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Trial CAROLINA: il rischio di eventi cardiovascolari associato a linagliptin non è maggiore di quello associato a glimepride

Lo studio CAROLINA è un trial di non inferiorità, randomizzato, in doppio cieco, su oltre 6000 pazienti selezionati tra il 2010 e il 2012 in ospedali e centri di cura di 43 Paesi. Lo studio ha valutato il numero di eventi cardiovascolari per linagliptin (inibitore della dipeptidil peptidasi 4) rispetto a glimepiride (una sulfonilurea) in pazienti con un diabete di tipo 2 precoce e fattori di rischio per l’insorgenza di aterosclerosi, tra cui malattia cardiovascolare aterosclerotica documentata, fattori multipli di rischio cardiovascolare, età di almeno 70 anni ed evidenze di complicanze microvascolari. L’outcome primario, ovvero il tempo alla morte cardiovascolare o al primo infarto miocardico non fatale o ictus non fatale, si è verificato in 356 su 3023 partecipanti (11,8%) nel gruppo trattato con linagliptin e in 362 su 3010 (12,0%) nel gruppo trattato con glimepiride (HR 0,98%; 0,84-1,14; p<0,001 per la non-inferiorità), dimostrando la non inferiorità.

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

Rosenstock J, Kahn SE, Johansen OE, Zinman B, Espeland MA, Woerle HJ, Pfarr E, Keller A, Mattheus M, Baanstra D, Meinicke T, George JT, von Eynatten M, McGuire DK, Marx N; CAROLINA Investigators.

JAMA. 2019 [Epub19Sep]

Importance: 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.
Objective: 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.
Interventions: 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.
Results: 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: ClinicalTrials.gov Identifier: NCT01243424.

JAMA. 2019 [Epub19Sep]