Treatment with linagliptin compared with glimepiride results in a noninferior risk for cardiovascular morbidity and mortality in patients with type 2 diabetes (T2D), according to results from the Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Type 2 Diabetes (CAROLINA; ClinicalTrials.gov Identifier: NCT01243424), published in JAMA.

The results were presented at the 55th Annual Meeting of the European Association for the Study of Diabetes, held September 16 to 20, 2019, in Barcelona, Spain.

Because there were no head-to-head trials comparing the long-term effects of linagliptin, a dipeptidyl peptidase-4 inhibitor, with glimepiride, a sulfonylurea, the goal of this study was to investigate the cardiovascular outcomes of these medications in patients with relatively early T2D and cardiovascular risk factors or prior history of atherosclerotic cardiovascular disease.

The multicenter randomized double-blind active-controlled clinical trial enrolled patients from 607 centers across 43 countries between November 2010 and December 2012. Of 6042 patients randomly assigned to treatment, 6033 participants (mean age, 64 years, 39.9% women; mean T2D duration, 6.3 years) received ≥1 dose of the study medication and were included in the statistical analysis.


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The primary aim of the study was to evaluate whether linagliptin was noninferior to glimepiride for the time to 3-point major adverse cardiovascular event, including cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.

During median duration follow-up of 6.3 years, the 3-point major adverse cardiovascular event measure occurred in 356 of 3023 patients (11.8%) who received linagliptin (2.1 per 100 person-years) and 362 of 3010 (12.0%) who received glimepiride (2.1 per 100 person-years), meeting the criterion for noninferiority (hazard ratio, 0.98; multiplicity-adjusted 2-sided 95.47% CI, 0.84-1.14; P <.001 for noninferiority). Testing for superiority was not statistically significant.

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Frequencies of adverse events, including serious adverse events and adverse events leading to discontinuation of study medication, were comparable between groups. There were 1245 (41.2%) participants with ≥1 hospitalization in the linagliptin group and 1303 (43.3%) in the glimepiride group. There was also no imbalance in adjudication-confirmed pancreatitis or pancreatic cancer between the groups.

Incidence of hypoglycemic events was lower in the linagliptin group vs the glimepiride group across all predefined hypoglycemia severity categories. At least 1 episode of hypoglycemic adverse events occurred in 320 (10.6%) patients in the linagliptin group and 1132 (37.7%) in the glimepiride group (hazard ratio, 0.23; 95% CI, 0.21-0.26; P <.001).

The researchers noted that the study had several limitations. Among them were the focus on patients with relatively early diabetes and exclusion of insulin-treated patients, thus the results may not be applicable to patients with more advanced disease. In addition, there were inherent limitations of long-term trials, such as early termination of study medication.

“Among adults with relatively early type 2 diabetes and elevated cardiovascular risk, the use of linagliptin compared with glimepiride over a median of 6.3 years resulted in a noninferior risk of a composite cardiovascular outcome,” concluded the researchers.

Disclosure: This clinical trial was supported by Boehringer Ingelheim and Eli Lilly and Company. Please see the original reference for a full list of authors’ disclosures.

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Reference

Rosenstock J, Kahn SE, Johansen OE, et al. Effect of linagliptin vs glimepiride on major adverse cardiovascular outcomes in patients with type 2 diabetes: the CAROLINA randomized clinical trial. JAMA. 2019;322(12):1155-1166.