Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial

Abstract

Importance: Type 2 diabetes is associated with increased cardiovascular risk. In placebo-controlled cardiovascular safety trials, the dipeptidyl peptidase-4 inhibitor linagliptin demonstrated noninferiority, but it has not been tested against an active comparator.

Objective: This trial assessed cardiovascular outcomes of linagliptin vs glimepiride (sulfonylurea) in patients with relatively early type 2 diabetes and risk factors for or established atherosclerotic cardiovascular disease.

Design, setting, and participants: Randomized, double-blind, active-controlled, noninferiority trial, with participant screening from November 2010 to December 2012, conducted at 607 hospital and primary care sites in 43 countries involving 6042 participants. Adults with type 2 diabetes, glycated hemoglobin of 6.5% to 8.5%, and elevated cardiovascular risk were eligible for inclusion. Elevated cardiovascular risk was defined as documented atherosclerotic cardiovascular disease, multiple cardiovascular risk factors, aged at least 70 years, and evidence of microvascular complications. Follow-up ended in August 2018.

Interventions: Patients were randomized to receive 5 mg of linagliptin once daily (n = 3023) or 1 to 4 mg of glimepiride once daily (n = 3010) in addition to usual care. Investigators were encouraged to intensify glycemic treatment, primarily by adding or adjusting metformin, α-glucosidase inhibitors, thiazolidinediones, or insulin, according to clinical need.

Main outcomes and measures: The primary outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with the aim to establish noninferiority of linagliptin vs glimepiride, defined by the upper limit of the 2-sided 95.47% CI for the hazard ratio (HR) of linagliptin relative to glimepiride of less than 1.3.

Results: Of 6042 participants randomized, 6033 (mean age, 64.0 years; 2414 [39.9%] women; mean glycated hemoglobin, 7.2%; median duration of diabetes, 6.3 years; 42% with macrovascular disease; 59% had undergone metformin monotherapy) were treated and analyzed. The median duration of follow-up was 6.3 years. The primary outcome occurred in 356 of 3023 participants (11.8%) in the linagliptin group and 362 of 3010 (12.0%) in the glimepiride group (HR, 0.98 [95.47% CI, 0.84-1.14]; P < .001 for noninferiority), meeting the noninferiority criterion but not superiority (P = .76). Adverse events occurred in 2822 participants (93.4%) in the linagliptin group and 2856 (94.9%) in the glimepiride group, with 15 participants (0.5%) in the linagliptin group vs 16 (0.5%) in the glimepiride group with adjudicated-confirmed acute pancreatitis. At least 1 episode of hypoglycemic adverse events occurred in 320 (10.6%) participants in the linagliptin group and 1132 (37.7%) in the glimepiride group (HR, 0.23 [95% CI, 0.21-0.26]).

Conclusions and relevance: Among adults with relatively early type 2 diabetes and elevated cardiovascular risk, the use of linagliptin compared with glimepiride over a median 6.3 years resulted in a noninferior risk of a composite cardiovascular outcome.

Trial registration: ClinicalTrials.gov Identifier: NCT01243424.

Figure 1.. Enrollment, Randomization, and Follow-up of Participants in a Study of the Effect of Linagliptin vs Glimepiride on Cardiovascular Outcomes in Patients With Type 2 Diabetes

There were 19 participants (9 in the linagliptin group and 10 in the glimepiride group) identified to have been enrolled and treated at multiple sites. For these participants, treatment group allocation according to first randomization was used and only objective data (eg, selected baseline characteristics, serious adverse events, and trigger events sent for adjudication) were included in the analyses. Patients could meet more than 1 exclusion criteria. BMI indicates body mass index; CV, cardiovascular; HbA_1c, glycated hemoglobin.

Figure 2.. Time to Occurrence of End Points Based on Cox Regression Analyses in Patients Treated With at Least 1 Dose of the Study Drug

A, Composite end point of cardiovascular death, first nonfatal myocardial infarction, or first nonfatal stroke (3-point major cardiovascular event [3P-MACE] outcome). Median (quartile [Q] 1, Q3) follow-up was 6.2 (5.8, 6.6) years in the linagliptin group and 6.2 (5.6, 6.5) years in the glimepiride group. The 95.47% CI for the primary end point was adjusted for multiplicity due to 2 interim analyses and change of the primary end point. B, Median (Q1, Q3) follow-up was 6.3 (5.9, 6.6) years in the linagliptin group and 6.3 (5.9, 6.6) years in the glimepiride group. C, Median (Q1, Q3) follow-up was 6.3 (5.9, 6.6) years in the linagliptin group and 6.3 (5.9, 6.6) years in the glimepiride group. D, Median (Q1, Q3) follow-up was 6.3 (5.9, 6.6) years in the linagliptin group and 6.3 (5.9, 6.6) years in the glimepiride group. 3P-MACE indicates 3-point major adverse cardiovascular event.

Figure 3.. Glycated Hemoglobin (HbA_1c) and Weight Over Time by Treatment Groups

Weighted average mean difference for panels A and B based on mixed-model repeated measures, including treatment, week repeated within participants, week × treatment interaction, continuous baseline HbA_1c and weight, and baseline HbA_1c × week and weight × week interaction for patients who received at least 1 dose of a study drug and had a baseline and at least 1 postbaseline measurement. The squares and triangles indicate the unadjusted mean, the solid lines indicate the median (quartile [Q] 1, Q3), and the dashed lines indicate the median value at baseline. A, Median (Q1, Q3) follow-up was 6.1 (5.2, 6.4) years in the linagliptin group and 6.1 (4.8, 6.4) years in the glimepiride group. B, Median (Q1, Q3) follow-up was 6.1 (5.2, 6.5) years in the linagliptin group and 6.1 (4.9, 6.4) years in the glimepiride group.

Figure 4.. Moderate or Severe Hypoglycemia Over Time by Treatment Groups

Median (quartile 1, quartile 3) follow-up was 5.9 (2.8, 6.5) years in the linagliptin group and 4.3 (0.8, 6.2) years in the glimepiride group. Moderate or severe hypoglycemia was defined as time to the first occurrence of symptomatic investigator-defined hypoglycemic adverse event with plasma glucose ≤70 mg/dL or a severe hypoglycemic adverse event. Analysis based on hypoglycemic adverse events occurring between first study drug intake until 7 days after receiving the study drug for the final time. Severe hypoglycemia was defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Hazard ratio (HR) for hypoglycemia derived by Cox regression model analyses in patients treated with ≥1 dose of the study drug.