Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial - VERTIS CV
Contribution To Literature:
Ertugliflozin is noninferior for reducing CV events in patients with T2DM and established CVD. The effects, especially on HF, were consistent with the benefits seen in the SGLT2 inhibitor class.
The goal of the trial was to assess the cardiovascular (CV) safety of ertugliflozin in patients with type 2 diabetes mellitus (T2DM) and established atherosclerotic cardiovascular disease (ASCVD).
Patients were randomized in a 1:1:1 fashion to either ertugliflozin 5 mg (n = 2,752), 15 mg (n = 2,747), or matching placebo (n = 2,747).
- Total number of enrollees: 8,246
- Duration of follow-up: 3.5 years
- Mean patient age: 64.4 years
- Percentage female: 30%
- Age ≥40 years
- T2DM diagnosis according to American Diabetes Association (ADA) guidelines: glycated hemoglobin (HbA1c) 7.0-10.5% (53-91 mmol/mol)
- Established ASCVD involving the coronary, cerebrovascular, and/or peripheral artery systems
- Stable on allowable antihyperglycemic agents (AHAs) or on no background AHA for ≥8 weeks prior to study participation
- History of type 1 DM or ketoacidosis
- Experiencing a CV event (e.g., myocardial infarction [MI] or stroke) or undergoing coronary or peripheral intervention procedure between the screening visit and randomization
- Undergoing any CV surgery (e.g., valvular surgery) within 3 months of the screening visit
- Planned revascularization or peripheral intervention procedure or other CV surgery
- Estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 at the screening visit
- New York Heart Association class IV heart failure (HF) at screening visit (class III-IV prior to protocol amendment)
Other salient features/characteristics:
- White 88%; Europe: 56%
- Diagnosis of T2DM: 13 years
- Baseline low-density lipoprotein: 89 mg/dl
- Known coronary artery disease: 76%, prior MI: 48%, known CVD: 23%
- Metformin: 76%; insulin: 48%; glucagon-like peptide-1 (GLP-1): 3.5%
- Statin: 82%, antiplatelet: 85%
The primary outcome, CV death, nonfatal MI, or stroke for ertugliflozin vs. placebo: 11.9% vs. 11.9% (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.85-1.11, p < 0.001 for noninferiority)
- CV death: 1.8% vs. 1.9% (p = 0.39)
- MI: 1.7% vs. 1.6% (p = 0.66)
- Stroke: 0.8% vs. 0.8% (p = 0.99)
- HF hospitalization: 2.5% vs. 3.6% (p = 0.006)
- HbA1c at 18 weeks for 5 mg ertugliflozin vs. placebo: -0.5% (p < 0.0001)
- HbA1c at 18 weeks for 15 mg ertugliflozin vs. placebo: -0.5% (p < 0.0001)
- Mean decrease in body weight for ertugliflozin 5 mg vs. placebo: 2.4 kg; for ertugliflozin 15 mg vs. placebo: 2.8 kg
- Symptomatic hypoglycemic event: 27.2% vs. 28.8%
- Urinary tract infection: 12.1% vs. 10.2% (p < 0.05)
- Amputation: 2.0% vs. 1.6% (p > 0.05)
- Renal composite (renal death, dialysis/transplant, doubling of serum creatinine): 3.2% vs. 3.9% (p = 0.08)
- Doubling of serum creatinine: 3.1% vs. 3.8%
HF outcomes: Time to first HF hospitalization for ertugliflozin vs. placebo, was 0.73 vs. 1.05 events/100 person-years (HR 0.70, 95% CI 0.54-0.90, p = 0.006). The benefit was consistent across ertugliflozin dose. History of HF and EF ≤45%/>45%. Total and recurrent HF events were also reduced in the ertugliflozin arm. On subgroup analysis, effects were more pronounced among patients with eGFR <60 (p = 0.04), presence of macro- or microalbuminuria (p = 0.04), and patients already on diuretic (p = 0.02).
The results of this trial indicate that ertugliflozin is noninferior to placebo for reducing CV events in patients with T2DM and established CVD. Trends were noted for beneficial effect on renal outcomes, although this was not statistically significant.
This is the fourth sodium glucose cotransporter-2 (SGLT2) drug to report on CV outcomes (after empagliflozin, canagliflozin, and dapagliflozin). There appeared to be a consistent class effect with respect to reductions in HF hospitalizations, but major adverse cardiac event reductions were statistically significant only for canagliflozin and empagliflozin. Unlike canagliflozin, no safety signals with respect to amputations were noted. The salutary effects of ertugliflozin appear to be somewhat diminished compared with canagliflozin and empagliflozin; it is unclear if this represents a difference in patient populations between the trials, or a true biological difference in drug efficacy (or other issues). Overall, these are important findings, even as SGLT2 inhibitors are becoming first-line agents for patients with T2DM, and also for patients with HF, with or without DM. These results add to the body of evidence supporting the use of this class in the guidelines.
Presented by Dr. Francesco Cosentino at the European Society of Cardiology Virtual Congress, August 31, 2020.
Presented by Dr. Christopher P. Cannon at the American Diabetes Association Virtual Scientific Sessions, June 16, 2020.
Keywords: Amputation, Atherosclerosis, Diabetes Mellitus, Type 2, Heart Failure, Hemoglobins, Hypoglycemia, Metabolic Syndrome X, Myocardial Infarction, Primary Prevention, Renal Insufficiency, Renal Dialysis, Sodium-Glucose Transporter 2, Stroke, Vascular Diseases, ESC Congress, ESC20
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