The Association between Sulfonylurea Use and All-Cause and Cardiovascular Mortality: A Meta-Analysis with Trial Sequential Analysis of Randomized Clinical Trials

Background: Sulfonylureas are an effective and inexpensive treatment for type 2 diabetes. There is conflicting data about the safety of these drugs regarding mortality and cardiovascular outcomes. The objective of the present study was to evaluate the safety of the sulfonylureas most frequently used and to use trial sequential analysis (TSA) to analyze whether the available sample was powered enough to support the results. Methods and Findings: Electronic databases were reviewed from 1946 (Embase) or 1966 (MEDLINE) up to 31 December 2014. Randomized clinical trials (RCTs) of at least 52 wk in duration evaluating second- or third-generation sulfonylureas in the treatment of adults with type 2 diabetes and reporting outcomes of interest were included. Primary outcomes were all-cause and cardiovascular mortality. Additionally, myocardial infarction and stroke events were evaluated. Data were summarized with Peto odds ratios (ORs), and the reliability of the results was evaluated with TSA. Forty-seven RCTs with 37,650 patients and 890 deaths in total were included. Sulfonylureas were not associated with all-cause (OR 1.12 [95% CI 0.96 to 1.30]) or cardiovascular mortality (OR 1.12 [95% CI 0.87 to 1.42]). Sulfonylureas were also not associated with increased risk of myocardial infarction (OR 0.92 [95% CI 0.76 to 1.12]) or stroke (OR 1.16 [95% CI 0.81 to 1.66]). TSA could discard an absolute difference of 0.5% between the treatments, which was considered the minimal clinically significant difference. The major limitation of this review was the inclusion of studies not designed to evaluate safety outcomes. Conclusions: Sulfonylureas are not associated with increased risk for all-cause mortality, cardiovascular mortality, myocardial infarction, or stroke. Current evidence supports the safety of sulfonylureas; an absolute risk of 0.5% could be firmly discarded. Review registration: PROSPERO CRD42014004330 In a meta-analysis of randomized clinical trials, Dimitris Rados and colleagues find that sulfonylurea use is not associated with an increased risk of all-cause or cardiovascular mortality.Background: Worldwide, more than 400,000 people have diabetes, a chronic condition characterized by poor glycemic control—dangerously high levels of glucose (sugar) in the blood (hyperglycemia). Blood sugar levels are usually controlled by insulin, a hormone released by beta cells in the pancreas after meals (glucose levels in the blood increase when food is digested and glucose is absorbed). In people with type 2 diabetes (the most common type of diabetes), blood sugar control fails because the fat and muscle cells that normally respond to insulin by removing excess sugar from the blood become resistant to insulin. Type 2 diabetes can often be controlled initially with diet and exercise and with antidiabetic drugs such as metformin (which suppresses glucose production by the liver) and sulfonylureas (which stimulate the secretion of insulin by the pancreas). However, as the disease progresses, the pancreatic beta cells become impaired, and many patients eventually need insulin injections to prevent hyperglycemia. Long-term complications of diabetes, which include an increased risk of cardiovascular problems such as heart attacks (myocardial infarctions) and stroke, reduce the life expectancy of people with diabetes by about ten years compared to people without diabetes. Why Was This Study Done?: Sulfonylureas have been used for decades to improve glycemic control in people with diabetes, but doubts about their safety were first raised in 1970. Since then, there have been conflicting reports about whether these inexpensive but effective drugs are associated with an increased risk of cardiovascular events and death. Because at least 20%–30% of people with diabetes in high-income countries take second- or third-generation sulfonylureas, such as glipizide and glimepiride, it is important to know whether sulfonylurea use increases the risk of a cardiovascular event or death by even a small amount. Here, the researchers evaluate the safety of the most widely used sulfonylureas by undertaking a systematic review and meta-analysis, with trial sequential analysis, of randomized clinical trials (RCTs) that evaluated second- or third-generation sulfonylureas for the treatment of adults with type 2 diabetes. A systematic review uses predefined criteria to identify all the research on a given topic, a meta-analysis combines the results of several trials, and trial sequential analysis is used to establish whether the sample size of a meta-analysis is sufficiently large to reach firm conclusions about the effect of interventions. What Did the Researchers Do and Find?: The researchers identified 47 RCTs that met their criteria for inclusion in their study. In total, these RCTs involved 37,650 patients, 890 of whom died during follow-up. Meta-analysis of the results of these trials indicated that sulfonylurea use was not associated with an increased risk of all-cause mortality (death) or cardiovascular mortality. Moreover, sulfonylurea use was not associated with an increased risk of myocardial infarction or stroke. Trial sequential analysis indicated that the sample size in the meta-analysis was large enough that sufficient information was included in the analysis to conclude that fewer than one in 200 patients were likely to have been harmed by the use of sulfonylureas. That is, trial sequential analysis excluded the possibility that—compared to placebo (dummy drug), diet, or an active comparator drug—sulfonylurea use was associated with more than one death (or major cardiovascular event) in every 200 treated patients, which the researchers defined as the minimal clinically significant difference. Importantly, this finding did not change when sulfonylureas were used as an add-on to metformin treatment. What Do These Findings Mean?: These findings suggest that sulfonylureas are not associated with a clinically significant increased risk for all-cause mortality, cardiovascular mortality, myocardial infarction, or stroke. The accuracy of these findings may be affected by some aspects of the researchers’ analyses, such as the inclusion of studies in their meta-analysis that were not designed to evaluate safety outcomes. Moreover, because this study was not designed to compare different sulfonylureas, further studies are needed to evaluate whether all second- and third-generation sulfonylureas are associated with similar all-cause and cardiovascular mortality risks. Overall, however, these findings are reassuring, and the researchers conclude that sulfonylureas should continue to be used in patients with type 2 diabetes provided their efficacy in controlling hyperglycemia outweighs the risks of weight gain and hypoglycemia (low blood sugar) that are known to be associated with these drugs. Additional Information: This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001992.