There are cardiovascular (CV) outcome trials for dipeptidyl peptidase (DPP)-4 inhibitors in patients with type 2 diabetes, and 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 inhibitor 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 Medicine in 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.
Medication: linagliptin 5 mg/day
Patient population: N=6979, at high CV risk or with existing chronic kidney disease (74%) or CV disease (57%)
Again, CARMELINA was powered to demonstrate cardioprotection, but again it proved only to be noninferior to placebo.
The investigators reported their findings at the 2018 EASD annual meeting, revealing cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke rates of 12.4% and 12.1% in the linagliptin and placebo groups, respectively, over a median 2.1 years of follow-up.
The trial is now published in JAMA.
Medications: linagliptin, glimepiride
Patient population: N=6033, at high risk or with established cardiovascular disease (42%)
The CAROLINA trial was designed to test whether a DPP-4 inhibitor would have a more favorable CV profile than a sulfonylurea. This head-to-head comparison showed no significant difference between linagliptin and glimepiride, with respective rates of 11.8% and 12.0% for the composite primary outcome.
Although not the hoped-for outcome for linagliptin, the trial did clear up lingering concerns about the CV safety of sulfonylureas, although glimepiride was, as expected, associated with an increased risk for hypoglycemia.
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