Study results showing two DPP-4 inhibitors neither increased nor decreased the risk of cardiovascular events in type 2 diabetes patients came as no surprise to endocrinologists contacted by MedPage Today.

Both alogliptin (Nesina) and saxagliptin (Onglyza) had a null effect on risk of fatal and nonfatal cardiac events in the safety studies reported simultaneously at the European Society of Cardiology meeting here and online in the New England Journal of Medicine.

But neither did they diminish cardiovascular disease risk in patients with type 2 diabetes who’d either had a previous cardiovascular event or were at higher risk for heart disease, according to findings from the EXAMINE and SAVOR-TIMI 53 studies.

Endocrinologists contacted by MedPage Today said the results aren’t unexpected, because the drugs haven’t shown any signals of heart risk. And few were concerned by an increased risk of hospitalizations for heart failure that turned up in one of the trials.

“The neutral effects should not be surprising,” Silvio Inzucchi, MD, director of the Yale Diabetes Center, told MedPage Today in an interview. “We’ve known that in DPP-4 inhibitors, cardiovascular parameters have been very modest.”

On the other hand, Inzucchi said, the other drugs in the incretin class, GLP-1 agonists, “may potentially have greater cardiovascular effects. If those results would be neutral, then that might be considered disappointing. But DPP-4s have always been neutral on lipids and have shown no major effects on inflammatory markers.”

Sue Kirkman, MD, an endocrinologist at the University of North Carolina Chapel Hill, called the results “reassuring.”

“The point of the cardiovascular outcome studies is to make sure there are no off-target adverse effects on cardiovascular disease,” Kirkman said in an email to MedPage Today. “It isn’t to prove that the drugs reduce risk of cardiovascular disease. There are other reasons to treat hyperglycemia, such as symptom reduction and microvascular complication reduction.”

“Between the two studies,” she added, “they studied a large number of patients at high cardiovascular risk, and saw no adverse effects on major cardiovascular endpoints.”

The EXAMINE study, reported here by William B. White, MD, of the University of Connecticut School of Medicine, recruited 5,380 type 2 diabetes patients within 3 months of hospitalization for acute MI or unstable angina. It found that, compared with placebo, treatment with alogliptin for up to 40 months did not increase the risk of a second acute event.

The second study, SAVOR TIMI 53 - top-line results of which were reported in June - enrolled 16,492 diabetes patients who had a history of cardiovascular disease or were considered high risk for cardiovascular disease. Those patients were randomly assigned to either saxagliptin or placebo and followed for just over 2 years.

Again, the DPP-4 inhibitor neither increased nor decreased the risk of ischemic events. There was an increase, however, in hospitalizations for heart failure, said Deepak L. Bhatt, MD, MPH, of the TIMI Study Group, Brigham and Women’s Hospital, and Harvard Medical School in Boston.

Increased heart failure had previously been documented among patients treated with drugs in the thiazolidinedione class, pioglitazone (Actos) and rosiglitazone (Avandia), and rosiglitazone was also linked to increased risk of ischemic events, although re-analysis of data suggested there was no association between the drug and acute events.

Endocrinologists didn’t seem to be concerned about the heart failure data.

Inzucchi cautioned that the numbers were small, and the study did not report other heart failure outcomes such as new diagnoses and mortality.

“It’s one heart failure outcome that goes in the wrong direction, but we can’t understand why,” Inzucchi said. “There’s no biological reason DPP-4 inhibitors would exacerbate heart failure endpoints.”

Kirkman added that the heart failure risk was “a small absolute increase, and it seems like it would have to be confirmed with other studies.”

But Yale cardiologist Harlan Krumholz, MD, suggested that the studies provided evidence to warrant caution.

“The increased risk of heart failure with saxagliptin raises concerns about the class - the alogliptin trial was smaller and may not have been able to pick up that signal. This is important because many have considered this class to have a low risk of side effects,” Krumholz wrote in an email to MedPage Today.

Steven Nissen, MD, of the Cleveland Clinic and an investigator in the EXAMINE study, said that while “neutral” was not bad, he had hoped that one of the DPP-4 studies would demonstrate a cardiovascular advantage, or at least “a signal that aggressive glucose control, which the endocrinologists are always pushing, was protecting the heart.”

Nissen was a leading critic of rosiglitazone and a public crusader for cardiovascular safety review of diabetes drugs.

“These two trials show that DPP-4 inhibition was noninferior to placebo for patients with a high risk of CVD. I think, in that case, placebo wins,” Krumholz said. “The onus is still on makers of these drugs to show benefit to patients, not just incremental gains in glucose control.”

In the EXAMINE study, patients were randomized to alogliptin or placebo on top of standard therapy - usually metformin (alone or in combination with other agents), which was taken by about two-thirds of the patients. Almost half of the patients were taking sulfonylureas and roughly 30% were using insulin. Less than 3% were taking thiazolidinediones.

Most patients (71.4%) in the alogliptin treatment group received 25 mg daily, 25.7% took 12.5 mg, and 2.9% were dosed at 6.25 mg daily. Alogliptin patients achieved a mean 0.33 percentage-point decrease in glycated hemoglobin versus a 0.03-point increase in the placebo group. The investigators reported that the least-squares mean difference between the alogliptin and placebo groups was -0.36 percentage points (95% CI minus 0.43-minus 0.26, P

<0.001).

There were no significant differences in weight or lipid profiles between the two groups.

The alogliptin study was designed to evaluate noninferiority with a "prespecified noninferiority margin of 1.3 for the hazard ratio for the primary endpoint of death from cardiovascular causes, myocardial infarction, or nonfatal stroke," White and colleagues wrote.

After a median of 18 months, 305 patients in the alogliptin group versus 316 in the placebo arm - 11.3% versus 11.8% - had one of these endpoint events.

In the saxagliptin study, 613 patients taking the study drug reached the primary composite endpoint of cardiovascular death, myocardial infarction, or ischemic stroke versus 609 patients assigned to placebo. Just as in the EXAMINE study, the study drug was given on top of standard therapy.

###

By

Kristina Fiore, Staff Writer, MedPage Today