Physicians should be aware of the excess risk for severe hypoglycemia with concomitant use of sulfonylureas and β-blockers, especially in the initial months.

“Sulfonylureas and β-blockers are commonly used together among patients with T2D and arterial hypertension or cardiovascular disease,” explains Antonios Douros, MD. “While both medication classes are known to increase the risk for severe hypoglycemia when given separately, it was unclear whether their concomitant use can lead to an even higher risk for this potentially fatal adverse effect.”

Dr. Douros points out that two observational studies have examined the effects of β-blockers on risk for hypoglycemia in patients taking sulfonylureas. Both studies, however, had some methodological limitations. “Based on the limitations of the available evidence, and considering the clinical importance of this question, more research was needed,” Dr. Douros says.

To examine the potential link between concomitant use of sulfonylureas and β-blockers versus use of sulfonylureas alone and the risk for severe hypoglycemia, Dr. Douros, Jenny Dimakos, MD-candidate, and colleagues conducted a population-based cohort study using the Clinical Practice Research Datalink, a primary care database. The results of their investigation were published in Diabetes Care.

Analysis Adjusted for Numerous Comorbidities

The analysis included 252,869 patients starting sulfonylureas between 1998 and 2020. “Given the observational nature of our study, we adjusted our analyses for co-medications, numerous comorbidities, proxies of diabetes severity, and overall health to minimize confounding,” Dr. Douros says.

Dr. Douros and colleagues utilized time-dependent Cox models, which estimated HRs with 95% CIs for severe hypoglycemia (hospitalization with, or death resulting from, hypoglycemia) associated with concomitant use of β-blockers and sulfonylureas, compared with sulfonylurea use alone, which were adjusted for baseline confounders. “We also compared concomitant use of sulfonylureas and non-cardio-selective β-blockers versus cardio-selective β-blockers,” he notes.

53% Increased Risk for Severe Hypoglycemia

The study team observed that concomitant use of sulfonylureas and β-blockers was associated with a 53% increase in the risk for severe hypoglycemia compared with use of sulfonylureas alone (Table). “The increase in the risk reached a peak at 60% after 6 months of concomitant use and decreased thereafter,” Dr. Douros notes. “Our results maintain that physicians treating patients with T2D should be aware of the excess risk for severe hypoglycemia in patients concomitantly using sulfonylureas and β-blockers, especially during the initial months of concomitant use.”

Dimakos also notes that cardioselectivity of β-blockers did not alter this link.

These findings are critical “given the common concomitant use of these medications, the clinical importance of severe hypoglycemia, and the costs associated with this adverse event,” Dimakos continues. “Therefore, physicians treating patients with T2D and arterial hypertension or heart failure should consider the use of alternative antidiabetic drugs (e.g., sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide 1 receptor agonists) or cardiovascular drugs (e.g., diuretics or inhibitors of the renin angiotensin system), especially if the baseline risk for hypoglycemia is elevated.”

Dr. Douros, Dimakos, and colleagues concur that future studies should focus on identifying additional medications that, when given together with sulfonylureas, increase the risk for hypoglycemia. “Avoiding such drug combinations in routine clinical practice could then reduce the hypoglycemic burden of sulfonylureas, improving the safety of these efficacious and affordable antidiabetic drugs,” Dr. Douros says.