VERTIS CV: Ertugliflozin Benefit Falls Short of Other SGLT2 Inhibitors

Mitchel L. Zoler, PhD

September 25, 2020

Further analyses from the cardiovascular outcome trial of the sodium-glucose transporter 2 inhibitor ertugliflozin in patients with type 2 diabetes helped better define positive effects the drug had on preserving renal function, and also gave a tantalizing hint that this drug, and hence possibly the entire SGLT2 inhibitor drug class, may benefit patients with heart failure with reduced ejection fraction.

But the underlying problem for ertugliflozin (Steglatro) – first seen when results from the VERTIS CV trial initially came out in June 2020 at the annual meeting of the American Diabetes Association – was that, while the trial met its primary endpoint of proving noninferiority to placebo for the combined endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke, treatment with ertugliflozin showed no suggestion of benefit, compared with placebo for reducing this endpoint, producing a nonsignificant 3% relative cut in the combined rate of these adverse events, compared with placebo treatment.

"Somewhat Disappointing" Trial Performance

Overall, results from VERTIS CV with ertugliflozin were "somewhat disappointing," commented Melanie J. Davies, MD, who was not involved with the study and chaired a session at the virtual annual meeting of the European Association for the Study of Diabetes that reviewed the main results, put them into perspective, and added a few new exploratory analyses.

Although the results from 8,246-patient VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial) put ertugliflozin in the same league as other drugs from its class for safety, "we do not see the significant benefits observed in many of the previous cardiovascular outcomes trials" for other drugs in the SGLT2 inhibitor class, specifically canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), Dr. Davies said in an interview. The upshot, for at least the time being, is that ertugliflozin "is unlikely to receive a label for any new indications," she predicted. In contrast, the other drugs in the class have, for example, received a U.S. labeled indication to reduce cardiovascular death (empagliflozin) or major cardiovascular disease events (canagliflozin) in adults with type 2 diabetes (T2D) and cardiovascular disease, or to reduce heart failure hospitalizations (dapagliflozin).

The main results from VERTIS CV, posted online in the New England Journal of Medicine after the EASD session, showed a single significant outcome difference between treatment with ertugliflozin and placebo over a median of 3.0 years of follow-up from among 10 reported secondary outcomes: a 30% relative reduction (a 1.1% absolute reduction) in the rate of hospitalization for heart failure, the sole criterion in the report by which ertugliflozin matched the benefits of the other SGLT2 inhibitors.

But the prespecified design of VERTIS CV called for a hierarchical sequence of secondary analyses. The statistically significant noninferiority of the primary endpoint allowed calculation of the initial secondary endpoint, a reduction in the combined rate of cardiovascular death or hospitalization for heart failure. Ertugliflozin treatment cut this outcome by a relative 12%, compared with placebo, a difference that was not significant.

This neutral finding brought to a stop further statistical testing of any of the other secondary endpoints, including impact on hospitalization for heart failure by itself. It also guaranteed that no beneficial effect inferred from the trial's data would qualify for statistical validity, making it unlikely that ertugliflozin would gain any new label indications from these results. The drug carries a U.S. label that is limited to providing glycemic control.

Choosing Among the SGLT2 Inhibitors

"What we can say for sure is that there is a glycemic benefit and a heart failure hospitalization benefit" across all four of the SGLT2 inhibitors. "Beyond that, the best we can say today [about using these drugs in practice] is to follow regulatory indications and guidelines recommendations," commented Javed Butler, MD, a cardiologist and professor and chair of medicine at the University of Mississippi Medical Center, Jackson.

"These results are going to lead to some serious discussions among the research, clinical, and regulatory communities about class effects versus drug effects, and specific trial data versus the totality of evidence," he said in an interview.

"I think it will influence prescribing ertugliflozin, particularly in patients with established cardiovascular disease, or when the goal is to improve heart failure outcomes of reduce chronic kidney disease," added Dr. Davies, a professor of diabetes medicine at the University of Leicester (England). "We already have positive benefits [proven for these outcomes] using other agents in the class."

