Significant reductions in A1C were found at both doses, and bigger declines were seen among patients with the worst glycemic control. The cardiovascular outcomes trial for the SGLT2 inhibitor took a different turn after a rival drug showed a CV benefit.
Merck and Pfizer are highlighting published results for ertugliflozin, the sodium glucose co-transporter-2 (SGLT2) inhibitor they are developing jointly to compete in the class, which has been shown to not only improve glycemic control in patients with type 2 diabetes (T2D) but also help them lose weight and lower blood pressure.
Results for ertugliflozin as a monotherapy appeared last week in the journal Diabetes, Obesity and Metabolism, and showed significant reductions in glycated hemoglobin (A1C) at 26 weeks for both the 5 mg and the 15 mg doses. The trial, known as VERTIS MONO, involved 461 men and women with baseline A1C between 7% and 10.5%, from 67 sites across 7 countries. Researchers found that the patients taking the 5 mg dose saw an average A1C reduction of 0.99%, while those taking the 15 mg dose saw an average reduction of 1.16% (both P <.001).
“We do think those are meaningful reductions,” said James Rusnak, MD, PhD, chief development officer for Cardiovascular and Metabolic Disease for Pfizer’s Global Product Development Group, in an interview with The American Journal of Managed Care®.
Patients who started the study with an A1C of at least 8% saw greater reductions, of 1.11% for the 5 mg dose and 1.52% for the 15 mg dose. And shares of patients who attained an A1C of less than 7% were 28.2% for those taking the 5 mg dose and 35.8% for those taking the 15 mg dose, compared with 13.1% on placebo. The American Diabetes Association recommends that patients with T2D maintain an A1C below 7%.
SGLT2 inhibitors work by causing patients to expel excess glucose through the urine; the mechanism has been shown to help patients lose weight and control hypertension, in contrast with some diabetes therapies that have caused patients to gain weight. Results from VERTIS MONO showed significant improvements in body weight: average reductions were 1.76 kg for the 5 mg dose and 2.16 kg for the 15 mg dose.
“We did see 4 to 4.5 pounds in weight loss,” Rusnak said. “That actually can be of great value to patients; for some patients who would have expected to gain weight, that loss is very important.”
Reductions in blood pressure were not statistically significant compared with placebo.
Rusnak said VERTIS MONO is part of a group of 9 phase 3 trials involving ertugliflozin; 1 trial, VERTIS CV, is the cardiovascular outcomes trial required by FDA. Interest in these studies, known as CVOTs, has been intense since another SGLT2 inhibitor, empagflozin (Jardiance) was shown not only to be safe but also to offer cardiovascular (CV) benefits. It remains to be seen if this is a class effect. In response to the empagliflozin results, Merck and Pfizer expanded VERTIS CV, which is still enrolling patients and will conclude no later than October 2019.
Rusnak said researchers want to find out “alternate benefits of the drug,” including the potential for reductions in CV deaths and hospitalizations for heart failure. “It’s an exciting class,” he said.
New drug applications have been filed for ertugliflozin as a monotherapy, as well as 2 fixed dose combinations: one with metformin and the other with sitagliptin (Januvia), Merck’s top-selling dipeptidyl peptidase-4 (DPP-4) inhibitor. Positive results from studies involving these combinations have been presented at scientific conferences in the past year.
Sales of sitagliptin are still massive; in 2016, they came to $1.51 billion for sitagliptin and sitagliptin/metformin. Sales have fallen short of expectations as SGLT2 inhibitors have become popular, but a combination of sitagliptin and ertugliflozin could be a winner. Said Rusnak, “That one has a lot of opportunity.”
The new SGLT2/DPP-4 combo would compete against Glyxambi, consisting of empagliflozin and linagliptin. The FDA recently approved a supplemental NDA for Glyxambi to include data showing that empagliflozin reduced the risk of CV death for those with T2D and established CV disease.
Terra SG, Focht K, Davies M, et al. A phase 3, efficacy and safety study of ertugliflozin monotherapy in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise alone [published online January 24, 2017]. Diabetes Obes Metab. 2017; DOI: 10.1111/dom.12888.