Cardiac Risk the Same With All Sulfonylureas in Diabetes

Pam Harrison

September 21, 2017

The cardiovascular risk profile associated with the use of sulfonylureas in type 2 diabetes does not differ significantly between specific, short-acting agents and their nonspecific, long-acting counterparts, a large new cohort study suggests.

However, the nonspecific, long-acting drugs are more likely to cause severe hypoglycemia, the work finds.

"Several drug-utilization studies show that the sulfonylureas are the second most commonly used oral antidiabetic drugs after metformin, and they are recommended in most guidelines as second-line treatment in patients with type 2 diabetes, so they are still widely used in many countries," lead author Samy Suissa, PhD, professor of epidemiology, biostatics, and medicine at McGill University in Montreal, Quebec, told Medscape Medical News in an email.

"Our study shows that choosing one sulfonylurea over another does not affect cardiovascular safety. However, because of the severe hypoglycemia effect [of the nonspecific, long-acting sulfonylureas], the specific, short-acting compounds should be preferred," he added.

The study was published online September 1 in Diabetes Care.

Trial Details

The analysis involved 1863 patients who had been newly prescribed a nonspecific long-acting sulfonylurea and another 15,741 patients who had been newly prescribed a specific, short-acting sulfonylurea.

The nonspecific, long-acting sulfonylureas included glyburide and glimepiride, while the specific, short-acting agents included gliclazide, glipizide, and tolbutamide.

Mean follow-up was relatively short, at 1.2 years, and patients in both groups were well matched, with a mean age of 68 and a mean duration of treatment of 1.6 years.

As Dr Suissa observed, the sulfonylureas are a highly heterogeneous class of antidiabetic agents, with nonspecific, long-acting agents such as glyburide and glimepiride being nonselective for pancreatic β-cells.

This would allow them to bind to other receptors, including cardiomyocyte and vascular smooth-muscle-cell receptors.

Looking at the incidence of acute myocardial infarction (AMI), ischemic stroke, and death from either cardiovascular causes or all-cause mortality, the researchers found no significant differences between the nonspecific, long-acting sulfonylureas and the specific, short-acting agents.

Cardiovascular End Points for Type of Sulfonylurea at Study End Point

  AMI (per 1000/y) Ischemic stroke (per 1000/y) Cardiovascular death (per 1000/y)  All-cause mortality (per 1000/y)
Specific, short-acting sulfonylureas 9.1 9.1 16.8 40.6
Nonspecific long-acting sulfonylureas 12.1 11.7 22.5 67.3

"Our findings indicate that the binding of glyburide and glimepiride to cardiac and vascular structures…does not necessarily translate into an increased risk of ischemic adverse events or cardiovascular death as compared with other pancreas-specific sulfonylureas," Dr Suissa and his coauthors observe.

Severe Hypoglycemia Almost Tripled With Long-Acting Agents

But the use of nonspecific, long-acting sulfonylureas was strongly associated with a higher risk of severe hypoglycemia at a rate of 7.4 per 1000/year compared with a rate of 3.8 per 1000/year for the specific, short-acting drugs, for an adjusted hazard ratio of 2.83.

Although severe hypoglycemia now rarely occurs in patients with type 2 diabetes, "our data suggest that the specific, short-acting compounds should be preferred over the nonspecific, long-acting ones," Dr Suissa reemphasized.

Hypoglycemia has been singled out as a potential contributor to cardiovascular disease and as such is especially undesirable for a patient population already at elevated risk for cardiovascular events, he and his coauthors say.

Dr Suissa cautioned, however, that their relatively short follow-up interval did not allow the group to assess long-term risk of either type of sulfonylurea.

Nevertheless, "this continuous treatment follow-up reflects real-world clinical practice, since many patients initiating treatment for type 2 diabetes with a sulfonylurea in monotherapy tend to rapidly add or switch to other classes of antidiabetic drugs," he noted.

This research was funded in part by grants from the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, and Boehringer Ingelheim. Dr Suissa reports receiving research grants and has participated in advisory board meetings or as a speaker at conferences for AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, and Novartis. The coauthors have no relevant financial relationships.

Diabetes Care. Published online September 1, 2017. Abstract

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