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

Abstract

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.

Keywords: Cardiovascular; Diabetes mellitus, type 2.

Fig. 1

CV outcomes and mortality in overall trial population and Asian patients. ^aHR and 95% CI not calculated as < 14 patients with event. CI confidence interval, CV cardiovascular, HR hazard ratio, 3P-/4P-MACE three-point/four-point major adverse CV events

Fig. 2

Time to first CV, CV death, event or death in Asian patients based on Kaplan–Meier estimates. CI confidence interval, CV cardiovascular, HR hazard ratio, 3P-MACE major adverse cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke)

Fig. 3

HbA1c over time in Asian patients. Baseline values are descriptive; post-baseline values are from a mixed model for repeated measures. BL baseline, CI confidence interval, HbA1c glycated hemoglobin, SE standard error

Fig. 4

Body weight over time in Asian patients. Baseline values are descriptive; post-baseline values are from a mixed model for repeated measures. BL baseline, CI confidence interval, SE standard error

Fig. 5

Hypoglycemia in Asian patients. ^aHR and 95% CI not calculated as < 14 patients with event; ^bAny investigator-defined hypoglycemia adverse event; ^chypoglycemia adverse event reported with typical symptoms of hypoglycemia and plasma glucose ≤ 70 mg/dl; ^dhypoglycemia event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions. CI confidence interval, HR hazard ratio, PY patient-years

Fig. 6

Time to first occurrence of moderate^a or severe^b hypoglycemia in Asian patients based on Kaplan–Meier estimates using data obtained until 7 days after treatment end. ^aHypoglycemia adverse event reported with typical symptoms of hypoglycemia and plasma glucose ≤ 70 mg/dl; ^bhypoglycemia event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions. CI confidence interval, HR hazard ratio