麻豆传媒

The SGLT-2 inhibitor ertugliflozin (Steglatro) was deemed safe for the heart, according to results from the phase III VERTIS-CV trial.

Compared with those on placebo, patients who received either 5 mg or 15 mg of daily ertugliflozin did not see any significant differences in the rate of the major adverse cardiovascular event (MACE) outcome -- including cardiovascular (CV) death, nonfatal myocardial infarction (MI), or nonfatal stroke -- meeting the primary endpoint (HR 0.97, 95% CI 0.85-1.11, P<0.001 for non-inferiority), reported Christopher Cannon, MD, of Brigham and Women's Hospital in Boston, and colleagues.

"VERTIS-CV is the latest SGLT-2 inhibitor trial conducted to fulfill the 2008 regulatory guidance on new diabetes medications," co-investigator Richard Pratley, MD, of AdventHealth Translational Research Institute for Diabetes and Metabolism in Orlando, explained during a presentation at the American Diabetes Association (ADA) virtual meeting.

In total, 11.9% of the 5,499 individuals on ertugliflozin and 11.9% of the 2,747 individuals on placebo experienced a MACE during 6.1-year follow-up.

When the composite endpoint was broken down, ertugliflozin did not show any significant difference in individual event rates compared with placebo:

• CV death: HR 0.92 (95% CI 0.77-1.11)
• Nonfatal MI: HR 1.0 (95% CI 0.86-1.27)
• Nonfatal stroke: HR 1.0 (95% CI 0.76-1.32)

Separately, both doses of ertugliflozin were not significantly different for MACE compared with placebo: HR 0.91 for 5 mg (95% CI 0.77-1.07) and HR 1.04 for 15 mg (95% CI 0.89-1.21).

VERTIS-CV did not meet key secondary endpoints, however. First, this included no statistical difference in time to the first occurrence of the composite of CV death or hospitalization for heart failure (HR 0.88, 95% CI 0.75-1.03, P=0.11 for superiority).

On the other hand, ertugliflozin did display a risk reduction benefit on the rate of heart failure hospitalization alone. Compared with placebo, treatment with ertugliflozin had a 30% reduced risk for heart failure hospitalization (2.5% vs 3.6%; HR 0.70, 95% CI 0.54-0.90, P=0.006).

Similarly, ertugliflozin failed to show a statistically significant benefit for a composite renal endpoint of the time to the first occurrence of the composite of renal death, dialysis/transplant, or doubling of serum creatinine (HR 0.81, 95% CI 0.63-1.04, P=0.08). But there was a significantly lower degree of eGFR decline over follow-up seen with ertugliflozin. By month 60, those on 5 mg and 15 mg of ertugliflozin had a 3.01 and 3.05 mL/min/1.73m² higher eGFR rate compared with placebo, respectively (P<0.001 for both).

Ertugliflozin was first approved in December 2017 as a once-daily, single-therapy oral agent and indicated as an adjunct to diet and exercise. The three other approved agents in the SGLT-2 inhibitor class -- canagliflozin (Invokana), empagliflozin (Jardiance), and dapagliflozin (Farxiga) -- have all previously shown a significant risk reduction in CV events in adults with type 2 diabetes in their respective CV outcomes trials, suggesting possible class effects with these drugs.

This has also led to expanded indications for many of these drugs. Canagliflozin currently holds an indication for reduction of MACE, while empagliflozin is also indicated to reduce the risk of CV death in adults with type 2 diabetes. Dapagliflozin also holds an indication for reduction of heart failure hospitalization in adults with type 2 diabetes and established CV disease (CVD).

This randomized trial included 2,747 adults on 15 mg of once-daily ertugliflozin, 2,752 on 5 mg of ertugliflozin, and 2,747 on placebo. As an event-driven trial, participants were followed up with until the first occurrence of a MACE. All participants were ages 40 and older with a diagnosis of type 2 diabetes according to ADA guidelines -- an HbA1c level between 7.0% and 10.5% -- along with established atherosclerotic CVD. Some exclusion criteria included type 1 diabetes, previous history of a CV event, undergoing XC surgery within 3 months, class IV heart failure, or renal failure.

In a subgroup analysis of those on concomitant cardioprotective or diabetes medications at baseline, there was a similar rate of MACE among those on ertugliflozin or placebo. Some of these concomitant medications included statins, acetylsalicylic acid/antiplatelet drugs, diuretics, mineralocorticoid RA, RAAS blockers, insulin, DPP-4 inhibitors, metformin, and GLP-1 receptor agonists.

Ertugliflozin was generally safe, with a similar profile to that of other agents in the SGLT-2 inhibitor class. There was no difference in the rate of adverse events between either dose of ertugliflozin compared with placebo. As expected with an agent in this class, there was a significantly higher rate of urinary tract infections, and both male and female genital mycotic infections. There were no reports for Fournier's gangrene, and no significant difference in the rate of amputation.

"I think most of the data would fit in with the concept that this is probably all a class effect, and that VERTIS-CV just builds on the other data that we've obtained from other trials," commented Mark Cooper, MBBS, PhD, of Monash University in Melbourne, Australia, during a virtual presentation of the findings.

"This study does not change the current recommendations, nor should it facilitate revisiting the current ADA/EASD guidelines," said Cooper, who was not involved in the trial.

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