Vildagliptin in Ventricular Dysfunction Diabetes - VIVIDD

Contribution To Literature:

The VIVIDD trial showed that vildagliptin is noninferior for change in LVEF among patients with DM2 and prior HF, with an increase in LV systolic and diastolic volumes over 52 weeks of follow-up.


Among patients with diabetes mellitus (DM), prior data suggest that dipeptidyl peptidase-4 (DPP-4) inhibitors may increase the risk of heart failure (HF), particularly among patients with a higher baseline risk. The current trial sought to assess the safety of vildagliptin, a novel DDP-4 inhibitor, among patients with type 2 DM (DM2) and pre-existing HF.

Study Design

Patients were randomized in a 1:1 fashion to either vildagliptin 50 mg BID (n = 128) or placebo (n = 126).

  • Total number of enrollees: 254
  • Duration of follow-up: 52 weeks
  • Mean patient age: 63 years
  • Percentage female: 23%

Inclusion criteria:

  • Age between 18 and 85 years
  • DM2 (hemoglobin [Hb] A1c 6.5-10.0%)
  • Body mass index 22-42 kg/m2
  • HF with a reduced ejection fraction (<40%) and in New York Heart Association (NYHA) functional class I-III

Exclusion criteria:

  • NYHA functional class IV
  • Fasting plasma glucose of ≥15 mmol/L
  • Thiazolidinedione or incretin therapy
  • Recent cardiovascular event or procedure
  • Creatinine clearance <30 ml/min
  • Liver disease or elevated transaminases or bilirubin

Other salient features/characteristics:

  • Mean diabetes duration: 9.3 years
  • Mean HbA1c: 7.8%
  • Diabetes medications: Insulin: 34%, metformin: 35%, sulfonylurea: 50%
  • Prior myocardial infarction: 63%
  • Prior hospitalization for HF: 48%
  • NYHA class I: 10%, II: 53%, III: 37%
  • Mean left ventricular ejection fraction (LVEF): 30%; LVEF ≤35%: 72%
  • Baseline median B-type natriuretic peptide (BNP): ~230 pg/ml
  • Angiotensin-converting enzyme inhibitor: 66%, angiotensin receptor blocker: 26%, beta-blocker: 78%, mineralocorticoid receptor antagonist: 42%
  • Implantable cardioverter-defibrillator: 8%, cardiac resynchronization therapy: 11%

Principal Findings:

The primary outcome for vildagliptin vs. placebo, adjusted mean change in LVEF: 4.95% vs. 4.33%, p for noninferiority = 0.025, p for superiority = 0.67

Secondary outcomes for vildagliptin vs. placebo:

  • Difference in adjusted mean change in LV end-diastolic volume: 17.06 (95% confidence interval [CI], 4.62-29.51; p = 0.007)
  • Difference in adjusted mean change in LV end-systolic volume: 9.44 (95% CI, -0.49 to 19.38; p = 0.062)
  • Major adverse cardiac events: 27.3% vs. 24.6%, p > 0.05
  • Cardiovascular death: 5.5% vs. 3.2%, p > 0.05; all-cause death: 8.6% vs. 3.2%, p > 0.05
  • Worsening HF: 18.0% vs. 17.5%, p > 0.05
  • Adjusted mean change from baseline in HbA1c at 16 weeks: 0.45% vs. 0.17%, p < 0.001


The results of this trial indicate that vildagliptin, a novel DPP-4 inhibitor, is noninferior for change in LVEF among patients with DM2 and prior HF, with an increase in LV systolic and diastolic volumes over 52 weeks of follow-up. The incidence of worsening HF was similar, while all-cause mortality was numerically higher in the vildagliptin arm.

Among the DPP-4 inhibitors, saxagliptin appears to increase the risk of HF among patients with DM2, as noted in the SAVOR-TIMI 53 trial. The risk was numerically higher with alogliptin compared with placebo in the EXAMINE trial, but similar between sitagliptin and placebo in the TECOS trial. In general, the risk is felt to be higher among patients at higher risk for HF, such as those with a higher baseline value of BNP. However, the ascertainment of HF was not uniform across these trials. VIVIDD is the first trial of DPP-4 inhibitors exclusively conducted among patients with DM and HF. It is unclear if the worsening in LV dimensions noted in this trial is generalizable to other agents. Also, the discrepancy between adverse changes in LV dimensions despite a mild improvement in LVEF and no change in BNP in this trial is not easily reconcilable, and merits further investigation.   


McMurray JJ, Ponikowski P, Bolli GB, et al., on behalf of the VIVIDD Trial Committees and Investigators. Effects of Vildagliptin on Ventricular Function in Patients With Type 2 Diabetes Mellitus and Heart Failure: A Randomized Placebo-Controlled Trial. JACC Heart Fail 2017;Oct 11:[Epub ahead of print].

Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Body Mass Index, Diabetes Mellitus, Type 2, Diastole, Dipeptidyl Peptidase 4, Heart Failure, Hemoglobin A, Glycosylated, Metabolic Syndrome X, Natriuretic Peptide, Brain, Primary Prevention, Risk, Stroke Volume, Systole, Ventricular Dysfunction

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