score to estimate the adjusted hazard ratio (aHR) and a corresponding bootstrap 95% confidence interval (CI) for VA with sulphonylurea monotherapy versus metformin monotherapy. Results The cohort included 92 638 new users of sulphonylurea and 506 882 new users of metformin. A total of 279 VA events occurred among sulphonylurea users (rate per 10 000 person‐years: 25.5, 95% CI: 22.7 to 28.7) and 1537 VA events occurred among metformin users (rate per 10 000 person‐years: 18.5, 95% CI: 17.6 to 19.5). Compared with metformin, sulphonylureas were associated with an increased risk of VA (aHR: 1.42, 95% CI: 1.18 to 1.69). Conclusions Sulphonylureas are associated with an increased risk of VA when used as first‐line therapy for type 2 diabetes relative to metformin use. This increased risk should be considered when prescribing sulphonylureas as an initial treatment for type 2 diabetes.

Associations between Oral Glucose-Lowering Agents and Increased Risk for Life-Threatening Arrhythmias in Patients with Type 2 Diabetes Mellitus—A Literature Review

“…A similar study from 2022 is the one published in 2023 by Islam et al [38] conducted on adult patients newly treated with sulfonylurea monotherapy in comparison to those who received metformin monotherapy. From the UK's Clinical Practice Research Datalink Aurum, the authors identified 92,638 new users of sulfonylurea and 506,882 new users of metformin.…”

“…Numerous clinical trials have been performed and, subsequently, abundant medical literature has been written, especially in the years since the development of new classes of GLA with favorable CV effects. By contrary, less information on their potential association with VA and/or SCA are available [1,[38][39][40]. However, there are several studies (19 of them analyzed in this review), and even some meta-analyses [15,16,20,41,42], most of them focusing on SGLT2, written in the last five years.…”

“…Accurate data on its effects on arrhythmias, especially on VA or SCA, are missing [16,42]. In our research, by analyzing seven studies who aimed to highlight if therapy with metformin decreases the risk of VA and/or SCA, most of them comparing diabetic patients treated with this drug to other therapies [8,25,29,31], although evidencing a beneficial effect on general mortality and rate of major CV events, and apparently on supraventricular arrhythmias, failed to emphasize a certain positive influence on VA and SCA [29,31,38]. However, most studies demonstrate that the incidence of VA, specifically SCA, is lower in patients treated with metformin in comparison to those receiving sulfonylurea products [31,33,38].…”

“…In our research, by analyzing seven studies who aimed to highlight if therapy with metformin decreases the risk of VA and/or SCA, most of them comparing diabetic patients treated with this drug to other therapies [8,25,29,31], although evidencing a beneficial effect on general mortality and rate of major CV events, and apparently on supraventricular arrhythmias, failed to emphasize a certain positive influence on VA and SCA [29,31,38]. However, most studies demonstrate that the incidence of VA, specifically SCA, is lower in patients treated with metformin in comparison to those receiving sulfonylurea products [31,33,38]. The studies analyzing the impact of second generation of sulfonylurea on VA and SCA, most of them realized in comparison to metformin, revealed a higher incidence of malignant arrhythmias, probably explained by the interference of this class of medication on ATP modulated K channels, altogether with potential episodes of hypoglycemia [31,33,38].…”

“…However, most studies demonstrate that the incidence of VA, specifically SCA, is lower in patients treated with metformin in comparison to those receiving sulfonylurea products [31,33,38]. The studies analyzing the impact of second generation of sulfonylurea on VA and SCA, most of them realized in comparison to metformin, revealed a higher incidence of malignant arrhythmias, probably explained by the interference of this class of medication on ATP modulated K channels, altogether with potential episodes of hypoglycemia [31,33,38]. However, sulfonylurea is a heterogeneous group and differences regarding the arrhythmogenic risk between its drugs have been evidenced [18,25,29,31].…”