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This article is part of a live interview about VERTIS CV with Dr. Engel, Associate Vice President, Cardiometabolic and Women’s Health, Merck Research Laboratories.
Cardiovascular events and renal disease in type 2 diabetes are an area of focus seen in studies across the world, including studies of heart failure, stroke, myocardial infarction, and renal disease progression.
Sodium-glucose cotransporter 2 (SGLT-2) inhibitors play a critical role in managing type 2 diabetes and its complications. The purpose of the VERTIS CV study was to evaluate the cardiovascular effects of ertugliflozin, an SGLT-2 inhibitor. Other studies have assessed SGLT-2 inhibitors’ effects on cardiovascular and kidney outcomes, showing significant hospitalization benefits for heart failure and renal disease progression. DAPA-CKD showed that dapagliflozin reduced the risk of kidney disease progression and death in patients with chronic kidney disease with or without type 2 diabetes. The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction reported a lower combined risk for cardiovascular death or hospitalization for heart failure than placebo. These studies and the ertugliflozin study reported significant findings related to cardiovascular events and renal outcomes with SGLT-2 inhibitors.
The VERTIS CV study was a multicenter, double-blinded, randomized, placebo-controlled non-inferiority trial. The study population was patients at least 40 years of age with type 2 diabetes and established atherosclerotic cardiovascular disease. Eligible patients were randomized in a 1:1:1 ratio to receive 5 mg or 15 mg of ertugliflozin or placebo once daily, added to background standard-of-care treatment.
In an interview on the results of VERTIS CV, Dr. Sam Engel, Associate Vice President, Diabetes, Endocrinology and Women’s Health, Merck Research Laboratories, said, “The VERTIS CV study was conducted to assess the cardiovascular safety of ertugliflozin. We also had opportunities to look at several other important factors related to the complications associated with type 2 diabetes.”
The primary endpoint was non-inferiority to placebo on major adverse CV events (MACE), which comprised as a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke, compared to placebo. With the data from the two ertugliflozin dose groups pooled for analysis, the trial had approximately 96% power to show ertugliflozin’s non-inferiority to placebo (the primary objective). The critical secondary endpoints included time to the first occurrence of the composite of CV death or hospitalization for heart failure (HHF), time to CV death alone, and time to the first occurrence of renal death, dialysis/transplant, doubling of serum creatinine.
Dr. Engel stated, “In that primary analysis ertugliflozin met the primary endpoint, establishing non-inferiority to placebo, concerning major adverse cardiovascular events, a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.”
Among 8,238 patients who received at least one dose of ertugliflozin or placebo, a major adverse cardiovascular event occurred in 653 of 5493 patients (11.9%) ertugliflozin group and 327 of 2745 patients (11.9%) in the placebo group. Resulting in a (hazard ratio, 0.97; 95.6% confidence interval [CI], 0.85 to 1.11; P<0.001 for non-inferiority).
Death from cardiovascular causes or hospitalization for heart failure occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and 250 of 2747 patients (9.1%) in the placebo group (hazard ratio, 0.88; 95.8% CI, 0.75 to 1.03; P=0.11 for superiority). The hazard ratio for death from cardiovascular causes was 0.92 (95.8% CI, 0.77 to 1.11). The hazard ratio for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63 to 1.04).
“At EASD, we reported on a series of prespecified exploratory kidney endpoints,” Dr. Engel stated. “The kidney composite has become a much more common and potentially more meaningful endpoint which is a sustained 40% reduction in an estimated glomerular filtration rate or a transplant or renal death. In addition to the composite, we also looked at the impact of ertugliflozin on urinary albuminuria excretion, which is, of course, a marker of kidney disease that we see in patients with diabetes. We also looked at the overall rate of change in glomerular filtration rate, which again is the fundamental metric that we use to monitor kidney function.”
In the prespecified exploratory analyses presented at EASD, compared to placebo, ertugliflozin reduced the risk of the kidney composite, which included a sustained 40% decrease from baseline in estimated glomerular filtration rate (eGFR), chronic kidney dialysis/transplant or renal death (HR 0.66 [95.0% CI 0.50, 0.88]).
Ertugliflozin also reduced the risk for progression of albuminuria (HR 0.79 [95% CI 0.72, 0.86], and increased the rate of regression of albuminuria by approximately 23% (HR 1.23 [95% CI 1.10, 1.36].
The American Diabetes Association and the European Association for the Study of Diabetes recommend the use of SGLT-2 inhibitors in patients with type 2 diabetes and heart failure, particularly those with heart failure with reduced ejection fraction, to reduce hHF, MACE, and CVD death, as well as in patients with type 2 diabetes with CKD (estimated glomerular filtration rate 30 to ≤60 mL min–1 [1.73 m]–2 or urinary albumin-to-creatinine ratio >30 mg/g, particularly >300 mg/g) to prevent the progression of CKD, hHF, MACE, and cardiovascular death.
In conclusion, the main results of VERTIS CV showed that ertugliflozin was non-inferior compared to placebo in patients with type 2 diabetes and atherosclerotic cardiovascular disease concerning major adverse cardiovascular events. This study is of interest, as type 2 diabetes increases the risk of cardiovascular events. Ongoing studies of SGLT-2 inhibitors are looking at the potential benefit of the SGLT-2 inhibitor class on heart failure and kidney disease in general, not just in people with diabetes, said Dr. Engel: “I anticipate future studies will continue to evaluate SGLT-2 inhibitors for the treatment of heart failure and preservation of kidney function.”
Practice Pearls:
- VERTIS CV showed that ertugliflozin, an SGLT-2 inhibitor, showed non-inferiority compared to placebo concerning major cardiovascular events.
- Death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke are major cardiovascular events associated with type 2 diabetes.
- Type 2 diabetes patients‘ options of SGLT-2 inhibitors, such as ertugliflozin, reduce prespecified exploratory renal composite risk and cardiovascular events.
Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. https://www.nejm.org/doi/full/10.1056/NEJMoa2004967
Dapagliflozin in Patients with Chronic Kidney Disease. https://www.nejm.org/doi/full/10.1056/NEJMoa2024816
Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. https://www.nejm.org/doi/10.1056/NEJMoa2022190
Tarshay Boyd, PharmD. Candidate, LECOM School of Pharmacy