The investigational sodium/glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin (Merck), being developed to improve glycemic control in adults with type 2 diabetes, met the primary outcomes in two yearlong phase 3 trials, VERTIS SU and VERTIS SITA2.
The two trials, which are part of the nine-trial VERTIS program, were presented in an oral session at the recent European Association for the Study of Diabetes (EASD) 2017 Annual Meeting.
Ertugliflozin is awaiting approval in the United States and European Union.
Brett Lauring, MD, from Merck, Kenilworth, New Jersey, reported that in the VERTIS SU trial, a 15-mg/day dose of ertugliflozin was not inferior to the sulfonylurea glimepiride in reducing HbA1c at 52 weeks, the study’s primary end point.
HbA1c was reduced by 0.6% with 15-mg/day ertugliflozin and by 0.7% with glimepiride, for a between-group difference of 0.1%.
And Roy Eldor, MD, Ichilov Hospital, Tel Aviv, Israel, reported that in the VERTIS SITA2 trial, patients in both ertugliflozin arms had improved glycemic control and reduced body weight and blood pressure at 52 weeks compared with those in the placebo arm, which were generally consistent with the 26-week findings from the same study that were presented at the American Diabetes Association (ADA) 2017 Scientific Sessions in June.
“This group of agents and this mechanism have really got potential,” cochair Chantal Mathieu, MD, Catholic University Leuven, Belgium, told Medscape Medical News, “so all companies are putting their bets on a horse that is an SGLT2 inhibitor.”
Ertugliflozin has similar characteristics to the other drugs in this class — canagliflozin (Invokana, Janssen), dapagliflozin (Farxiga/Formia, AstraZeneca), and empagliflozin (Jardiance, Boehringer Ingelheim) — she noted.
The drug class has been boosted by positive cardiovascular-outcomes data from the EMPA-REG trial with empagliflozin and the CANVAS study with canagliflozin. There are, however, question marks over side effects, with an increased rate of amputations reported with canagliflozin in CANVAS, and concerns about diabetic ketoacidosis with all drugs in the class, among other things.
VERTIS SU: 15 mg of Ertugliflozin Noninferior to Glimepiride
VERTIS SU assessed the safety and efficacy of ertugliflozin compared with glimepiride in patients with type 2 diabetes inadequately controlled with metformin monotherapy, Dr Lauring said.
Patients who were taking at least 1500 mg/day metformin for at least 8 weeks and still had HbA1c between 7% and 9% were randomized to remain on metformin and also take 5-mg/day ertugliflozin (448 patients), 15-mg/day ertugliflozin (440 patients), or the sulfonylurea glimepiride up to 6 or 8 mg/day (437 patients).
“At 52 weeks, in patients with type 2 diabetes inadequately controlled with metformin, ertugliflozin 15 mg was noninferior to glimepiride in lowering HbA1c, provided greater body-weight reduction relative to glimepiride, and was associated with less hypoglycemia compared with glimepiride,” Dr Lauring summarized.
On average, with glimepiride, patients had gained 0.9 kg, whereas with the two ertugliflozin doses combined they had lost 3.0 or 3.4 kg, at 1 year (P < .001),
The rate of symptomatic hypoglycemia (requiring help) was 19% in the glimepiride group but only 5.2% in the group that received 15-mg/day ertugliflozin and 4.0% in the group that received 5-mg/day ertugliflozin (P < .001).
Both doses of ertugliflozin were generally well tolerated, rates of urinary-tract infections and hypovolemia were similar in the three groups, but men and women who received either dose of ertugliflozin had higher rates of genital mycotic infection than those who received glimepiride.
Dr Mathieu said she was “very surprised” that the sulfonylurea brought down the HbA1c quite effectively by 26 weeks and “only at 52 weeks was there no difference between the SGLT2 inhibitor (both doses) and glimepiride.”
But the patients on the sulfonylurea had a much greater rate of symptomatic hypoglycemia and weight gain, and patients taking ertugliflozin had better blood pressure.
“Sulfonylurea brought down HbA1c but, wow, what a price to pay!” Thus, it is very important to stop focusing only at HbA1c and to also “look at the big picture,” she said.
VERTIS SITA2: Ertugliflozin Patients Lost More Weight, Dropped BP
The VERTIS SITA 2 trial randomized patients who had stable HbA1c > 7% but < 10.5% while taking > 1500 mg/day metformin and 100 mg/day of the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin (Januvia, Merck) to also receive 5-mg/day ertugliflozin (156 patients), 15-mg/day ertugliflozin (153 patients), or placebo (153 patients).
The efficacy end points at 52 weeks included proportion of patients with HbA1c < 7%.
“In patients with type 2 diabetes inadequately controlled with metformin > 1500 mg/day and sitagliptin 100 mg/day, the addition of ertugliflozin — both 5 mg/day and 15 mg/day relative to placebo — provides clinically meaningful and durable reductions from baseline in HbA1c and fasting plasma glucose,” Dr Eldor reported.
At 52 weeks, a greater proportion of patients receiving either dose of ertugliflozin vs placebo attained an HbA1c <7% (33% vs 13.7%).
Patients in the ertugliflozin groups lost more weight than patients in the placebo group (3.5 kg and 2.8 kg vs 1.0 kg), and their systolic blood pressure dropped by 4.1 mm Hg vs 0.8 mm Hg.
Patients in all three groups had similar rates of symptomatic hypoglycemia and urinary-tract infections, but those in the ertugliflozin groups had higher rates of genital mycotic infections.
US Decision Expected by Year End; VERTIS CV Data by 2019
A Merck spokesperson told Medscape Medical News in an email that new drug applications (NDAs) for ertugliflozin and for two fixed-dose combination products — ertugliflozin and sitagliptin and ertugliflozin and metformin — are under review with the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
The FDA is expected to complete its review in December 2017.
The company also notes that VERTIS CV, a cardiovascular-outcomes trial with ertugliflozin, recently completed enrollment with about 8000 patients with type 2 diabetes and established vascular disease.
The primary outcome is time to first occurrence of major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke, and final data for this outcome are expected by the end of 2019.
The study was conducted and funded by Merck and Pfizer. Dr Lauring is a Merck employee and shareholder. Dr Eldor was a Merck employee when the study was being conducted. Other coauthors are employees and shareholders of Merck or Pfizer.
European Association for the Study of Diabetes 2017 Annual Meeting; September 12, 2017; Lisbon, Portugal. Abstract 38, Abstract 41
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