Merck/Pfizer SGLT2 Inhibitor Steglatro Meets Primary CV Endpoint but Lags Behind Competitors in Outcomes Trial

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Merck Sharp & Dohme and Pfizer recently jointly announced the results of the Phase III VERTIS CV cardiovascular (CV) outcomes trial at the 80th Scientific Sessions of the American Diabetes Association (ADA). The data showed that, in adult patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD), Steglatro (ertugliflozin), when added to standard background care, demonstrated non-inferiority to placebo in terms of major adverse cardiovascular events (MACE), thereby meeting the study’s primary endpoint.

The VERTIS CV trial was a multicenter, prospective, randomized, event-driven Phase III study that enrolled 8,246 adult patients (aged ≥40 years) with both type 2 diabetes mellitus and atherosclerotic cardiovascular disease (ASCVD), including elderly patients aged ≥65 years and those with renal impairment or heart failure, to investigate the impact of Steglatro on cardiovascular outcomes. In the trial, over 99% of patients had cardiovascular disease, 75.9% had coronary artery disease, 22.9% had cerebrovascular disease, 18.7% had peripheral artery disease, and 23.7% had a history of heart failure. Patients were randomly assigned to receive once-daily Steglatro 5 mg (n=2,752), 15 mg (n=2,747), or placebo (n=2,747), in addition to standard background care.

This study aims to assess cardiovascular (CV) safety (non-inferiority) to meet the US FDA guidance requirements for demonstrating CV safety of novel glucose-lowering drugs in both pre-approval and post-approval periods. The primary endpoint is non-inferiority for the composite major adverse cardiovascular events (MACE) endpoint, which consists of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. The key secondary endpoints evaluate the superiority of Steglatro versus placebo in terms of: time to first occurrence of cardiovascular death or hospitalization for heart failure (HHF), time to occurrence of cardiovascular death, and time to first occurrence of the composite endpoint of renal death/dialysis/transplantation or doubling of serum creatinine.

The data showed that the study met the primary MACE endpoint: 11.9% of patients treated with Steglatro (5 mg and 10 mg) reported MACE events, compared to 11.9% in the placebo group; Steglatro demonstrated non-inferiority versus placebo (HR=0.97; 95% CI: 0.85-1.11; p<0.001).

However, Steglatro did not demonstrate superiority over placebo for any of the key secondary endpoints. Notably, although hospitalization for heart failure (HHF) was not part of the hierarchical testing sequence, Steglatro showed a 30% reduction in the risk of HHF compared with placebo (2.5% vs. 3.6%; HR=0.70; 95% CI: 0.54–0.90).

In the study, the incidence of serious adverse events was similar across all groups: 34.9% in the Steglatro 5 mg group, 34.1% in the 15 mg group, and 36.1% in the placebo group. The incidence of urinary tract infections was 10.2% in the placebo group, and 12.2% and 12.0% in the 5 mg and 15 mg groups, respectively (p < 0.05).

The incidence rates of amputation in the 5 mg and 15 mg groups were 2.1% and 2.0%, respectively (1.6% in the placebo group), and the incidence rates of diabetic ketoacidosis were 0.3% and 0.4%, respectively (0.1% in the placebo group). No cases of Fournier’s gangrene occurred in patients treated with Steglatro or placebo, and there were no differences in the incidence rates of acute kidney injury, hypovolemia, fracture, or symptomatic hypoglycemia.

Steglatro is an oral SGLT2 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes. This medication is not recommended for use in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Results from the VERTIS CV trial confirmed that Steglatro demonstrated non-inferiority to placebo for the composite endpoint of myocardial infarction, stroke, and cardiovascular death in patients with type 2 diabetes at high cardiovascular risk, thereby meeting FDA requirements. However, Steglatro fell far short of the benchmarks set by other SGLT2 inhibitors. Specifically, Jardiance (Eli Lilly/Boehringer Ingelheim), Invokana (Johnson & Johnson), and Farxiga (AstraZeneca) have been proven in cardiovascular outcomes trials to reduce the risk of major adverse cardiovascular events (MACE).

Jardiance received FDA approval as early as 2016 to reduce the risk of cardiovascular (CV) death in patients with type 2 diabetes mellitus (T2DM) at high risk, becoming the first glucose-lowering agent globally approved to reduce CV mortality in T2DM. Invokana was approved by the FDA in October 2018 to reduce the risk of major adverse cardiovascular events (MACE) in patients with T2DM at high risk, and in October 2019, it further received FDA approval for use in patients with T2DM and diabetic kidney disease (DKD) to treat DKD and reduce the risk of hospitalization for heart failure. Farxiga has been approved to reduce the risk of hospitalization for heart failure in patients with T2DM at high risk; in May this year, it was also approved to reduce the risk of CV death and hospitalization for heart failure in adult patients with heart failure with reduced ejection fraction (HFrEF), becoming the first SGLT2 inhibitor approved for the treatment of heart failure, regardless of whether patients have T2DM.

Reference Source:

1、Merck and Pfizer’s SGLT2 Inhibitor STEGLATRO™ (ertugliflozin) Meets Primary Endpoint in VERTIS CV Trial for Patients with Type 2 Diabetes and Atherosclerotic Cardiovascular Disease

2、ADA: Merck, Pfizer's Steglatro rings up CV safety win but still lags heart-helping peers