The CAROLINA Trial—First Results of the Cardiovascular Outcomes Trial Comparing Linagliptin vs. Glimepiride
Julio Rosenstock, MD
Dallas Diabetes Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA Mark A. Espeland, MD
Wake Forest School of Medicine, Winston-Salem, NC, USA Steven E. Kahn, MD
University of Washington, Seattle, WA, USA Nikolaus Marx, MD
Rheinisch-Westfälische Technische Hochschule, Aachen University, Aachen, Germany Bernard Zinman, MD
University of Toronto, Toronto, ON, Canada
Despite their use in the treatment of type 2 diabetes for decades, there is still controversy regarding the cardiovascular (CV) safety of sulfonylureas from both CV outcomes trials and observational studies. CAROLINA (CARdiovascular Outcome study of LINAgliptin versus glimepiride in patients with type 2 diabetes) is the only active-comparator CV outcome trial for a DPP-4 inhibitor, comparing the long-term CV safety profile of linagliptin to glimepiride in patients with early type 2 diabetes and with increased CV risk. This trial adds evidence to the debate on the CV safety of sulfonylureas and also provides robust insights into the overall safety and efficacy of linagliptin and glimepiride in the long-term.
6,033 patients were randomized to linagliptin (n=3,023) or glimepiride (n=3,010).
Glycemic inclusion criteria were HbA1c 6.5-8.5% if treatment-naïve or treated with metformin and/or an α-glucosidase inhibitor OR HbA1c 6.5-7.5% if on sulfonylurea/glinide + metformin/α-glucosidase inhibitor (≤5 years).
CV risk inclusion criteria was one or more of the following: previous vascular disease, evidence of vascular-related end-organ damage, age ≥70 years, ≥2 CV risk factors.
Primary outcome measure
Time to first occurrence of any of the following adjudicated components of the primary composite endpoint (3P-MACE, three-point major adverse CV event): CV death (including fatal stroke and fatal myocardial infarction (MI)), non-fatal MI (excluding silent MI), or non-fatal stroke.
Median treatment exposure was 5.9 years for both groups.
CAROLINA demonstrated non-inferiority for 3P-MACE of linagliptin vs. glimepiride in participants with relatively early type 2 diabetes and increased CV risk (HR 0.98; 95% CI 0.84-1.14; P <0.0001 for non-inferiority; P=0.76 for superiority).
Risk for CV mortality or overall mortality was not significantly different between groups:
HR 0.91 (95% CI 0.78-1.06) all-cause mortality.
HR 1.00 (95% CI 0.81-1.24) CV mortality.
HR 0.82 (95% CI 0.66-1.03) non-CV mortality.
The frequency of adverse events, serious adverse events and adverse events leading to discontinuation of study drug were comparable between groups.
The incidence of hypoglycemic events was substantially lower with linagliptin across all pre-defined hypoglycemia severity categories.
Hypoglycemia risk was increased early and sustained across the entire dose range for glimepiride.
Rosenstock J, Marx N, Kahn SE, et al. Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: rationale for the active-comparator CAROLINA trial. Diab Vasc Dis Res. 2013 Jul;10(4):289-301.
Present disclosure: J. Rosenstock: Boehringer Ingelheim, Eli Lilly, Intarsia, Janssen, Novo Nordisk S/A. M.A. Espeland: National Institute of Health, Boehringer Ingelheim, Ironwood. S.E. Kahn: Boehringer Ingelheim, Eli Lilly, Intarsia, Janssen, Merck & Co., Novo Nordisk S/A. N. Marx: Amgen, AstraZeneca, Bayer Vital, Boehringer Ingelheim, Bistol-Myers Squibb, Merck Sharpe & Dohme. B. Zinman: Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck & Co.
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