VERTIS-CV: Late-Comer Ertugliflozin Shows HF Benefit Only in CVOT

June 18, 2020

The cardiovascular outcome trial results for a fourth sodium-glucose cotransporter 2 (SGLT2) inhibitor, ertugliflozin, were most notable for their consistency with the four prior, similar trials run on the three other drugs from this class on the U.S. market, canagliflozin, dapagliflozin, and empagliflozin, further solidifying the important role this drug class has recently taken on for patients with type 2 diabetes.

But the ertugliflozin results, which showed statistically significant superiority to placebo for just one endpoint, hospitalization for heart failure, made it unclear whether clinicians will regard ertugliflozin as the top agent from this class to prescribe.

"Our big takeaway is that the findings are consistent with what's been seen in the other studies" of cardiovascular and renal outcomes in the EMPA-REG OUTCOME study of empagliflozin (N Engl J Med. 2015 Nov 26;373[22]:2117-28), the CANVAS (N Engl J Med. 2017 Aug 17;377[7]:644-57) and CREDENCE (N Engl J Med. 2019 June 13;380[24]:2295-306) studies of canagliflozin, and the DECLARE-TIMI 58 trial with dapagliflozin (N Engl J Med. 2019 Jan 24;380[4]:347-57), Christopher P. Cannon, MD, said at the virtual annual scientific sessions of the American Diabetes Association.

The cardiovascular outcome trials (CVOTs), mandated in 2008 by Food and Drug Administration guidance for type 2 diabetes drugs that is now in the process of undergoing an update, have had the main goal of proving safety, and the primary endpoint of the new ertugliflozin trial, VERTIS-CV, was noninferiority to placebo when used on top of standard type 2 diabetes medications for the combined endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke.

Key Findings

Both of the tested dosages of ertugliflozin, 5 mg and 15 mg daily, met this endpoint, with event rates over a median 3.0 years of follow-up that ran very close to the placebo rate, clearly proving noninferiority. But the results showed no suggestion of superiority in a study that randomized 5,499 patients to either of the ertugliflozin regimens and 2,747 to placebo, reported Dr. Cannon, a cardiologist and professor of medicine at Harvard Medical School, Boston.

The primary outcome also showed similar event rates for each component of the composite endpoint, and subgroup analysis showed consistent results from ertugliflozin, compared with placebo, regardless of study-cohort subdivision by demographic, clinical, or treatment factors.

The trial design called for a hierarchical sequence of secondary-outcome superiority analyses, starting with the impact of ertugliflozin on cardiovascular death or heart failure hospitalization, and for this outcome ertugliflozin showed a point estimate of a 12% relative risk reduction, compared with placebo-treated patients, but this difference was not statistically significant. This meant that all subsequent superiority analyses in this trial could only be hypothesis generating and not definitive.

This negated the statistical validity of the only statistically significant treatment difference between ertugliflozin and placebo seen in VERTIS-CV, for the outcome of hospitalization for heart failure, where ertugliflozin treatment cut this outcome by 30%, compared with placebo patients. The rate of cardiovascular death alone, as well as a renal composite endpoint each showed no statistically significant benefit of ertugliflozin, compared with placebo, although the renal endpoint came close, with ertugliflozin reducing the combined rate of renal death, need for dialysis, need for renal transplant, or a doubling of serum creatinine from baseline by 19%, compared with placebo (P = .08).

How Results Compare With Prior CVOTs

In some ways, these results seemed to contrast with outcomes from the CVOTs for the other SGLT2 inhibitors, which all showed at least two statistically significant benefits for major endpoints when compared with placebo.

As summarized in a new meta-analysis of all the CVOTs by Darren K. McGuire, MD, a cardiologist and professor of medicine at the University of Texas, Dallas, both empagliflozin and canagliflozin showed statistically significant superiority compared with placebo for their trial's primary, combined major cardiovascular adverse event endpoint, but dapagliflozin and ertugliflozin did not. Empagliflozin was the sole SGLT2 inhibitor to show a statistically significant cut in cardiovascular deaths, compared with placebo.

The primary, composite renal efficacy endpoints used in these trials were hardest to compare because they differed from study to study, but unlike ertugliflozin, all the other three drugs in the class showed a statistically significant improvement, compared with placebo, for their respective renal outcomes. On the other hand, the pattern of estimated glomerular filtration rates measured at multiple times during the various trials showed a high level of consistency across the CVOTs.

The greatest consistency among the major endpoints across the trials was for heart failure hospitalization. All four agents showed statistically significant improvements, compared with placebo, and all four had roughly equal magnitudes of effect, a cut in event rates by about one-third.

"The greatest magnitude of benefit is for reductions in heart failure hospitalizations and for renal outcomes," with the heart failure outcomes the "most consistent" across the studies and the renal outcomes "largely consistent," concluded Dr. McGuire. All together, the five CVOTs for these four SGLT2 inhibitors involved more than 46,000 patients.

"A lot of data suggest these are all class effects," that are roughly similar across all four of these SGLT2 inhibitors, commented Mark E. Cooper, MBBS, a professor and head of the department of diabetes at Monash University, Melbourne, and designated discussant for the study.

There was "clear homogeneity" between the VERTIS-CV results for hospitalization for heart failure and the other CVOTs, he noted. "I think there is a difference" in the cardiovascular death outcomes, specifically the sole statistically significant, 38% relative risk reduction with empagliflozin that stood out from the other CVOTs, but this difference is "totally unexplained," added Dr. Cooper. "To really determine differences you'd need head-to-head studies that are unlikely to happen."

The results of the new SGLT2 inhibitor meta-analysis appeared to also "support contemporary society recommendations to prioritize the use of SGLT2 inhibitors independent of glucose-control considerations in patients with type 2 diabetes with or at high risk for cardiovascular and renal complications," said Dr. McGuire.

"The guidelines have it right. Now it's on us to implement these treatments to appropriate patients," concluded Dr. Cannon.

Study Details

VERTIS-CV (Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease) enrolled and followed patients with type 2 diabetes and established atherosclerotic cardiovascular disease at 531 centers in 34 countries during December 2013–December 2019. Other effects from ertugliflozin recorded during the trial were consistent with prior studies of the drug, which is already FDA approved for glycemic control: Compared with placebo, ertugliflozin treatment reduced hemoglobin A1c by an average of 0.5% after 1 year, cut average body weight by about 2.5 kg after 1 year with additional modest weight loss, during subsequent years on the drug, and reduced systolic blood pressure by about 3 mm Hg after 1 year.

The drug's safety profile was generally reassuring and consistent with prior studies of this drug and others in the class, with overall no increase in total adverse events or serious adverse events, compared with placebo, and modestly increased rates of urinary tract and mycotic genital infections.

VERTIS-CV was sponsored by Merck and Pfizer, the companies that market ertugliflozin (Steglatro). Dr. Cannon has received research funding and fees from Merck and Pfizer and from several other companies. Dr. McGuire has received honoraria from Merck, has been a consultant to Pfizer, and has had similar relationships with several other companies. Dr. Cooper has been an advisor to and received honoraria from Merck. He has also received honoraria from or been an adviser to AstraZeneca, Boehringer Ingelheim, Lilly, MundiPharma, Novartis, Reata, and Servier, and he has received research funding from Boehringer Ingelheim and Novo Nordisk.

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