Applied Evidence

How to use type 2 diabetes meds to lower CV disease risk

J Fam Pract. 2019 November;68(9):494-498,500-504

References

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Rather than improve CV outcomes, there was some evidence that DPP-4 inhibitors might be associated with an increased risk of hospitalization for heart failure (HHF). In the SAVOR-TIMI 53 trial, patients randomized to saxagliptin had a 0.7% absolute increase in risk of HHF (P = .98).⁶ In the EXAMINE trial, patients treated with alogliptin showed a nonsignificant trend for HHF.¹⁰ In both the TECOS and CARMELINA trials, no difference was recorded in the rate of HHF.^8,9,11 Subsequent meta-analysis that summarized the risk of HHF in CVOTs with DPP-4 inhibitors indicated a nonsignificant trend to increased risk.¹²

It’s likely that the CV benefits result from mechanisms other than a reduction in the serum glucose level, given the short time frame of the studies and the magnitude of the CV benefit.

From these trials alone, it appears that DPP-4 inhibitors are unlikely to provide CV benefit. Data from additional trials are needed to evaluate the possible association between these medications and heart failure (HF). However, largely as a result of the findings from SAVOR-TIMI 53 and EXAMINE, the FDA issued a Drug Safety Communication in April 2016, adding warnings about HF to the labeling of saxagliptin and alogliptin.¹³

CARMELINA was designed to also evaluate kidney outcomes in patients with T2D. As with other DPP-4 inhibitor trials, the primary aim was to establish noninferiority, compared with placebo, for time to MACE-3 (P < .001). Secondary outcomes were defined as time to first occurrence of end-stage renal disease, death due to renal failure, and sustained decrease from baseline of ≥ 40% in the estimated glomerular filtration rate. The incidence of the secondary kidney composite results was not significantly different between groups randomized to linagliptin or placebo.⁹

Cardiovascular outcomes trials: GLP-1 receptor agonists

ELIXA. The CV safety of GLP-1 receptor agonists has been evaluated in several randomized clinical trials. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial was the first¹⁴: Lixisenatide was studied in 6068 patients with recent hospitalization for acute coronary syndrome. Lixisenatide therapy was neutral with regard to CV outcomes, which met the primary endpoint: noninferiority to placebo (P < .001). There was no increase in either HF or HHF.

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