Effect of linagliptin, a dipeptidyl peptidase-4 inhibitor, compared with the sulfonylurea glimepiride on cardiovascular outcomes in Asians with type 2 diabetes: subgroup analysis of the randomized CAROLINA® trial

Objective Linagliptin, a dipeptidyl peptidase-4 inhibitor, recently demonstrated cardiovascular (CV) safety versus placebo in Asians with advanced type 2 diabetes mellitus (T2DM) in the CARMELINA ® trial. We assessed its CV safety compared with the sulfonylurea glimepiride in Asians with relatively early T2DM in the CAROLINA ® trial. Methods Based on prespecified and post hoc subgroup analyses of the multinational CAROLINA ® trial in which adults with relatively early T2DM and elevated CV risk were randomized to linagliptin or glimepiride added to usual care, we analyzed data for participants from Asian countries. This included the primary outcome defined as time to first CV death, non-fatal myocardial infarction, or non-fatal stroke [three-point major adverse cardiovascular events (3P-MACE)]. Results Of the 6033 participants, 933 (15.5%) were from Asia. During a median follow-up of 6.2 years, 3P-MACE occurred in 9.5% and 11.1% of the linagliptin and glimepiride groups, respectively (hazard ratio [HR] 0.85; 95% confidence interval [CI] 0.57–1.26]), consistent with the overall population (HR 0.98; 95% CI 0.84–1.13; P = 0.17 for treatment by region interaction). Similarly, there were no significant differences between groups for other outcomes, including CV death (HR 0.73; 95% CI 0.38–1.38), non-CV mortality (HR 0.76; 95% CI 0.37–1.57) and hospitalization for heart failure (HR 0.89; 95% CI 0.36–2.19). Hypoglycemia adverse events occurred in 13.1% of linagliptin patients versus 42.1% of glimepiride patients (HR 0.25; 95% CI 0.19–0.33; P < 0.0001) despite similar glycemic control. Body weight was slightly lower with linagliptin relative to glimepiride: weighted average mean difference over 256 weeks of − 1.82 kg (95% CI − 2.28 to − 1.35). Conclusions In Asian patients, linagliptin demonstrated similar CV safety to glimepiride with a markedly lower rate of hypoglycemia and modestly lower weight.