Phase 3 Results Show Lower A1C for Ertugliflozin, Combined With Metformin and With Sitagliptin

Ertugliflozin, the investigational SGLT2 inhibitor under development by Merck and Pfizer, achieved significant reductions in glycated hemoglobin (A1C) in studies unveiled Saturday that examined the type 2 diabetes (T2D) therapy in combination metformin and with sitagliptin, the top-selling dipeptidyl peptidase-4 (DPP-4) inhibitor sold as Januvia.

Studies reported at the 77th Scientific Sessions of the American Diabetes Association (ADA), meeting June 9-13, 2017, in San Diego, California, found A1C reductions in both the 5 mg and 15 mg daily doses of the sodium glucose co-transporter-2 (SGLT2) inhibitor. FDA must act by December 2017 on applications for ertugliflozin as a monotherapy and for fixed-dose combinations with metformin and with sitagliptin.

While there are already 3 approved SGLT2 inhibitors in the US market, there’s been interest in ertugliflozin because of the chance for a combination with sitagliptin, the DPP-4 inhibitor that has long been a top performer for Merck. There are so many choices in T2D therapy that some see the logic in combining an SGLT2 inhibitor with a drug doctors already know well.

More choice, said Sam Engel, MD, associate vice president, Merck clinical research, cardiometabolic and women’s health, “allows for the individualization of therapy for patients.”

Since the SGLT2 inhibitor empagliflozin reported a cardioprotective benefit in August 2015—a first ever for a diabetes therapy—it has given sitagliptin competition. In the aftermath of empagliflozin’s results, Merck and Pfizer have doubled to 8000 patients the size of VERTIS CV, the safety study required by FDA to report cardiovascular (CV) outcomes. Hoping for a repeat of empagliflozin’s results, they’ve added secondary endpoints to test superiority on the composite of CV death and hospitalization for heart failure, and superiority on CV death alone.

The VERTIS MET study lets ertugliflozin stand apart in another way, Engel said. “This study is unique in that it also includes bone mineral density measures,” he said. No adverse impacts were reported at week 26, he said.

While the treatment guidelines for T2D generally recommend starting with metformin, Engel said, “it’s fair to say that patients who start with an A1C in a higher range, of 9% or above, aren’t going to get goal on a single drug. Many are using 2 drugs from get go.”

For patients with uncontrolled T2D who can’t tolerate metformin, the fixed-dose combination of ertugliflozin and sitagliptin offers a new option, he said.

New results reported Saturday include:

• VERTIS MET. Patients with T2D taking ertugliflozin in combination with metformin had larger A1C reductions those on placebo with metformin; reductions after 26 weeks were 0.7% for the 5 mg dose and 0.9% for the 15 mg dose, compared with 0.0% for placebo. Also, more patients taking the study drug achieved the ADA recommended A1C goal of less than 7%: 5 mg dose, 35.3%; 15 mg dose, 40%, and placebo, 15.8%.¹

• VERTIS SITA. Patients taking the either the 5 mg or 15 mg dose of ertugliflozin in a fixed-dose combination with sitagliptin (100 mg) had greater A1C reductions than those on placebo. Patients saw A1C drop 1.6% on the 5 mg ertugliflozin dose and 1.7% on the 15 mg dose. As with the first study, more patients achieved the ADA goal of getting A1C below 7% while taking the study drug: 5 mg ertugliflozin dose, 35.7%; 15 mg dose, 31.3%, and placebo, 8.3%.²

Patients who took ertugliflozin also experienced reductions in fasting plasma glucose, systolic and diastolic blood pressure, as well as weight loss. Adverse event rates in VERTIS MET were: 5 mg dose, 42.5%; 15 mg dose, 50.2%; and placebo with metformin, 45%. Females were more likely to experience genital mycotic infections on the study drug than males.

In VERTIS SITA, adverse event rates were: 5 mg ertugliflozin, 44.9%; 15 mg, 44.8%; and placebo, 42.3%. Again, females were more likely to experience genital mycotic infections than males.

References

1.. Rosenstock J, Frias J, Pall D, et al. Effect of ertugliflozin on glycemic control, body weight, blood pressure, and bone mineral density in T2DM inadequately controlled with metformin monotherapy: VERTIS MET trial. Presented at the 77^th Scientific Sessions of the American Diabetes Association, San Diego, California, June 9-13, 2017. Abstract 1168-P.

2. Lauring B, Miller SS, Krumins T, et al. Safety and efficacy of ertugliflozin in combination with sitagliptin in subjects with T2DM inadequately controlled on diet and exercise: the VERTIS SITA trial. Presented at the 77^th Scientific Sessions of the American Diabetes Association, San Diego, California, June 9-13, 2017. Abstract 1197-P.