ESC 2013 Report – Neither up nor down: Two big trials of DPP-4 inhibitors meet non-inferiority ischemic target

Study presenter Deepak Bhatt (pictured)  – The anti-hyperglycemic agent saxagliptin neither increased or decreased therate of ischemic events when added to standard of care in patients with type 2 diabetes mellitus in the phase IV SAVOR-TIMI 450 study. However, the study, published online by the New England Journal of Medicine, did find that those taking saxagliptin were more likely to be hospitalised for heart failure than controls.

Although improved glycemic control has repeatedly been shown to reduce microvascular diabetic complications, uncertainty remains over the effect of glucose-lowering agents on cardiac safety. Most trials testing glucose-lowering strategies on cardiovascular outcomes have been insufficiently powered or shown no significant benefits.

The SAVOR-TIMI 450 study was designed to evaluate the safety and efficacy of saxagliptin, a selective dipeptidyl peptidase 4 (DPP-4) inhibitor, on cardiovascular outcomes. Between May 2010 and December 2011, the study randomly assigned 16,492 patients with type 2 diabetes to either saxagliptin 5 mg daily (2.5 mg daily in renal impairment) or placebo. The trial was conducted at 788 sites in 26 countries.

At a median follow-up of 2.1 years the primary endpoint (a composite of cardiovascular death, non-fatal MI, or non-fatal ischemic stroke) occurred in 7.3% (613) of patients in the saxagliptin group and 7.2% (609) in the placebo group (HR 1.00, P= 0.99 for superiority and P<0.001 for non-inferiority). This, said study presenter Deepak Bhatt from the VA Boston Healthcare System, met the FDA criteria for non-inferiority.

The major secondary endpoint (cardiovascular death, MI, stroke or hospitalisation for heart failure, unstable angina or coronary revascularisation) occurred in 12.8% (1059) of the saxagliptin group and 12.4% (1034) of the placebo group.

In terms of blood sugar control, 36.2% of patients treated with saxagliptin did achieve a glycated haemoglobin of less than 7% compared to 27.9% of controls (P<0.001). However, 15.3% of the saxagliptin group reported at least one hypoglycaemic event compared to 13.4% of controls (p<0.001). Overall, 3.5% of patients in the saxagliptin group were hospitalised for heart failure compared to 2.8% in the placebo group (HR 1.27; 95% CI 1.07-1.51; P=0.007). Rates of acute and chronic pancreatitis, of which there have been concerns, were similar in the two groups.

‘What’s clear is that neither saxagliptin or alogliptin [as used in the EXAMINE trial also reported yesterday], or indeed any of the other DPP-4 inhibitors, appear to impact favourably on cardiovascular outcomes with intermediate term follow up,’ said Bhatt. It might be, he added, diabetes is metformin, but the second line drug is up in the air,’ said William B White, the study’s principal investigator from the University of Connecticut School of Medicine.

Addressing the question of the effect of alogliptin on heart failure, White said: ‘In EXAMINE hospitalisation for heart failure was not increased relative to placebo.  However, it has to be borne in mind that the database was only unlocked five weeks ago and we have yet to finish our analysis of all the secondary endpoints.’ The trial had a median duration of just 18 months.