Round up of the DPP-4 inhibitor CV outcome trials
Three cardiovascular (CV) outcome trials for dipeptidyl peptidase (DPP)-4 inhibitors in patients with type 2 diabetes have so far reported their primary findings, with a fourth expected this year. A trial of vildagliptin in patients with heart failure has also been published.
As stipulated by the regulatory authorities, patients in the CV outcome trials were randomly assigned to receive the DPP-4 agonists in question versus placebo, with other medications added as needed to control blood glucose, and were followed up for a sufficient duration to demonstrate noninferiority of the active treatment for CV outcomes.
|Medication: alogliptin, 6.25 to 25.0 mg/day depending on kidney function||Patient population: N= 5380; 100% with acute coronary syndrome within 15 to 90 days before randomization|
The results of EXAMINE were published in The New England Journal of Medicinein 2013. The primary endpoint was a composite of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke.
This occurred in 11.3% of patients taking alogliptin and 11.8% of those assigned to placebo during a median 18 months of follow-up, giving a hazard ratio of 0.96, which was within the prespecified margin of 1.3 for the noninferiority of alogliptin to placebo.
|Medication: saxagliptin, 2.5 or 5.0 mg/day depending on kidney function||Patient population: N=16,492; high-risk patients, around 78% with established atherosclerotic disease|
SAVOR-TIMI 53 was designed to detect superiority of saxagliptin over placebo for CV safety; hence it had a much larger patient population than EXAMINE. However, the results, also published in The New England Journal of Medicine in the same year, showed only that the medication was no worse than placebo for CV safety.
During a median 2.1 years of follow-up, the composite primary endpoint of CV death, myocardial infarction, or ischemic stroke occurred in 7.3% and 7.2% of patients taking saxagliptin and placebo, respectively. Of concern, saxagliptin was associated with a significant increase in the rate of hospitalization for heart failure, at 3.5% versus 2.8%.
|Medication: sitagliptin, 50 or 100 mg/day depending on kidney function||Patient population: N=14,671; all with established CV disease|
TECOS, published 2 years later, was also designed with sufficient statistical power to prove superiority of sitagliptin to placebo, but again demonstrated only noninferiority. During a median follow-up of 3.0 years, 11.4% and 11.6% of patients taking sitagliptin and placebo, respectively, had a primary outcome event of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.
In this trial, however, there was no indication of an increased heart failure risk for patients taking the DPP-4 inhibitor.
|Medication: vildagliptin, 50 mg twice daily||Patient population: N=254; all with heart failure: New York Heart Association functional class I to III and left ventricular ejection fraction (LVEF) less than 0.40|
Vildagliptin has been approved by the EMA but not the FDA. There is no CV outcome trial equivalent to those for the other DPP-4 inhibitors, ie, involving patients at high CV risk and using a 3- or 4-point major adverse CV events endpoint. Instead, VIVIDD was designed to determine the effects of vildagliptin on LVEF in diabetes patients with heart failure.
The results showed that during 1 year of treatment LVEF declined by 4.95% in the vildagliptin group and by 4.33% in the placebo group, with the difference being within the prespecified noninferiority margin.
However, patients taking active treatment versus treatment had a nonsignificant increase in rates of any CV event (27.3 vs 24.6%) and death from any cause (8.6 vs 3.2%), as well as the individual secondary endpoints of CV death, acute coronary syndromes, and arrhythmia, although the trial was not powered to detect differences in these outcomes.
Yet to report
The CARMELINA trial, testing linagliptin 5 mg/day versus placebo, completed in December 2017 but has not yet reported its findings. The 6980 patients are at high CV risk, with 74% having existing chronic kidney disease, 57% having established CV disease, and 33% having both.
The trial design allows sufficient statistical power to demonstrate superiority of linagliptin over placebo for the composite primary outcome of CV death, nonfatal myocardial infarction, or nonfatal stroke.
In addition, the CAROLINA trial, a head-to-head comparison of the CV safety of linagliptin versus glimepiride versus matched placebos in high-risk patients, is due to complete in early 2019.
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