VERTIS CV: Ertugliflozin Falls Short of SGLT2s on CV Outcomes, Despite Promise in Heart Failure

Ertugliflozin, the late-comer to a new, important class of type 2 diabetes (T2D) drugs, fell short of its competitors in overall results of a cardiovascular (CV) outcomes trial released today during the 80th American Diabetes Association (ADA) Scientific Sessions.

However, ertugliflozin (Steglatro) produced a 30% drop in heart failure hospitalization risk, which drew notice even though this finding in the VERTIS CV trial fell outside the study’s primary and key secondary end points. Here, the drug performed on par with its class, the sodium glucose co-transporter 2 (SGLT2) inhibitors.

Presenters dug into the differences between VERTIS CV and other cardiovascular outcomes trials for the SGLT2 class, concluding that the ertugliflozin results for heart failure are important and they confirm SGLT2 inhibitors have earned priority in treatment guidelines for patients with T2D and elevated CV or renal risk. David Cherney, MD, PhD, of the University of Toronto, even wondered whether more aggressive treatment of blood pressure following the 2015 SPRINT trial or the introduction of lipid-lowering PCSK9 inhibitors that same year could have had an effect. "Each of these are worthy of further investigation and thought," Cherney said.

Merck, which developed ertugliflozin with Pfizer, previously announced that ertugliflozin had failed to match its rivals in producing benefits over placebo for a composite of CV death or hospitalization for heart failure (HHF), CV death alone, and a composite of renal death and decline. Overall, the HR for major cardiovascular events (MACE), the primary end point, was 0.97 (95.6% CI: 0.85-1.11), with P < .001 for noninferiority. The key secondary end point for superiority was not met. There was no significant difference between the 2 doses of ertugliflozin, 5 g and 15 g, including no signficant differences in safety outcomes.

“The VERTIS CV results add to the growing body of evidence regarding the clinical profile of ertugliflozin, including its safety in patients with a history of cardiovascular disease,” lead author Christopher P. Cannon, MD, cardiologist at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, said in a statement from Merck. “Although not a part of the hierarchical testing sequence, the results indicated the potential of ertugliflozin to reduce the risk of hospitalization for heart failure in patients with type 2 diabetes and established cardiovascular disease.”

Details released today show that ertugliflozin’s shortfall in achieving superiority was due to a failure to reduce CV death relative to placebo:

• the HR for the composite of CV death and HHF was 0.88 (95.8% CI, 0.75-1.03; P = .11 for superiority)
• the HR for CV death alone was 0.92 (95.8% CI, 0.77-1.11)

According to a statement from Merck, because earlier end points were not met, additional analysis “was not a part of the hierarchical testing sequence.” However, Merck officials said hospitalization for HF was a pre-specified end point, although not a key secondary end point. The HR for HHF was 0.70 (95% CI, 0.54-0.90).

The HR for the combined renal outcome (composite of renal death, dialysis/transplant, or doubling of serum creatine) was 0.81 (95.8% CI: 0.63-1.04), which speakers noted showed a positive trend consistent with other trials while falling short of superiority. Different trials have defined the renal outcome in different ways, noted commentator Mark Cooper, MBBS, PhD, of Monash University in Australia.

Sam Engel, MD, associate vice president of Clinical Research for Merck, told The American Journal of Managed Care^® in an interview that the heart failure results for VERTIS CV were “consistent with the class” and support other data that show SGLT2 inhibitors can benefit patients with heart failure risk.

“We’ve been very excited in the medical community, because these are new opportunities for patients with diabetes who are at risk for hospitalization for heart failure,” he said. “We are looking forward to sharing these results with regulatory agencies around the world.”

Engel said there has been interest in “mechanistic studies” to understand precisely how SGLT2 inhibitors produce benefits in heart failure and help patients avoid renal decline. Two such trials, ERADICATE-HF and EMMED-HF, are studying ertugliflozin in heart failure.

Heart Failure the Constant in SGLT2 Inhibitors

Although SGLT2 inhibitors were developed to treat T2D, surprising results in 2015 caused drug developers to study them in heart failure. Competitor dapagliflozin (Farxiga, AstraZeneca) has already been shown to reduce one type of heart failure regardless of diabetes status and just won a heart failure indication from the FDA.

SGLT2 inhibitors have reshaped the T2D treatment landscape since canagliflozin (Invokana, Janssen) reached the market in 2013. The drugs work by a separate mechanism than older glucose-lowering drugs by forcing excess glucose out through the urine; thus, they can work alongside other therapies.

In 2008, the FDA required manufacturers to study whether new glucose-lowering therapies increased patients’ risk of heart attacks, strokes, and early death. Heart failure at that time was not the primary focus. This produced a stunner in 2015: empagliflozin (Jardiance, Boehringer-Ingelheim/Eli Lilly) was found to cut the risk of CV death by 38%. Much of the result in EMPA-REG OUTCOME was powered by empagliflozin’s effects in heart failure; the risk of hospitalization for heart failure was reduced 35%.

In response, investigators for VERTIS CV doubled the size of the study population to 8246 patients and added superiority end points on CV outcomes, as well as an assessment of the composite renal outcome.

The empagliflozin result also caused investigators for DECLARE-TIMI 58, the CV outcomes trial for dapagliflozin, to add a second co-primary endpoint: besides a measure of major adverse cardiovascular events, the study would measure a composite of CV death and HHF. In late 2018, dapagliflozin failed to achieve the original end point, but it met the second, largely on the strength of the heart failure results: dapagliflozin reduced the risk of HHF 27%.

Canagliflozin was found to have CV and renal benefits in the CANVAS and CANVAS-R trials; a 2019 trial, CREDENCE, also produced clear benefits in preventing CV or renal death and renal decline, without any signal for amputation risk that had been seen previously.

AstraZeneca then followed up with DAPA-HF, which found 26% reduction in CV death or the worsening of heart failure status among patients with heart failure with reduced ejection fraction (HFrEF), regardless of diabetes status. Additional DAPA-HF data presented this week at ADA suggest dapagliflozin may prevent the onset of T2D among at-risk patients with prediabetes. Results are expected soon for the EMPEROR trials, which are studying empagliflozin in HFrEF and heart failure with preserved ejection fraction.

Differences in VERTIS CV

The study population of VERTIS CV was mostly male, obese, and more white than other outcomes trials, with an average glycated hemoglobin of 8.2% and a duration of T2D for 13 years. Heart failure was present in 23.7% of the population, which presenter Samuel Dagogo-Jack, MD, of the University of Tennessee said was one of the larger HF populations in a cardiovascular outcomes trial; presenter Darren K. McGuire, MD, MHSc, of UT Southwestern noted the HF population was twice as large as that of other trials.

Asked if there were any differences in the study population in VERTIS CV that might account for the results compared with other CV outcomes trials, Engel said, “We’ve been looking at these data and continue to … obviously, they’re fresh and there will be a lot of analyses forthcoming.”

He continued, “It’s impossible to compare across studies,” due to factors such as study design, population, and even the time frame when a study is conducted, which “may reflect differences in background rates or the use of other medications.”

Overall, Engel said, VERTIS CV “really helps broaden our understanding of the benefits and risks for this class of drug in patients with type 2 diabetes.”

Reference

Cannon CP, McGuire DK, Cherney D, et al. Results of the eValuation of ERTugliflozin EffIcacy and Safety CardioVascular Outcomes Trial (VERTIS CV). Presented at: 80th American Diabetes Association Scientific Sessions; June 16, 2020. Symposium.