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JAMA. 2019 Sep 19. doi: 10.1001/jama.2019.13772. [Epub ahead of print]

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

Author information

Dallas Diabetes Research Center at Medical City, Dallas, Texas.
University of Texas Southwestern Medical Center, Dallas.
Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System, Seattle, Washington.
University of Washington, Seattle.
Boehringer Ingelheim Norway KS, Asker, Norway.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
Division of Endocrinology, University of Toronto, Toronto, Canada.
Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Ulm University, Ulm, Germany.
Boehringer Ingelheim International GmbH & Co KG, Ingelheim, Germany.
Boehringer Ingelheim, Alkmaar, the Netherlands.
Boehringer Ingelheim International GmbH & Co KG, Biberach, Germany.
Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Germany.



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.


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.


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.


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: Identifier: NCT01243424.

[Available on 2020-03-19]

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