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Original Investigation
January 1/8, 2019

Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial

Author Affiliations
  • 1Dallas Diabetes Research Center at Medical City, Dallas, Texas
  • 2University of Texas Southwestern Medical Center, Dallas
  • 3George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, Australia
  • 4Boehringer Ingelheim Norway KS, Asker, Norway
  • 5Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
  • 6Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle
  • 7Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Germany
  • 8Duke Clinical Research Institute, Duke Health, Durham, North Carolina
  • 9Division of Nephrology, Department of Medicine, Würzburg University Clinic, Würzburg, Germany
  • 10Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
  • 11Division of Endocrinology, University of Toronto, Toronto, Ontario, Canada
  • 12Ulm University, Ulm, Germany
  • 13Boehringer Ingelheim, Alkmaar, the Netherlands
  • 14Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany
  • 15Boehringer Ingelheim International GmbH, Biberach, Germany
JAMA. 2019;321(1):69-79. doi:10.1001/jama.2018.18269
Key Points

Question  What is the effect of linagliptin compared with placebo on risk of major cardiovascular (CV) events in type 2 diabetes at high CV risk?

Findings  In this randomized noninferiority trial that included 6979 patients followed up for a median 2.2 years, use of linagliptin compared with usual care resulted in an incidence of the primary composite outcome (CV death, nonfatal myocardial infarction, or nonfatal stroke) of 12.4% vs 12.1%. The hazard ratio had a 1-sided 97.5% confidence limit of 1.17, which met the criterion for noninferiority (upper confidence limit <1.3).

Meaning  Among patients with type 2 diabetes and high CV risk, linagliptin, compared with placebo, demonstrated noninferiority with regard to risk of major CV events over a median of 2.2 years.


Importance  Type 2 diabetes is associated with increased cardiovascular (CV) risk. Prior trials have demonstrated CV safety of 3 dipeptidyl peptidase 4 (DPP-4) inhibitors but have included limited numbers of patients with high CV risk and chronic kidney disease.

Objective  To evaluate the effect of linagliptin, a selective DPP-4 inhibitor, on CV outcomes and kidney outcomes in patients with type 2 diabetes at high risk of CV and kidney events.

Design, Setting, and Participants  Randomized, placebo-controlled, multicenter noninferiority trial conducted from August 2013 to August 2016 at 605 clinic sites in 27 countries among adults with type 2 diabetes, hemoglobin A1c of 6.5% to 10.0%, high CV risk (history of vascular disease and urine-albumin creatinine ratio [UACR] >200 mg/g), and high renal risk (reduced eGFR and micro- or macroalbuminuria). Participants with end-stage renal disease (ESRD) were excluded. Final follow-up occurred on January 18, 2018.

Interventions  Patients were randomized to receive linagliptin, 5 mg once daily (n = 3494), or placebo once daily (n = 3485) added to usual care. Other glucose-lowering medications or insulin could be added based on clinical need and local clinical guidelines.

Main Outcomes and Measures  Primary outcome was time to first occurrence of the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Criteria for noninferiority of linagliptin vs placebo was defined by the upper limit of the 2-sided 95% CI for the hazard ratio (HR) of linagliptin relative to placebo being less than 1.3. Secondary outcome was time to first occurrence of adjudicated death due to renal failure, ESRD, or sustained 40% or higher decrease in eGFR from baseline.

Results  Of 6991 enrollees, 6979 (mean age, 65.9 years; eGFR, 54.6 mL/min/1.73 m2; 80.1% with UACR >30 mg/g) received at least 1 dose of study medication and 98.7% completed the study. During a median follow-up of 2.2 years, the primary outcome occurred in 434 of 3494 (12.4%) and 420 of 3485 (12.1%) in the linagliptin and placebo groups, respectively, (absolute incidence rate difference, 0.13 [95% CI, −0.63 to 0.90] per 100 person-years) (HR, 1.02; 95% CI, 0.89-1.17; P < .001 for noninferiority). The kidney outcome occurred in 327 of 3494 (9.4%) and 306 of 3485 (8.8%), respectively (absolute incidence rate difference, 0.22 [95% CI, −0.52 to 0.97] per 100 person-years) (HR, 1.04; 95% CI, 0.89-1.22; P = .62). Adverse events occurred in 2697 (77.2%) and 2723 (78.1%) patients in the linagliptin and placebo groups; 1036 (29.7%) and 1024 (29.4%) had 1 or more episodes of hypoglycemia; and there were 9 (0.3%) vs 5 (0.1%) events of adjudication-confirmed acute pancreatitis.

Conclusions and Relevance  Among adults with type 2 diabetes and high CV and renal risk, linagliptin added to usual care compared with placebo added to usual care resulted in a noninferior risk of a composite CV outcome over a median 2.2 years.

Trial Registration  ClinicalTrials.gov Identifier: NCT01897532