In this real-world observational study, the authors evaluated data from the Scottish national SCI-Diabetes database to compare the cardiovascular risk of sulfonylureas (SUs), DPP-4 inhibitors and pioglitazone.
People with an incident diagnosis of type 2 diabetes who initiated second-line therapy with one of the study drugs (in addition to metformin) on or after 1 January 2010 were followed up for rates of 4-point major adverse cardiovascular events (MACE) and its individual components, as well as all-cause mortality. Multivariable Cox proportional hazards regression and an instrumental variable approach were used to control confounding in a similar way to the randomisation process in randomised controlled trials.
The final cohort included 18,531 SU recipients, 9114 DPP-4 inhibitor recipients and 1873 pioglitazone recipients. The median follow-up was longer in the SU group than in the non-SU group (3.9 vs 3.0 years for MACE, and 4.1 vs 3.1 years for all-cause death.
All statistical analyses suggested that second-line SU use was not associated with increased risk of MACE compared with the other drug classes, with hazard ratios all around 1.00 and with the upper limits of the 95% confidence intervals all below 1.30, the upper limit recommended by the US Food and Drug Administration for cardiovascular safety trials. Similar results were observed for the individual MACE endpoints and for all-cause mortality. Subgroup analysis showed little difference between older and second-generation SUs; however, these analyses were likely to be underpowered as 87% of SU prescriptions were for gliclazide.
These findings provide robust evidence for the cardiovascular safety of SUs, although the authors acknowledge that there are other clinical risks associated with these agents, such as hypoglycaemia. They also acknowledge that SUs do not confer the cardiovascular and renal benefits associated with SGLT2 inhibitors and GLP-1 receptor agonists. However, when these newer agents are contraindicated or not tolerated, the authors state that cardiovascular safety concerns should not be a barrier to prescribing SUs. Their findings also support recent international guidelines that recommend SUs as a second-line therapy option in resource-limited healthcare systems.