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Long-acting vs. short-acting sulfonylureas present no CV risk increase
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The risk for major adverse cardiovascular events did not significantly differ between adults with type 2 diabetes who used long-acting or short-acting sulfonylureas, but the risk for severe hypoglycemia was higher with long-acting sulfonylurea use, according to findings.
Samy Suissa, PhD, of the Centre for Clinical Endocrinology, Lady Davis Institute, Jewish General Hospital in Montreal, and colleagues evaluated data from the U.K. Clinical Practice Research Datalink from 1998 to 2013 on adults (mean age, 68 years) with type 2 diabetes (mean duration of nonpharmacologically treated diabetes, 1.6 years) newly treated with nonspecific, long-acting sulfonylureas (n = 1,863) or specific, short-acting sulfonylureas (n = 15,741) to compare the risks for acute myocardial infarction, ischemic stroke, CV death, all-cause mortality and severe hypoglycemia among the two groups. Follow-up was a mean of 1.2 years.
Long-acting sulfonylureas included glyburide and glimepiride; short-acting sulfonylureas included gliclazide, glipizide and tolbutamide.
The most commonly observed comorbidity was arterial hypertension (56%), followed by coronary artery disease (29%) and hyperlipidemia. The most commonly reported comedication was acetaminophen (34%), followed by statins (33%) and acetylsalicylic acid (31%).
Overall, 245 acute MI events, 237 ischemic stroke events, 458 CV deaths, 1,332 deaths from any cause and 87 severe hypoglycemic events occurred. The most frequent causes of death were cancer and CVDs (both 34%), followed by respiratory diseases (14%) and gastrointestinal diseases (5%).
Long-acting sulfonylurea use was not associated with an increased risk for acute MI (adjusted HR = 0.86; 95% CI, 0.55-1.34), ischemic stroke (aHR = 0.92; 95% CI, 0.59-1.45), CV death (aHR = 1.01; 95% CI, 0.72-1.2) or all-cause mortality (aHR = 0.81; 95% CI, 0.66-1.003) compared with short-acting sulfonylurea use. The risk for severe hypoglycemia (aHR = 2.83; 95% CI, 1.64-4.88) was increased with long-acting sulfonylureas compared with short-acting sulfonylureas.
“Our population-based cohort study showed no difference in the risk of major cardiovascular adverse events, cardiovascular death and all-cause mortality between pancreas-nonspecific and pancreas-specific sulfonylureas, thereby contradicting previous studies and arguing that the clinical implications of the lack of pancreas specificity of certain sulfonylureas may have been overstated,” the researchers wrote. “Finally, it corroborates the previously reported increased risk of severe hypoglycemia associated with long-acting sulfonylureas as compared with short-acting compounds.” – by Amber Cox
Disclosures: Suissa receives grants, participates in advisory board meetings and speaks at conference for AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Merck and Novartis. The other authors report no relevant financial disclosures.
Perspective
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Jakob Starup-Linde, MD, PhD
Although previous studies have shown contradictory results and may suggest an increased CV risk when using beta cell-nonspecific long-term sulfonylureas, the study by Douros and colleagues indicates no increased risk of CVD or all-cause mortality when comparing users of beta cell-nonspecific long-term sulfonylureas with beta cell-specific short-term sulfonylureas. This is an important finding in the clinical setting. However, as the authors also note, long-term safety cannot be evaluated due to a relatively short follow-up of 1.2 years. Also, in the clinical setting, sulfonylureas are predominantly used as add-on to biguanide therapy, and the results may not be transferable the majority of type 2 diabetes patients receiving biguanides or other glucose-lowering drugs.
It is also worth noting that hypoglycemia was more than doubled among users of beta cell-nonspecific long-term sulfonylureas — an important finding — and also may relate to the increased risk of hip fractures in patients with type 2 diabetes, which may be attributable to hypoglycemia as current use of sulfonylureas is associated with an increased risk of fractures.
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