Results and implications of CAROLINA (CARdiOvascular Safety of LINAgliptin) comparing linagliptin vs glimepiride
Julio Rosenstock, MD
Dallas Diabetes Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA ark 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-WestfälischeTechnische Hochschule Aachen University, Germany Bernard Zinman, MD
University of Toronto, Toronto, Canada Darren McGuire, MD
University of Texas Southwestern Medical Center, Dallas, Texas
Considering the results of CAROLINA, cardiovascular (CV) safety should no longer be an issue for prescribers when choosing between linagliptin and glimepiride; the CV safety profile of glimepiride is reassuring.
Linagliptin has a robustly demonstrated CV safety vs glimepiride, and a lower risk for hypoglycaemia and weight gain.
Despite their use in the treatment of type 2 diabetes for decades, there is still controversy regarding the CV safety of sulphonylureas from both CV outcomes trials and observational studies. CAROLINA 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 to be considered in the decision-making process of selecting a second oral agent added to metformin in early type 2 diabetes.
6033 patients were randomised to linagliptin (n = 3023) or glimepiride (n = 3010).
Glycaemic 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 sulphonylurea/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 hypoglycaemic events was substantially lower with linagliptin across all pre-defined hypoglycaemia severity categories.
Hypoglycaemia 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
Presenter disclosure: The presenters has reported the follow relationships: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, Bristol-Myers Squibb, Merck Sharpe & Dohme. B. Zinman: Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck & Co. D. McGuire: AstraZencea, Sanofi Aventis, Eli Lilly, Boehringer Ingelheim, Merck & Co., Pfizer, Novo Nordisk, Metavant, Janssen, Lexicon, GlaxoSmithLine, Esperion
Medical writer: Patrick Moore, PhD
Reviewer: Marco Gallo, MD
Local reviewers: Marco Gallo, MD (Italia); Anna Novials Sardá, MD, PhD (España); Eric Renard, MD, PhD (France); Peter Schwarz, MD, PhD (Deutschland)