VERTIS CV: Ertugliflozin Meets Noninferiority Endpoint but Misses Other Marks

A large cardiovascular outcomes trial with ertugliflozin (Steglatro; Merck Sharp & Dohme), another of the sodium-glucose cotransporter 2 (SGLT2) inhibitors, has shown the drug is safe for the treatment of patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD).

And while there were some encouraging trends, plus a significant reduction in heart failure hospitalizations, the study did not live up to some of the expectations for efficacy set by the EMPA-REG Outcome study with another SGLT2 inhibitor, empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly).

Presented this week at the European Association for the Study of Diabetes (EASD) meeting and published in the New England Journal of Medicine, the VERTIS CV trial showed that ertugliflozin was noninferior to placebo with respect to the primary composite endpoint of death from cardiovascular causes, nonfatal MI, or nonfatal stroke. In superiority testing for the primary endpoint, as well as a key secondary endpoint of cardiovascular mortality and heart failure hospitalizations, ertugliflozin missed the mark.  

“Everyone remembers the [significant] 38% reduction in cardiovascular mortality in the EMPA-REG trial, but that hasn’t been seen since,” lead investigator Christopher Cannon, MD (Brigham and Women’s Hospital, Boston, MA), told TCTMD. “Everything else has been in the range of a 10% to 15% reduction. I’ve come away with the profile of the class showing a modest reduction in MACE and cardiovascular death and then a big reduction in heart failure and renal dysfunction. Our trial definitely falls in the range of all of that—it’s just the P values that differ. My takeaway is that this is yet another trial showing the benefits of this class, so now we need to get with the guidelines and use them.”

When it was published 5 years ago, the EMPA-REG Outcome study in patients with type 2 diabetes at high cardiovascular risk impressed when it showed that empagliflozin lowered the risk of the CV death, nonfatal MI, or nonfatal stroke by 14% compared with placebo. As Cannon noted, there were also large reductions seen in the risk of death from cardiovascular causes, hospitalization for heart failure, and death from any cause.

In subsequent studies, other SGLT2 inhibitors impressed as well. In CANVAS, canagliflozin (Invokana; Janssen Pharmaceuticals) significantly reduced the risk of death from cardiovascular causes, nonfatal MI, or nonfatal stroke and lowered the risk of heart failure and the progression of albuminuria. In DECLARE-TIMI 58, the risk of death from cardiovascular causes or hospitalization for heart failure was significantly reduced with dapagliflozin (Farxiga; AstraZeneca). 

Cardiovascular and Renal Outcomes

For VERTIS CV, investigators included 8,238 patients with type 2 diabetes and ASCVD and randomized them to treatment with ertugliflozin or placebo on top of optimal medical therapy. More than 75% of patients in the trial had coronary artery disease, 22.9% had cerebrovascular disease, and 18.7% had peripheral artery disease. Slightly less than one-quarter had a history of heart failure. The mean duration of diabetes was 13.0 years.

During the virtual EASD 2020, Francesco Cosentino, MD, PhD (Karolinska Institute, Stockholm, Sweden), presented the cardiovascular and safety outcomes from the trial. After a mean follow-up of 3.5 years, the primary endpoint occurred in 11.9% of patients treated with ertugliflozin and 11.9% of those who received placebo (P < 0.001 for noninferiority), while death from cardiovascular causes or hospitalization for heart failure occurred in 8.1% and 9.1% of the ertugliflozin- and placebo-treated patients, respectively (HR 0.88; 95% CI 0.75-1.03).

Cosentino explained that formal statistical testing for other secondary endpoints was stopped when ertugliflozin did not prove superior to placebo for reducing cardiovascular death/heart failure hospitalizations (P = 0.11 for superiority). However, they did look at those event rates, noting “there was a pattern of reduced hospitalizations for heart failure and a trend for the renal composite endpoint,” said Cosentino. Hospitalizations for heart failure occurred in 2.5% and 3.6% of the ertugliflozin- and placebo-treated patients (HR 0.70; 95% CI 0.54-0.90), while there was a trend toward a reduction in cardiovascular mortality (HR 0.92; 95% CI 0.77-1.11).

