The Safety of Dipeptidyl Peptidase 4 Inhibitors and the Risk for Heart Failure

Three of the four currently approved DPP-4 inhibitors (Nesina (alogliptin), Trajenta (linagliptin), Onglyza (saxagliptin),

Januvia (sitagliptin)) have published studies in regards to their cardiovascular outcomes. Both the EXAMINE study

with alogliptin and the SAVOR-TIMI 53 study with saxagliptin discovered that type 2 diabetics taking these drugs are

at an increased risk of hospitalization due to heart failure compared to those who received placebo. The results of

these two studies were compelling enough for the FDA to add warnings about the increased heart failure risk to the

labels of both Onglyza and Nesina, along with any combination products containing either drug. Additionally, the

results of these two trials brought up the question of whether all DPP-4 inhibitors possess a specific, albeit

unknown, mechanism of action associated with an increased risk of heart failure.

Januvia has just joined Onglyza and Nesina as the third DDP-4 inhibitor to have a cardiovascular outcomes trial.

However, unlike the previous two trials, the TECOS study with sitagliptin confirmed the drug is not associated with an

increased risk of heart failure in type 2 diabetics. The TECOS study is an international, randomized, double-blind,

placebo-controlled trial that involved over 14,000 stable type 2 diabetics with established cardiovascular disease in

almost 700 sites. Patients were randomized to receive either sitagliptin or placebo as add-on to their current

antidiabetic therapy with a median follow-up of 2.9 years. It was found the rate of hospitalization for heart failure in

both the sitagliptin and placebo treatment groups was the same (3.1% vs 3.1%; hazard ratio, 1.00; 95% CI, 0.83-

1.20; P = .98). While there are some differences in the patient populations of the TECOS, EXAMINE, and SAVOR-TIMI

53 studies, particularly in their cardiovascular and kidney disease status, the differences are believed to be subtle

and unlikely to explain the varying outcomes of the studies.

This now brings up suspicions of differing pharmacological properties within the DPP-4 inhibitor class. Given that

each of the DPP-4 inhibitors differ in their biochemical structure, it is hypothesized each agent may also differ in

their selectivity for some of DPP-4’s substrates, such as GLP-1, brain natriuretic peptide, neuropeptide Y, substance

P, and stromal cell-derived factor-1. While the effect of DPP-4 inhibition on these substrates, save for GLP-1, is

largely unknown, it is possible they may play a role in heart failure; further studies could reveal one or more as a

potential therapeutic target in heart failure prevention and treatment.

Type 2 diabetics are at a naturally increased risk for heart failure due to the macrovascular complications of their

disease. While the DPP-4 inhibitors have not been associated with an increase in cardiovascular death, the

increased risk of heart failure seen in both alogliptin and saxagliptin may cause healthcare providers to be more

wary of choosing these agents as add-on therapy. The results of the TECOS study have helped Januvia establish

itself atop the DPP-4 inhibitor class, at least in terms of its safety profile. However, this victory for Januvia may be

fleeting as the EMPA-REG OUTCOME results, which claim a reduction in major adverse cardiovascular events, heart

failure, and overall mortality with the use of Jardiance (empagliflozin), may shift the diabetes therapeutic landscape

away from DPP-4 inhibitors and towards the preferential use of SGLT-2 inhibitors as add-on therapy. Longer-term

studies will be needed if Januvia is to demonstrate it not only reduces the risk of heart failure hospitalization but

also reduces cardiovascular death and overall mortality.

More information: http://cardiology.jamanetwork.com/article.aspx?articleid=2513301

TECOS study: http://cardiology.jamanetwork.com/article.aspx?articleid=2513305