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Mortality risk among sulfonylureas: a systematic review and network meta-analysis

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Summary

Background

Sulfonylureas are common second-line options for management of type 2 diabetes; however, they are associated with a higher risk of cardiovascular events compared with other antidiabetic drugs. Since tissue selectivity and risk of hypoglycaemia differ among sulfonylureas, we aimed to assess whether mortality and the risk of cardiovascular events also varies.

Methods

We searched Medline and Embase from inception to June 11, 2014, to identify controlled studies reporting the risk of all-cause mortality, cardiovascular-related mortality, or myocardial infarction for at least two sulfonylureas. We examined differences in cardiovascular event risk among sulfonylureas with random effects models for direct pairwise comparisons and network meta-analyses to incorporate direct and indirect data.

Findings

14 970 (9%) of 167 327 patients in 18 studies died: 841 (4%) of 19 334 gliclazide users, 5482 (11%) of 49 389 glimepiride users, 2106 (15%) of 14 464 glipizide users, 5296 (7%) of 77 169 glibenclamide users, 1066 (17%) of 6187 tolbutamide users, and 179 (23%) of 784 chlorpropamide users. Inconsistency was low for the network meta-analysis of all-cause mortality, and the relative risk of death compared with glibenclamide was 0·65 (95% credible interval 0·53–0·79) for gliclazide, 0·83 (0·68–1·00) for glimepiride, 0·98 (0·80–1·19) for glipizide, 1·13 (0·90–1·42) for tolbutamide, and 1·34 (0·98–1·86) for chlorpropamide. Similar associations were noted for cardiovascular-related mortality: the relative risk compared with glibenclamide was 0·60 (95% credible interval 0·45–0·84) for gliclazide, 0·79 (0·57–1·11) for glimepiride, 1·01 (0·72–1·43) for glipizide, 1·11 (0·79–1·55) for tolbutamide, and 1·45 (0·88–2·44) for chlorpropamide.

Interpretation

Gliclazide and glimepiride were associated with a lower risk of all-cause and cardiovascular-related mortality compared with glibenclamide. Clinicians should consider possible differences in risk of mortality when selecting a sulfonylurea.

Funding

None.

Introduction

Sulfonylureas are recommended in clinical practice guidelines for management of patients with type 2 diabetes because they effectively lower blood glucose and reduce the risk of microvascular complications such as nephropathy and retinopathy.1, 2, 3 However, debate regarding the cardiovascular safety of sulfonylureas is ongoing.4 Findings from several studies and meta-analyses suggest that sulfonylureas are associated with a significantly higher risk of mortality and adverse cardiovascular events than metformin and other antidiabetic drugs.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15

Two mechanisms are often proposed to explain the higher risk of adverse cardiovascular effects associated with sulfonylureas. The first plausible biological mechanism centres on an extension of the beneficial pharmacological action of sulfonylureas. These drugs bind to sulfonylurea receptors (SUR1) on pancreatic β cells and inhibit ATP-sensitive potassium channels; this process promotes insulin release and lowers blood glucose concentrations.16 However, sulfonylureas also bind to receptors on myocardial (SUR2A) and vascular smooth muscle (SUR2B) cells, so can inhibit cardiac ATP-sensitive potassium channels.16, 17 Binding of sulfonylureas to SUR2A or SUR2B receptors can interfere with ischaemic conditioning—an endogenous cardiac protective mechanism—and possibly with cardiac conduction.18, 19 Findings from studies of animal models have shown that sulfonylureas binding to SUR2A or SUR2B receptors can abolish the beneficial effects of ischaemic conditioning.20, 21 The affinity characteristics seem to vary among sulfonylureas towards SUR1, SUR2A, and SUR2B, with some—such as gliclazide—binding selectively to SUR1 when given at usual therapeutic doses, and others—such as glibenclamide—binding to sulfonylurea receptors in both the heart and pancreas when given at therapeutic doses.16, 19, 22

