Switching to sulfonylureas from metformin monotherapy may increase risk of cardiovascular, hypoglycemic events

The results suggest that continuing metformin alone and accepting higher HbA1c targets may be preferable to switching to sulfonylureas when considering macrovascular outcomes and hypoglycemia, an accompanying editorial said.


Compared to continuing metformin monotherapy, sulfonylureas as second-line drugs are associated with increased risks of myocardial infarction (MI), all-cause mortality, and severe hypoglycemia, a recent observational study found.

Researchers used data from the U.K. Clinical Practice Research Datalink to assess patients with type 2 diabetes who started metformin monotherapy between 1998 and 2013. In a 1:1 ratio, they matched patients who added or switched to sulfonylureas with those who remained on metformin monotherapy by high-dimensional propensity score, HbA1c level, and number of previous metformin prescriptions. They then compared risk of MI, ischemic stroke, cardiovascular death, all-cause mortality, and severe hypoglycemia between groups. Results were published online on July 18 by the BMJ.

Among 77,138 patients who initiated metformin, 25,699 added or switched to sulfonylureas during the study period. During a mean follow-up of 1.1 years, sulfonylureas were associated with an increased risk of MI (incidence rate, 7.8 vs. 6.2 per 1,000 person-years; hazard ratio [HR], 1.26 [95% CI, 1.01 to 1.56]), all-cause mortality (incidence rate, 27.3 vs. 21.5 per 1,000 person-years; HR, 1.28 [95% CI, 1.15 to 1.44]), and severe hypoglycemia (incidence rate, 5.5 vs. 0.7 per 1,000 person-years; HR, 7.60 [95% CI, 4.64 to 12.44]) compared with continuing metformin monotherapy. There was also a trend toward increased risks of ischemic stroke (incidence rate, 6.7 vs. 5.5 per 1,000 person-years; HR, 1.24 [95% CI, 0.99 to 1.56]) and cardiovascular death (incidence rate, 9.4 vs. 8.1 per 1,000 person-years; HR, 1.18 [95% CI, 0.98 to 1.43]) with use of sulfonylureas compared to metformin monotherapy.

When sulfonylureas were introduced, continuing metformin appeared to be a safer approach than stopping it altogether. Switching to sulfonylureas was associated with an increased risk of MI (HR, 1.51; 95% CI, 1.03 to 2.24) and all-cause mortality (HR, 1.23; 95% CI, 1.00 to 1.50) compared to adding sulfonylureas to metformin. There were no significant differences in the outcomes of ischemic stroke, cardiovascular death, or severe hypoglycemia.

The study authors noted limitations, such as the potential for residual confounding, the relatively short duration of follow-up, and the omission of drug dose information from analyses. They added that metformin use is contraindicated in patients with severe kidney disease and decompensated heart failure, so those conditions may have led to discontinuing metformin, switching to sulfonylureas, and the observed increased risks.

The observed differences in risk between adding and switching to sulfonylureas could be driven by the possibility that higher doses were needed by those who switched, an accompanying editorial noted.

It is difficult to define clinical practice based on an observational study, the editorialists said. “This study, however, is well designed and the relations appear strong and consistent. … These data suggest that adding a sulfonylurea to metformin treatment is preferable to switching to sulfonylurea monotherapy. It also suggests that continuing metformin alone and accepting higher HbA1c targets is preferable to switching to sulfonylureas when considering both macrovascular outcomes and hypoglycaemia,” they wrote.