Given the number of SGLT2 inhibitor trials, Cannon said there will some variability in clinical outcomes, with one trial showing a reduction in one endpoint while another may not. He noted that empagliflozin, which demonstrated such a large reduction in EMPA-REG OUTCOME, failed to reduce cardiovascular deaths in the EMPEROR-Reduced trial of heart failure patients with reduced ejection fraction. On the other hand, there was a significant 18% reduction in risk of cardiovascular mortality with dapagliflozin in DAPA-HF which wasn’t seen in DECLARE.  

It’s a total shift in the management of diabetes from glycemic control to starting medications by patient characteristics. Christopher Cannon

At the EASD meeting, senior investigator Darren McGuire, MD (UT Southwestern Medical Center, Dallas, TX), also attempted to place VERTIS CV in the context of the other trials. He cited an unpublished meta-analysis, one that included EMPA-REG OUTCOME, the CANVAS program, DECLARE, CREDENCE, and VERTIS, showing that treatment with an SGLT2 inhibitor reduced the risk of cardiovascular mortality, nonfatal MI, and nonfatal stroke by 10% (HR 0.90; 95% CI 0.85-0.96). The risk of cardiovascular death was significantly reduced by 15%, although McGuire noted there was a large degree of heterogeneity between trials given the large reduction observed in EMPA-REG Outcome.

“EMPA-REG Outcome is the only trial that individually demonstrated a statistically significant reduction in [cardiovascular mortality] and this is reflected in product labeling,” said McGuire. “It’s a different story with heart failure outcomes.” Across the trials, there was a consistent reduction in heart failure hospitalizations with the SGLT2 inhibitors—a 32% reduction in the meta-analysis—with no heterogeneity between agents.

Kidney Outcomes from VERTIS

In addition to the cardiovascular outcomes, David Cherney, MD, PhD (University of Toronto, Canada), presented the kidney data, reporting that death from renal causes, renal replacement therapy, or a doubling of the serum creatinine level was observed in 3.2% of patients treated with ertugliflozin and 3.9% of those who received placebo (HR 0.81; 0.63-1.04).

When investigators performed an analysis focused on a renal endpoint that included a sustained 40% reduction in the estimated glomerular filtration rate (eGFR), renal replacement therapy, or renal death—the same endpoint used in CANVAS and DECLARE—they observed a 34% reduction in risk with ertugliflozin (P < 0.01), on par with that seen in those other trials. The event curves appeared to separate at roughly 36 months.  

“This was driven, in large part, by a reduction in the risk of a 40% decline in eGFR, with very few deaths related to renal death or renal replacement therapy,” said Cherney.

To TCTMD, Cannon said SGLT2 inhibitors have demonstrated a range of benefit across multiple populations, including patients with type 2 diabetes and ASCVD, heart failure patients with and without diabetes, and patients with chronic kidney disease. “It’s pretty remarkable how broadly the benefits have been seen,” said Cannon. “Now it really shifts to implementation—how do we get the drugs to patients where we know there is benefit?”

As for who should prescribe the drug class, Cannon emphasized the importance of a multidisciplinary approach to care. In these cardiovascular outcome studies, the average duration of diabetes often exceeds a decade, meaning that patients’ disease is either managed by an endocrinologist or family physician. While these drugs do provide cardiovascular benefit, cardiologists are not the specialists to care for hypoglycemia, should it occur, or to manage a urinary tract infection.

“There is a need for continued collaborative management, and yet the impetus to start the drugs for clinical indication falls to us [as cardiologists],” he said. “It’s a total shift in the management of diabetes from glycemic control to starting medications by patient characteristics.”