OBJECTIVES: Sulphonylureas (SUs) offer effective glycemic control; however, they are generally not recommended anymore due to concerns about cardiovascular (CV) safety, despite absence of a CV safety outcome trial (CVOT). CAROLINA – a randomized noninferiority CVOT concluded a comparable CV safety of linagliptin (a dipeptidyl peptidase 4 inhibitor [DPP4I]) and glimepiride (a SU). We synthesized similar CVOTs and indirectly compared the effect of glimepiride vs placebo, and DPP4Is on major CV safety outcomes.

METHODS: A systematic review was conducted to identify randomized controlled trials including type 2 diabetes (T2D) patients with increased CV risk; and DPP4Is, placebo, or glimepiride as one of the treatment arms. Log hazard ratios (HRs) of 3-Point MACE (a composite of nonfatal stroke, nonfatal myocardial infarction, and CV death), all-cause death, and CV death were pooled applying a generic inverse variance method using R package ‘netmeta’ (version 1.2-1).

RESULTS: A total of 5 studies were pooled – 4 comparing DPP4Is (saxagliptin, sitagliptin, linagliptin, omarigliptin) vs placebo, and one study comparing linagliptin vs glimepiride. Glimepiride was comparable vs placebo for all three major CV safety outcomes (HR [95% CI]): time to first 3-Point MACE (0.9608 [0.7827;1.1794]), all-cause death (0.9286 [0.7502;1.1494]), and CV death (1.0416 [0.7928;1.3686]). Hazard ratios of all three outcomes with glimepiride vs other DPP4Is were also not statistically significant.

CONCLUSIONS: Glimepiride has a noninferior risk of 3-Point MACE, all-cause death, and CV death compared to placebo, saxagliptin, sitagliptin, linagliptin, and omarigliptin in T2D patients with increased CV risk. Glimepiride may be used in this population to attain glycemic control, particularly in settings where cost of DPP4Is is a concern.