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

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Rosenstock reported that he has served on scientific advisory boards and received honoraria or consulting fees from Eli Lilly, Sanofi, Novo Nordisk, Janssen, AstraZeneca, Boehringer Ingelheim and Intarcia; he has also received grants/research support from Merck, Pfizer, Sanofi, Novo Nordisk, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Genentech, Janssen, Lexicon, Boehringer Ingelheim, and Intarcia. Dr Perkovic reported that he has received research support from the Australian National Health and Medical Research Council (Project and Program Grant), served on steering committees for trials supported by AbbVie, Boehringer Ingelheim, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Novartis, Novo Nordisk, Pfizer, Retrophin, and Tricida and served on advisory boards, spoken at scientific meetings, or both for AbbVie, Astellas Pharma, Astra Zeneca, Bayer, Baxter, Bristol-Myers Squibb, Boehringer Ingelheim, Durect Corporation, Eli Lilly, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Roche, Sanofi, Servier, and Vitae. He has a policy of having honoraria paid to his employer. Dr Johansen reported that he is employed by Boehringer Ingelheim. Dr Cooper reported that he has received fees for advisory services to Boehringer Ingelheim. Dr Kahn reported that he has received personal fees from Boehringer Ingelheim, Elcelyx, Eli Lilly, Intarcia, Janssen, Merck, Neurimmune, and Novo Nordisk. Dr Marx reported that he has given lectures for Amgen, Boehringer Ingelheim, Sanofi-Aventis, Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Eli Lilly, Novo Nordisk, has received unrestricted research grants from Boehringer Ingelheim, and has served as an advisor for Amgen, Bayer, Boehringer Ingelheim, Sanofi-Aventis, Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, and Novo Nordisk. In addition, he has served in trial leadership for Boehringer Ingelheim and Novo Nordisk. He reported that he declines all personal compensation from pharmaceutical or device companies. Dr Alexander reported that he has received personal fees from Abbvie, Bristol-Myers Squibb, CSL Behring, Jansen Pharmaceutics, Novo Nordisk, Pfizer, Portola, and Teikoku and institutional research support from Boehringer Ingelheim, Bristol-Myers Squibb, Cryolife, CSL Behring, Tenax Therapeutics, and VoluMetrix. Dr Pencina reported receipt of grants and personal fees from Boehringer Ingelheim and Merck and grants from Sanofi/Regeneron. Dr Toto reported that he is a consultant to Amgen, Boehringer Ingelheim, ZS Pharma, Relypsa, Novo Nordisk, Reata, and AstraZeneca and receives grant support from the National Institutes of Health. Dr Wanner reported that he has received fees for advisory services to Boehringer Ingelheim. Dr Zinman reported that he has received grant support from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk and consulting fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi-Aventis. Dr Woerle reported that he is a former employee of Boehringer Ingelheim. Messrs Baanstra, Pfarr, and Schnaidt and Drs Meinicke, George, and von Eynatten reported that they are employed by Boehringer Ingelheim. Dr McGuire reported that he has received personal fees from Boehringer-Ingelheim, Janssen Research and Development, Sanofi-Aventis, Merck Sharp & Dohme, Merck & Co, Eli Lilly, Novo Nordisk, GlaxoSmithKline, AstraZeneca, Lexicon, Eisai, Pfizer, Metavant, Applied Therapeutics, and Esperion.

Figures

Figure 1.. Flow of Participants in the CARMELINA Trial of Linagliptin

DPP-4 indicates dipeptidyl peptidase 4; SGLT-2, sodium-glucose cotransporter 2; GLP-1, glucagon-like peptide 1. aPatients could have more than 1 reason, so numbers sum to more than 4692. bDefined as serum levels of alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase at least 3 times the upper limit of normal.

Figure 2.. Time to Primary and Secondary Outcomes

Hazard ratio (HR) based on Cox regression analyses in patients treated with at least 1 dose of study drug. A, Time to 3-point major adverse cardiovascular event (MACE) primary outcome (first cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). Median observation time was 2.1 (interquartile range [IQR], 1.5-2.9) years for linagliptin and 2.1 (IQR, 1.5-2.8) years for placebo. B, Time to secondary kidney outcome (first sustained end-stage renal disease, death due to renal failure, or sustained decrease of ≥40% in estimated glomerular filtration rate from baseline). Median observation time was 1.9 (IQR, 1.2-2.6) years for linagliptin and 1.7 (IQR, 1.2-2.5) years for placebo.

Figure 3.. Hemoglobin A1c Measurements Over Time by Treatment Group

Median time in study was 2.0 (interquartile range [IQR], 1.3-2.6) years for linagliptin and 2.0 (IQR, 1.2-2.6) years for placebo. Baseline values are descriptive; postbaseline data from mixed-model repeated-measures analysis are adjusted for treatment, region, baseline hemoglobin A1c value, week, treatment × week interaction, and baseline hemoglobin A1c value × week interaction.