Perhaps one feature potentially in ertugliflozin's favor is its price, and whatever impact that might have for payers or patients with inadequate coverage for their drug costs. U.S. websites show a typical retail price for ertugliflozin that is roughly 40% below the three other agents in the class, a difference that can add up to an annual cost savings of about $2,500.

A major consideration for clinicians deciding which SGLT2 inhibitor to prescribe should be "what can the patient afford," noted Darren K. McGuire, MD, a coinvestigator for VERTIS CV, during discussion of the trial at the EASD virtual meeting.

New Analyses Show More Renal-Effect Consistency

One surprise in the initial VERTIS CV report was in the study's key renal outcome, a composite of renal death, need for dialysis, or a doubling of the serum creatinine level, which reflects a cut of at least a 50% in estimated glomerular filtration rate (eGFR). This composite outcome trended toward a significant benefit but fell short, producing a nominal 19% relative reduction. This combined endpoint probably "set the bar too high," said David Z.I. Cherney, MD, a nephrologist who led the renal assessments run in the trial. He presented several exploratory analyses during the virtual EASD session that provided reassuring evidence that ertugliflozin was not an outlier among the SGLT2 inhibitors when it came to kidney benefits.

Perhaps the most compelling analysis he reported was a slight tweak to the main renal composite endpoint that substituted prevention of a 40% or greater reduction in eGFR for prevention of a 50% or greater reduction. By this somewhat lower bar for efficacy, treatment with ertugliflozin in VERTIS CV linked with a 34% relative risk reduction, compared with placebo (a roughly 1% absolute reduction) that was statistically significant, and importantly came out very close to the effect for this revised endpoint that had been seen for the other three SGLT2 inhibitor drugs.

Focusing on prevention of a 40% or greater drop in eGFR "gives a much more robust measure of renal protection," Dr. Cherney, a clinician and researcher at the University of Toronto, said in an interview. "The key message is that renal protection is much more uniform" with the rest of the drugs in the class when looked at this way or by some of the other alternative parameters he reported. But the new renal analyses do not address disparities seen among the drugs in the class for several cardiovascular disease effects.

"The overall impression from VERTIS CV is that there was less cardiovascular disease benefit," except for prevention of heart failure hospitalization, he said.

A Teaser for HFpEF

One additional notable new finding discussed during the EASD session stemmed from the investigators ability to mine the medical records of enrolled patients for information about their heart failure history and left ventricular ejection fractions, a data set that was "unique," compared with the other cardiovascular outcome trials for the drugs in the class, noted Francesco Cosentino, MD, another VERTIS CV coinvestigator and professor of cardiology at the Karolinska Institute in Stockholm.

Roughly a quarter of the enrolled patients had a history of heart failure, and about half of these patients had heart failure with preserved ejection fraction, about 1,000 total patients. In this subgroup treatment with ertugliflozin linked with a 30% relative reduction in hospitalization for heart failure, compared with placebo, a roughly 0.5% absolute reduction. The numbers were small and underpowered for producing convincing evidence, but it provided an intriguing hint of benefit for an unmet need that is currently undergoing further testing in studies designed to specifically explore benefit in this type of heart failure patient, said Dr. Cosentino.

VERTIS CV was sponsored by Merck and Pfizer, the companies that market ertugliflozin. Dr. Davies has been a speaker on behalf of Merck and has had relationships with several other companies. Dr. Butler is a consultant to Merck and several other companies. Dr. McGuire has received honoraria from Merck, nonfinancial support from Pfizer, and has had relationships with several other companies. Dr. Cherney has received honoraria from Merck, nonfinancial research support from Pfizer, and has also had relationships with several other companies. Dr. Cosentino has received fees from Merck and Pfizer, and also from Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, and Novo Nordisk.

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