CARMELINA reassuring for linagliptin CV safety in T2D
Treatment with the DPP-4* inhibitor linagliptin in addition to the standard of care has no impact on heart failure, cardiovascular (CV), or renal events compared with standard of care alone in patients with type 2 diabetes (T2D) who had a very high risk of CV events and/or kidney disease progression, according to the CARMELINA** postmarketing outcomes study, thus providing reassurance on the CV safety of at least one member of the drug class.
Following concerns over the association between DPP-4 inhibitors such as saxagliptin and alogliptin with an increased risk of hospitalization for heart failure (HF; although the latter did not reach statistical significance vs placebo) in previous trials, the US FDA mandated that CV outcome trials be performed to show CV safety in this class of drug. [N Engl J Med 2013;369:1317-1326; N Engl J Med 2013;369:1327-1335]
“CARMELINA was conducted to decide whether there is a real class effect or whether there is heterogeneity and perhaps linagliptin may be free of risk for HF,” said Dr Julio Rosenstock of University of Texas Southwestern Medical Centre in Dallas, Texas, US, who presented the study at EASD 2018.
The linagliptin arm did not significantly differ from the placebo arm in the primary endpoint of time to first occurrence of 3-point MACE*** comprising CV death, nonfatal myocardial infarction (MI), or nonfatal stroke (HR, 1.02; p=0.0002 for noninferiority). The finding remained even when the analyses were stratified by baseline characteristics including sex, HbA1c levels, heart failure, or eGFR. Individual component of the 3-point MACE was also comparable between the two arms. [EASD 2018, session S35]
Furthermore, adding the endpoint of hospitalization for unstable angina to the 3-point MACE (4-point MACE) did not change the results (HR, 1.00; p<0.0001 for noninferiority).
Linagliptin also did not significantly affect the risk of all-cause mortality (HR, 0.98, 95 percent confidence interval [CI], 0.84–1.13) and hospitalization for HF (HR, 0.90, 95 percent CI, 0.74–1.08).
Although the overall rates of combined renal endpoint were not significantly different between the two groups, microvascular events was significantly reduced with linagliptin over placebo — which according to the researchers, was mainly driven by reductions in albuminuria progression (HR, 0.86; p=0.0034), particularly the progression of baseline microalbuminuria to macroalbuminuria (HR, 0.84; p=0.0067).
There were no new safety signals. Investigator-reported hypoglycaemia (including severe hypoglycaemia) occurred in a similar proportion of patients in the linagliptin and placebo arms.
“[The adverse event] findings are consistent with the known safety profile of linagliptin … Consistent with current labelling, acute pancreatitis and pemphigoid events were rare but occurred numerically more frequently with linagliptin than placebo,” said copresenter Professor Mark Cooper, director of JDRF Centre for Diabetes Complications in Melbourne, Australia.
Clinically relevant population
“Linagliptin demonstrated CV safety in a clinically relevant population of patients with T2D, CV disease, and CKD … CARMELINA fills an important data gap [through recruitment of] a clinically relevant patient population across all stages of kidney function … [which] represents a previously understudied patient population,” said Professor Bernard Zinman of Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
The global, multicentre study (605 sites across 27 countries) randomized 6,991 T2D patients (mean age 66 years) at very high risk# of CV events to receive either linagliptin 5 mg/day (n=3494) or placebo (n=3485), both in addition to standard of care. About three-quarter of the participants had chronic kidney disease (CKD; with 62.3 percent in stage 3–5) and over half had established CV disease, while another one third had both conditions.
“We know that CV risk is increased in people with T2D complicated with CKD. People with T2D have two to three times increased risk of CVD and that risk is even doubled in people with CKD,” said Rosenstock.
“[However,] patients with T2D and kidney disease are [often] underrepresented in CV outcomes trials,” he continued, pointing out 62.3 percent of the participants in CARMELINA had low eGFR## compared with <30 percent enrolment for other major CV outcome trials.
“The overall safety profile including kidney outcomes in this high risk patient population was reassuring,” commented Zinman. “Linagliptin did not increase hospitalization for HF, even in patients at high risk for HF.”