Sulfonylureas as Second Line Agents: Risk of Cardiovascular and Hypoglycemic Events

Crosby Tindal, Pharm.D., Supervalu

Background and Study Objective: Sulfonylureas are a common second line choice after metformin for the treatment of type 2 diabetes. Previous studies have questioned the cardiovascular and hypoglycemic safety profile of sulfonylureas. However, much of this investigation has been in the setting of evaluating sulfonylureas against newer agents or as an alternative to metformin in patients for whom metformin would be suboptimal. The practice of either adding a sulfonylurea to metformin monotherapy, or switching from metformin monotherapy to sulfonylurea monotherapy, is commonplace in primary care; however, the risk burden of this practice is relatively unknown. A recent entry in The BMJ describes an attempt by Douros and colleagues to characterize this risk.

Objectives and Study Design: The authors conducted a population-based cohort study using data from the United Kingdom’s Clinical Practice Research Datalink (CPRD), Health Episode Statistics (HES), and the Office of National Statistics (ONS) databases. The study evaluated patients over 40 years old with or without cardiovascular disease who initiated metformin monotherapy between April 1, 1998 and Match 31, 2013.  Exclusion criteria were a history of other antihyperglycemic drugs prior to enrollment and polycystic ovary syndrome. This population was deemed the base cohort and patients were followed by prescription fill history and health outcomes. Those who continued metformin only were used as controls. Two subsequent cohorts were established: patients who first initiated metformin and later added a sulfonylurea to their regimen and patients who ceased to fill metformin and initiated a sulfonylurea.

The investigators employed several means of eliminating residual confounding. Patients were characterized by A1C at the time of cohort entry, number of metformin prescriptions filled, and propensity score for receiving a sulfonylurea. The propensity score was calculated using a logistic regression model to evaluate 500 measures expressing the likelihood of receiving a sulfonylurea prescription. Patients were matched 1:1 according to propensity scores, A1C, and number of metformin prescriptions received at entry. Patients were followed forward from entry into a cohort and evaluated on time to event basis until the end of the study period or when they either discontinued treatment, stopped receiving care at an enrolled practice, or experienced one of the following five primary outcomes: myocardial infarction, ischemic stroke, cardiovascular death, all cause mortality, or severe hypoglycemia. Analysis was conducted by person time per cohort. The investigators evaluated and compared the risk for occurrence of one of the outcomes in each of the three cohorts.

Results: Out of 77,138 metformin initiators, 25,699 either added or switched to a sulfonylurea. Of these, 23,592 were selected for analysis based on the availability of a match in the base cohort. Mean time to follow-up was 1.1 (SD 1.4) years. Patients who added or switched to a sulfonylurea experienced significantly higher rates of myocardial infarction (HR = 1.26 [95% CI 1.01 – 1.56]), all-cause mortality (1.28, [95% CI 1.15 – 1.44]), and severe hypoglycemia (5.5 [95% CI 4.64 – 12.44]) compared to those remaining on metformin only. Rates of ischemic stroke and cardiovascular death were non-significant but trended in favor of metformin monotherapy. The increased risk of sulfonylureas was driven by their use as monotherapy. Compared to combination therapy, patients only on sulfonylureas were at increased risk for myocardial infarction (HR 1.51 [95% CI 1.03 – 2.24]) and all-cause mortality (1.23 [95% CI 1.00 – 1.50]). There was no difference in risk for severe hypoglycemia between patients receiving both drugs as compared to sulfonylurea monotherapy (1.06 [95% CI 0.65 – 1.71]).

Conclusions: This data suggests that the addition of or the switching to sulfonylureas in patients initially treated with metformin carries a significant risk. Patients taking sulfonylureas experienced significantly higher rates of myocardial infarction, all cause mortality, and severe hypoglycemia. With the exception of hypoglycemia, this risk appears to be driven primarily by the replacement of metformin monotherapy by a sulfonylurea. Clinicians should employ sulfonylurea drugs judiciously and sparingly. When they are added to therapy, it would seem preferable to supplement metformin rather than replace it entirely. Admittedly, some patients are unable to continue metformin due to absolute contraindications or repeated history of intolerance. These patients may be better candidates for newer second line agents with demonstrated cardiovascular benefits as opposed to sulfonylureas which may be cardiotoxic and carry a high risk for hypoglycemia.

Key Points: Compared to metformin, sulfonylureas appear to confer a significant risk of mortality, including cardiovascular and severe hypoglycemic events. Concurrent therapy with metformin appears to be safer than sulfonylurea monotherapy. Sulfonylurea monotherapy appears to carry the greatest risk of adverse cardiovascular events; however, any sulfonylurea therapy carries risk for hypoglycemic events.


1. Douros A, Dell’Aniello S, Ohy Y, Filion KB, Azoulay L, Suissa S. Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycemic events: population based cohort study. BMJ. 2018;362:k2693. doi:  10.1136/bmj.k2693