How Does Vildagliptin Affect the Heart in Patients with Reduced Ejection Fraction?

By Will Boggs MD

NEW YORK (Reuters Health) - The oral anti-hyperglycemic agent vildagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, does not appear to worsen ventricular systolic function in patients with type 2 diabetes and heart failure with reduced ejection fraction (HFrEF), according to results from a 52-week randomized trial.

Recent controlled trials have reported conflicting evidence about the risk of heart failure with different DPP-4 inhibitors.

In the VIVIDD trial, Dr. John J.V. McMurray from the University of Glasgow, in Scotland, and colleagues randomized 254 patients with type 2 diabetes and HFrEF to receive vildagliptin (50 mg twice daily or once daily if using a sulfonylurea) or placebo, in addition to standard therapy.

Findings were published online October 12 in JACC: Heart Failure.

Planned follow-up was completed by 79% of both groups. Eleven vildagliptin recipients (8.6%) and four placebo recipients (3.2%) died.

Left-ventricular ejection fraction (LVEF) increased by a mean 4.95 percentage points in the vildagliptin group and 4.33 in the placebo group, a difference that satisfied the predefined noninferiority criterion.

Vidagliptin also showed a significant advantage over placebo in LV end-diastolic volume and a trend toward an advantage in LV end-systolic volume.

B-type natriuretic peptide levels decreased to a similar extent in the two groups, whereas hemoglobin A1c levels decreased significantly more with vildagliptin than with placebo.

The groups did not differ in other measures of heart failure status.

“While the clinical significance of our findings is unknown, there are other data with an agent in the same class, saxagliptin, showing an increase in risk of incident heart failure hospitalization,” the researchers write. “While both sets of results may reflect the play of chance, they do, along with the earlier thiazolidinedione findings, highlight the need to examine the safety of new glucose-lowering treatments specifically in patients with diabetes and HFrEF who are a particularly high-risk and possibly vulnerable group.”

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“More evidence is needed regarding the safety of DPP-4 inhibitors in patients with established heart failure and left ventricular systolic dysfunction,” they conclude.

“It is however important to recognize that VIVIDD was not a traditional cardiovascular safety trial, focusing instead on ventricular function," write Dr. Javed Butler from Stony Brook University, in New York, and Dr. Muthiah Vaduganathan from Brigham and Women's Hospital, in Boston, in a related editorial. “Given uncertain risks of heart failure with the DPP-4 inhibitors, this trial provides initial data regarding the stability of left ventricular ejection fraction, but also raises concerns regarding increased left ventricular volumes and potentially higher clinical event rates with vildagliptin.”

“The clinical significance of these signals will need to be further clarified in larger studies of DPP-4 inhibitors in patients with type 2 diabetes and established heart failure,” they conclude.

Dr. Gian Paolo Fadini from the University of Padova, in Italy, who recently found no difference in the risk of hospitalization for heart failure between DPP-4 inhibitors and sulfonylureas, told Reuters Health by email, "It is very surprising that about 50% of heart failure patients in this study were taking sulfonylurea. This reflects inappropriate treatment and means that 50% of patients used an underdosage of vildagliptin (50 mg instead of 100 mg), which is something not recommended and not reflecting clinical practice.”

“Physicians should be aware that data on DPP-4 inhibitors do not support any clear signal for heart failure induction or worsening,” he said. “The VIVIDD trial does not help to challenge this view.”

“A much larger pragmatic trial with serial measurements of cardiac function should be performed to collect clinically relevant data,” Dr. Fadini said.

Dr. Yi-Cheng Chang from National Taiwan University Hospital, in Taipei, who has reported no increased risk of hospitalization for heart failure for patients treated with DPP-4 inhibitors there, told Reuters Health by email, "Since they do not report increased heart failure events, this study just adds a warning sign to vildagliptin.”

“Vildagliptin use might dilate heart chambers without changes in pumping function,” she said. “Randomized controlled trials with endpoints of heart failure events or hospitalization for heart failure are awaited.”

Dr. McMurray did not respond to a request for comment.

Novartis (which makes vildagliptin) funded the trial, employed three of the eight authors, and compensated the remaining five or their institutions for participation in the trial. Dr. Butler has been a consultant for Novartis.

SOURCES: https://bit.ly/2lw2XfP and https://bit.ly/2gZbjeg

JACC Heart Fail 2017.

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