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Data shed light on vildagliptin in diabetes, heart failure
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The antihypertensive agent vildagliptin may have an effect in patients with type 2 diabetes and those with heart failure and reduced ejection fraction.
According to late-breaking research presented at the European Society of Cardiology Heart Failure Congress in May, the effect of vildagliptin (Galvus, Novartis) on left ventricular ejection fraction was noninferior to that of placebo. Similarly, recent data published in The Lancet suggest that vildagliptin may be a safe and effective treatment option in elderly patients with diabetes.
“Diabetes and heart failure is a common dual problem, and these patients have a particularly bad outlook. But, remarkably, patients with heart failure are excluded from most trials testing diabetes drugs. At the moment, it’s not at all clear how clinicians should choose between the various antidiabetes drugs when confronted with a heart failure patient,” VIVIDD researcher John McMurray, MD, from the University of Glasgow, said in a press release.
Positive results in HF
The VIVIDD trial compared the effects of vildagliptin 50 mg twice daily (n=128) vs. placebo (n=126) added to standard glucose-lowering and heart failure therapy.
The primary endpoint was change in left ventricular ejection fraction from baseline to 52 weeks. According to results, the trial met the primary endpoint of statistical noninferiority (difference: 0.54; 95% CI, –1.97 to 3.06). Additionally vildagliptin was associated with a decrease in HbA1c over 16 weeks, a secondary endpoint of the trial (difference: –0.62%; 95% CI, –0.93 to –0.3).
Unexpectedly, according to the researchers, vildagliptin increased left ventricular end-diastolic volume (difference: 17.06 mL; 95% CI, 4.62-29.51) and left ventricular end-systolic volume (difference: 9.44 mL; 95% CI, –0.49 to 19.38).
“Normally an increase in the size of the left ventricle is associated with a decline in systolic function, but we saw no change in ejection fraction and a fall rather than increase in [B-type natriuretic peptide]. We speculate that the surprising findings of VIVIDD indicate that this antidiabetes drug may have improved the distensibility and compliance of the left ventricle,” McMurray stated.
Researchers noted a nonsignificant excess of deaths in the vildagliptin group (11 vs. four). Time to first cardiovascular event was 27.3% in the vildagliptin group vs. 24.8% in the placebo group.
Patients enrolled in VIVIDD were aged 18 to 85 years with type 2 diabetes and NYHA Class I to III HF. Baseline mean HbA1c was 7.8% and left ventricular ejection was 30.6% in the vildagliptin group and 29.6% in the placebo group.
Beneficial effects in elderly patients with diabetes
Similar to the VIVIDD, patients with type 2 diabetes aged 70 years or older enrolled in the double blind, 24-week INTERVAL study were randomly assigned vildagliptin (n=139) or placebo (n=139).
According to data, 27% of patients assigned placebo reached individualized targets through education and interactions with the study team vs. 52.6% assigned vildagliptin (OR=3.16; 96.2% CI, 1.81-5.52). Patients administered vildagliptin demonstrated a 0.9% reduction in HbA1c from a baseline of 7.9%, indicating a between-group difference of –0.6% (98.8% CI, –0.81 to –0.33).
“The results of this study support global guidelines recommending individualized care and demonstrate the feasibility of the study design and the setting of individualized targets. The findings show that individualized targets are achievable and, for the very first time, provide an evidence base for treatment guidelines for patients with type 2 diabetes,” researcher W. David Strain, MD, senior clinical lecturer and honorary consultant at University of Exeter Medical School, Institute of Biomedical and Clinical Science, and of the department of diabetes and vascular research at Royal Devon & Exeter Hospital in the United Kingdom, said in an interview.
Next steps
Researchers from the INTERVAL study wrote that an understanding of the importance of assessing individualized glycemic targets is needed in the aging elderly population.
Strain told Endocrine Today that the next step is to gain a better understanding of the factors that affected targets and potential barriers to treatment.
“Our longer-term aims are to carry this work forward to a study of greater duration using clinically meaningful outcomes for an elderly population, such as frailty progression, hospitalizations for any cause and quality of life, using the more conventional outcomes for secondary outcomes,” Strain said. “We believe that at the age of 75, patients are far more interested in the quality of their remaining years than the quantity, and this should be the principal focus of studies.” – by Samantha Costa
Perspective
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Douglass Mann, MD
The results of the VIVIDD trial were recently presented at the European Society of Cardiology Heart Failure Association Meeting in Lisbon, Portugal. The trial evaluated the safety of vildagliptin, a DPP-IV inhibitor, in patients with diabetes and heart failure secondary to a reduced ejection fraction. DPP-IV is a peptidase that degrades GLP-1, a family member of incretin peptides that have been used for treatment of type 2 diabetes because of their ability to regulate glucose metabolism and insulin secretion. The rationale for the VIVIDD trial was that GLP-1 analogs have been shown to be cardio-protective in multiple settings, including heart failure. VIVIDD was a randomized, intention-to-treat trial that included men and women aged 18 to 65 years with type 2 diabetes and NYHA Class 1 to Class 3 heart failure, who were receiving evidence-based medical therapies for heart failure. The baseline left ventricular ejection fraction (LVEF) was approximately 30% in the treatment and control groups, and the mean HbA1c was roughly 7.8%. The primary endpoint of the trial was a change in LVEF from baseline to 52 weeks. It was designed as a noninferiority trial with respect to change in LVEF. The VIVIDD trial showed that vildagliptin did not adversely affect LVEF (ie, was noninferior) when compared with placebo. However, there was a small but significant increase in LV end-diastolic volume and a trend toward an increase in LV end-systolic volume in the treatment group. Although there was no overall difference in the time to the first CV event between the two groups, there were more CV deaths in the treatment arm vs. placebo arm. Moreover, there were 11 deaths in the vildagliptin arm and four deaths in the placebo arm, raising potential concerns about safety. However, it bears emphasis that the overall event rate was quite small in the trial and the increased deaths in the treatment arm could simply reflect “play of chance.” Importantly, the HbA1c levels were decreased in the treatment group.
In summary, the VIVIDD trial is an important trial that evaluates the role of a novel class of agents, DPP-IV inhibitors that may be useful in treating patients with diabetes who have heart failure secondary to reduced ejection fraction. Although the trial met its primary endpoint of noninferiority with respect to changes in LVEF, there are residual concerns and unanswered questions with respect to the increase in LV end-diastolic volumes and the increase in CV events and mortality in the treatment group.
Further studies will be necessary to evaluate the safety and utility of this agent in patients with diabetes and heart failure secondary to reduced ejection fraction.
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