![]() ![]() The CARMELINA design has previously been described. These analyses include assessments of recurrent hHF events in the overall cohort and of outcomes by baseline history of HF, chronic kidney disease categories, and the subset of participants with such information available, by left ventricular ejection fraction (LVEF). Here, we comprehensively explore the impact of linagliptin on hHF and associated clinical outcomes using a statistical analysis plan specific to HF-related outcomes, with most analyses being prespecified, in the overall study population and in key participant subgroups. 10–12 The primary analysis for CARMELINA revealed no difference in risk for hHF with linagliptin. 16 The overall trial results revealed safety but not incremental efficacy of linagliptin with respect to the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke as well as for all-cause mortality, 17 in line with observations from 3 other DPP-4 inhibitor CVOTs. ![]() 3ĬARMELINA (The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin) was designed to evaluate the cardiovascular safety and kidney outcomes of linagliptin, a highly selective DPP-4 inhibitor with minimal renal excretion, 15 in people with T2DM at high cardiovascular and renal risk. 14 In a pooled analysis including data from the 3 pivotal CVOTs with saxagliptin, alogliptin, and sitagliptin, the overall hHF risk was not significantly different (hazard ratio, 1.14 95% CI, 0.97–1.34), but because of heterogeneity across the trials, a meta-analytic approach to this matter is of uncertain validity. 10–12 Across these trials, there has been heterogeneity with regard to the effects of the 3 DPP-4 inhibitors on the risk of hHF, ranging from no effect with sitagliptin, 3 numeric imbalance that was not statistically significant with alogliptin, 13 and statistically significant increased risk with saxagliptin. 8, 9 To date, results from 3 cardiovascular outcome trials (CVOTs) of dipeptidyl peptidase-4 (DPP-4) inhibitors have consistently demonstrated cardiovascular safety with regard to ASCVD outcomes, but none has demonstrated incremental cardiovascular efficacy. 4, 5 Since 2008, evaluation of the cardiovascular safety of new glucose-lowering medications for T2DM has been required by international regulatory agencies. 3–5 The increased risk for hHF is particularly strong in people with coexisting chronic kidney disease, 6, 7 or with pre-existing HF. Type 2 diabetes mellitus (T2DM) is commonly complicated by atherosclerotic cardiovascular disease (ASCVD) and/or chronic kidney disease, 1, 2 and is also associated with an increased risk of hospitalization for heart failure (hHF) and heart failure (HF)–related outcomes. Customer Service and Ordering Information.Stroke: Vascular and Interventional Neurology.Journal of the American Heart Association (JAHA).Circ: Cardiovascular Quality & Outcomes.Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB). ![]()
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