Investigational DPP-IV inhibitor lowered HbA1c in patients with type 2 diabetes

44th Annual Meeting of the EASD

ROME — Saxagliptin, when used in combination with metformin as initial therapy, produced reductions across all key measures of glucose control in treatment-naive participants with inadequately controlled type 2 diabetes, according to results of a study presented yesterday at the 44th Annual Meeting of the European Association for the Study of Diabetes.

Results of this randomized, double-blind, active-controlled, phase-3 study showed “clinically relevant improvements that were significantly greater across all key glycemic parameters studied, such as HbA1c <7%, fasting plasma glucose and postprandial glucose,” said Roland Chen, MD, group director of global clinical research at Bristol-Myers Squibb.

Saxagliptin (Onglyza; Bristol-Myers Squibb, AstraZeneca) is an investigational DPP-IV inhibitor. On June 30, the companies submitted a New Drug Application to the FDA and are awaiting approval.

Improvements shown

The study consisted of 1,306 participants with type 2 diabetes aged 18 to 77 years who were treatment naive. Participants also had HbA1c levels ≥8% and ≤12% and BMI ≤40 kg/m².

After a one-week placebo lead-in phase, Chen and colleagues randomized the participants to one of four treatment arms: saxagliptin 5 mg and metformin 500 mg (n=320); saxagliptin 10 mg and metformin 500 mg (n=323); saxagliptin 10 mg and placebo (n=335); and metformin 500 mg and placebo (n=328). Treatment was administered daily. Metformin was titrated weekly in 500-mg increments, as tolerated by the participants, to a maximum total daily dose of 2,000 mg per day, according to Chen.

After 24 weeks, participants in the saxagliptin/metformin arms had a HbA1c mean change from baseline of –2.5%, compared with –1.7% for the placebo groups (P>.0001).

“We saw greater decreases in those who actually had higher baseline HbA1c levels,” Chen said. According to Chen, 41% to 45% of participants in the saxagliptin arms achieved decreases in HbA1c compared with 20% to 29% in the groups receiving placebo.

HbA1c <7 was more prevalent in the saxagliptin/metformin arms: 60.3% for saxagliptin 5 mg/metformin; 59.7% for saxagliptin 10 mg/metformin; 32.2% for saxagliptin 10 mg/placebo; and 41.1% for metformin/placebo (P>.001). The same was found for achievement of HbA1c ≤6.5%: 45.3% for saxagliptin 5 mg/metformin; 40.6% for saxagliptin 10 mg/metformin; 20.3% for saxagliptin 10 mg/placebo; and 29% for metformin/placebo (P>.0026).

The researchers also found a mean change in fasting plasma glucose from baseline. There was a change of –60 mg/dL for the saxagliptin 5 mg/metformin arm; –62 mg/dL for saxagliptin 10 mg/metformin; –31 mg/dL for saxagliptin 10 mg/placebo; and –47 mg/dL for metformin/placebo (P>.0002).

Both saxagliptin/metformin arms were well tolerated over the course of the study period, according to Chen. Adverse events consisted of headache, hypertension, diarrhea and nasopharyngitis, and were equally represented across all arms, he said. There were three cases of confirmed hypoglycemia; two occurred in the saxagliptin 10 mg/metformin arm and one in the metformin/placebo arm. Chen added that similar reductions in weight were seen across all treatment arms. – by Tara Grassia

Saxagliptin is a potential new addition to the ‘gliptin’ group of drugs that are becoming increasingly popular in the treatment of patients with type 2 diabetes. What I particularly liked about the study presented was the large number of patients recruited (over 1,300). In this study, saxagliptin was introduced alone or in combination with metformin in naive type 2 diabetic patients. Two different doses of saxagliptin were also tested. Metabolic control was generally poor at baseline. The drop in HbA1c was impressive and greatest with combined use of metformin-saxagliptin compared with either drug used alone. Data presented were clear and convincing, although this was only a short-term drug trial. There were some adverse events reported but nothing out of the ordinary compared with placebo nor out of line with the ‘gliptin’ group as a whole. Impact (good or bad) on lipids or weight were either unreported or neutral.

Obviously, interesting data to consider but as we have learned before, it's sometimes wiser to wait for greater experience and long-term safety of a drug to be established. It will, however, be nice to follow up future progress of saxagliptin and see where this drug will ultimately fit in amongst existing therapies. This also tells us as diabetes specialists that we are spoiled for choice given the wide range of drugs now available for us in treatment of type 2 diabetes when just over a decade ago we had so little available!

– Aus Alzaid, MD

Consultant Diabetologist
Riyadh Military Hospital, Saudia Arabia

For more information:

• Chen R, Pfutzner A, Jadzinsky M, et al. OP13, #78. Initial combination therapy with saxagliptin and metformin improves glycemic control compared with either monotherapy alone in drug-naive patients with type 2 diabetes. Presented at: the 44th Annual Meeting of the European Association for the Study of Diabetes; Rome; Sept. 7-11, 2008.