STOCKHOLM – While they are effective glucose-lowering agents, sulfonylureas seem to substantially increase the risk for cardiovascular events relative to other antihyperglycemic agents, according to several presentations given at the annual meeting of the European Association for the Study of Diabetes.
In a systematic review and meta-analysis of 84 randomized controlled trials (RCTs) and 26 observational studies, accounting for more than 36,573 and more than 1.5 million subjects with type 2 diabetes mellitus, respectively, treatment with a sulfonylurea was found to significantly increase all-cause mortality and cardiovascular-related mortality when compared to no active treatment or placebo and to other antidiabetic drugs.
In the RCTs, the hazard ratios comparing sulfonylureas to all treatments combined were 1.26 (95% confidence interval, 1.10-1.44) for all-cause mortality and 1.46 (95% CI, 1.21-1.77) for cardiovascular mortality. HR for CV mortality was highest when comparing sulfonylureas with GLP-1 agonists and SGLT-2 inhibitors, at 45.4 (95% CI, 2.07-362.8) and 42.6 (95% CI, 1.71-359.1), with significantly elevated risk also seen when compared with DPP-4 inhibitors (HR, 4.42; 95% CI, 1.92-13.0), thiazolidinediones (HR, 3.05; 95% CI, 1.79-5.54), and insulin (HR, 1.30; 95% CI, 1.02-1.66).
There was also an increase in the risk for acute myocardial infarction and stroke in some comparisons of sulfonylureas versus other treatments.
“We think this study is the most comprehensive review of RCTs and observational studies to compare CV-related outcomes and all-cause mortality among patients receiving sulfonylureas versus [other] antidiabetic agents,” said Dr. Steve Bain of Abertawe Bro Morgannwg University NHS Trust in Swansea, England.
“We accept that the confidence intervals were wide, but there is a tendency for all significant results to trend in the same direction.” Results of the observational studies analyses generally supported the results from the RCTs, he added. A notable limitation was that there had been no differentiation between the risk according to different sulfonylureas. Dr. Bain said this was to try to keep the number of patients available for analysis as high as possible in the sulfonylurea group.
Data from the German CREST (CV Risk and Events on SU Treatment) study also showed that there was a higher CV risk associated with sulfonylureas when compared with metformin in patients newly diagnosed with type 2 diabetes mellitus. The retrospective cohort database study included more than 35,000 individuals, of whom 26,883 received no antihyperglycemic treatment or treatment with an antihyperglycemic agent other than a sulfonylurea or metformin between January 2010 and December 2011, leaving 7,874 who were given metformin monotherapy and 904 given sulfonylurea monotherapy. Propensity score matching was used to form the final study groups consisting of 730 patients each.
Crude, propensity-matched, and adjusted HRs for death comparing sulfonylurea with metformin as first-line treatment were 3.32 (95% CI, 2.6-4.3; P less than .001), 1.4 (95% CI, 0.9-2.3; P less than .12), and 2.01 (95% CI, 1.5-2.6; P less than .001), respectively. Corresponding HRs for major cardiovascular events (MACE) were 1.9 (95% CI, 1.4-2.4; P less than .001), 1.4 (95% CI, 0.9-2.2; P less than .14), and 1.3 (95% CI, 1.03-1.74; P less than .05).
Dr. Thomas Wilke of the University of Wismar (Germany) who presented the CREST study findings, noted that there were some differences between the groups in terms of the baseline demographics, with those receiving sulfonylureas being somewhat older and more likely to be women, have comorbid disease, and discontinue monotherapy earlier than patients treated with metformin, or possibly be more likely to have contraindications to the use of metformin.
“Taking these differences into account, patients treated with sulfonylureas seem to be at increased risk of death, MACE, and type 2 diabetes hospitalization, compared with metformin-treated patients,” in this German population, Dr. Wilke concluded.
Finally, Dr. Jan Eriksson of Uppsala (Sweden) University presented findings from an observational study of more than 50,000 patients with type 2 diabetes treated with a combination of two noninsulin antidiabetic agents between 2006 and 2013. Of these, 40,736 had received metformin in combination with a sulfonylurea and 12,024 had received a combination of metformin and a DPP-4 inhibitor and were studied further.
Compared with the patients who received a DPP-4 inhibitor on top of metformin, those who received a sulfonylurea had an increased risk of both fatal and nonfatal cardiovascular disease (HR, 1.17; 95% CI, 1.01-1.37) and death from any cause (HR, 1.25; 95% CI, 1.02-1.54) even in the presence of confounding factors such as age, gender, existing cardiovascular disease, and cardio-preventative medication use.
The risk for severe hypoglycemia was also greater with sulfonylurea than DPP-4 use (HR, 2.07; 95% CI, 1.11-3.86), and experiencing severe hypoglycemia was associated with an increased risk for cardiovascular events (HR, 1.51; 95% CI, 1.21-1.88).