Sulphonylureas up risk of cardiovascular, hypoglycaemic events in T2D patients
Patients with type 2 diabetes (T2D) treated with sulphonylureas as second-line drugs are at an increased risk of myocardial infarction (MI), all-cause mortality and severe hypoglycaemia compared with those who remained on metformin monotherapy, a recent study has found.
“The associations with MI and all-cause mortality were driven by the switching to sulphonylureas and not the addition of sulphonylureas,” researchers said. “Thus, in line with current recommendations on the treatment of T2D, continuing metformin when introducing sulphonylureas is safer than switching.” [Diabetes Care 2016;39(Suppl 1):S52-59]
During the study period, 25,699 of the 77,138 metformin initiators added or switched to sulphonylureas. During a mean 1.1 years of follow-up, sulphonylureas as second-line treatment vs continuing metformin monotherapy correlated with an elevated risk of MI (incidence rate [IR], 7.8 vs 6.2 per 1,000 person-years; hazard ratio [HR], 1.26; 95 percent CI, 1.01–1.56), all-cause mortality (IR, 27.3 vs 21.5; HR, 1.28; 1.15–1.44) and severe hypoglycaemia (IR, 5.5 vs 0.7 ; HR, 7.60; 4.64–12.44). [BMJ 2018;362:k2693]
A trend towards increased risk of ischaemic stroke (IR, 6.7 vs 5.5; HR, 1.24; 0.99–1.56) and cardiovascular mortality (IR, 9.4 vs 8.1; HR, 1.18; 0.98–1.43) was noted. Switching to vs adding sulphonylureas correlated with an increased risk of MI (HR, 1.51; 1.03–2.24) and all-cause mortality (HR, 1.23; 1.00–1.50). There were no differences for ischaemic stroke, cardiovascular death or severe hypoglycaemia.
“The results of the primary analysis remained consistent in sensitivity analyses, as well as after classifying sulphonylureas in two different groups based on important pharmacologic properties,” researchers said.
There are several mechanisms driving the increased risk with sulphonylureas vs patients continuing metformin monotherapy. First, sulphonylureas are associated with weight gain, which is an important predictor of MI. Second, hypoglycaemia is tied to the development of arrhythmias and cardiac ischaemia, so, sulphonylurea-related hypoglycaemia may result in the elevated MI risk. Third, the absence of an increased MI risk linked to adding sulphonylureas to metformin suggest the beneficial effects of biguanide. [Diabetes Care 2017;40:1506-1513; Drugs 2005;65:385-411; Nat Rev Endocrinol 2014;10:711-722]
“Interestingly, metformin was recently shown to also positively modify the cardiovascular effects of a newer class of antidiabetic drugs, dipeptidyl peptidase-4 inhibitors,” researchers said. [Diabetes Care 2017;40:1787-1789]
This population-based cohort study included T2D patients initiating metformin monotherapy between 1998 and 2013. General practices contributing data to the UK Clinical Practice Research Datalink were analysed.
Researchers used the prevalent new-user cohort design to match patients adding or switching to sulphonylureas with those remaining on metformin monotherapy on high-dimensional propensity score, haemoglobin A1c and number of previous metformin prescriptions. Cox proportional hazard models were used to compare the two groups.