The second plausible mechanism for the higher risk of adverse cardiovascular effects associated with sulfonylureas involves hypoglycaemia—a common, well known adverse effect of sulfonylurea treatment. Episodes of hypoglycaemia can prolong the QT interval and are associated with cardiac ischaemia.23, 24 A prolonged QT interval and cardiac ischaemia can increase the risk of adverse cardiovascular events, such as ventricular arrhythmias, myocardial infarction, and sudden cardiac death.25 Differences in SUR1 receptor affinity and pharmacokinetic properties seem to create differences in the risk of hypoglycaemia, with glibenclamide, which has the highest affinity for SUR1,22 having the highest risk among the sulfonylureas.26, 27 Other mechanisms that might explain the increased risk of cardiovascular events with sulfonylureas compared with other antidiabetic drugs include increased secretion of intact proinsulin, increased amount of visceral adipose tissue, and weight gain.28, 29

Despite this controversy regarding cardiovascular safety, sulfonylureas remain the most commonly used second-line oral antidiabetic drugs in patients with type 2 diabetes when metformin monotherapy does not successfully control blood glucose or is contraindicated.30, 31, 32, 33 Regardless of the mechanism, assessment of whether the risk of adverse cardiovascular events is similar among sulfonylureas is important. Ideally, the question of relative cardiovascular safety among sulfonylureas should be tested in a randomised controlled trial. Although seven studies have randomly allocated patients to more than one sulfonylurea and reported deaths or cardiovascular events, there are important limitations to this source of evidence.3, 34, 35, 36, 37, 38, 39 First, the UK Prospective Diabetes Study (UKPDS)3 was the only trial to report cardiovascular events as prespecified outcomes. Second, the remaining six randomised controlled trials34, 35, 36, 37, 38, 39 were not designed to examine risk of adverse cardiovascular events and therefore had insufficient power because of small sample sizes (30–1044 patients enrolled), short follow-up (median 6 months), and few reported events (24 deaths in total). In the absence of definitive evidence from randomised controlled trials, observational studies and meta-analyses of these data can provide information to help guide treatment decisions.40

Network meta-analyses are regarded as an important source of information to compare the safety or efficacy of several treatment options.41 This analytical technique is increasingly used to synthesise evidence from both direct and indirect comparisons to assess the effect of different treatment options on an outcome of interest.42, 43

We undertook a network meta-analysis to compare the relative risk of mortality and adverse cardiovascular events among sulfonylureas. On the basis of our previous findings,22, 44 we hypothesised that gliclazide use would be associated with a significantly lower risk of mortality and adverse cardiovascular events compared with glibenclamide use.

Section snippets

Search strategy and selection criteria

We followed standard methodology to undertake and report a systematic review and network meta-analysis.45, 46, 47, 48 We searched Medline and Embase from inception to June 11, 2014, with database-appropriate terms and text words for type 2 diabetes, sulfonylureas, and comparative study; we excluded review articles, editorials, commentaries, and animal studies (appendix). We supplemented the electronic database search by examining reference lists of potentially relevant studies and review

Results

The literature search identified 5669 unique citations; after screening the titles and abstracts, 469 papers were deemed potentially relevant (figure 1). We requested additional information from the authors of 46 studies (9·8%) and disagreed on the inclusion of eight (1·7%) articles. 24 studies met all inclusion criteria.

The table summarises characteristics of the seven studies that randomly allocated patients to different sulfonylureas3, 34, 35, 36, 37, 38, 39 and 17 observational studies in

Discussion

In this systematic review, we identified 24 controlled studies that reported the risk of adverse cardiovascular outcomes for two or more sulfonylureas. We were able to combine mortality data from 23 of these studies that enrolled a total of 172 349 patients who used a sulfonylurea; 18 of these studies (167 327 patients) were included in our main analyses. In all direct or direct and indirect analyses, gliclazide use was associated with a significantly lower risk of all-cause and

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