Initial type 2 diabetes treatment with a combination of sitagliptin and pioglitazone produced more robust hemoglobin A_1c (HbA_1c) lowering than either agent alone, and sitagliptin as add-on therapy to insulin with or without metformin also showed significantly enhanced HbA_1c reduction compared to insulin alone.

In one randomized, placebo-controlled trial of 497 patients with type 2 diabetes with baseline HbA_1c levels between 8.0% and 12.0% (mean, 9.5%), patients received either 100 mg sitagliptin and 30 mg pioglitazone once daily or 30 mg pioglitazone once daily for 24 weeks.

Researchers report that there was a 2.4% HbA_1c reduction from baseline among the patients receiving the combination versus a 1.5% reduction among those in the pioglitazone monotherapy group (p<0.001). Overall, 60% of patients treated with the combination achieved American Diabetes Association (ADA) HbA_1c goal levels of 7.0% or less compared with 28% of those treated with pioglitazone alone (p<0.001).

The magnitude of reduction was similar regardless of baseline HbA_1c level, reports lead investigator Kun Ho Yoon, MD, Catholic University of Korea, Seoul, Korea. Those with baseline HbA_1c levels greater than 10.0% experienced a reduction of 3.0% with combination treatment compared with 2.1% for pioglitazone monotherapy; those with baseline HbA_1c levels less than 10.0% achieved reductions of 2.0% and 1.1%, respectively.

Patients in both treatment groups had similar incidences of hypoglycemia, gastrointestinal adverse events, and edema. However, weight gain was significantly greater in the combination group than the monotherapy group (3.0 kg vs 1.9 kg; p=0.005), Dr. Yoon says.

Another 24-week study included 564 patients with type 2 diabetes taking insulin with or without metformin who were randomized to receive 100 mg sitagliptin daily or placebo for 24 weeks. Patients had a mean baseline HbA_1c of 8.7%, and the addition of sitagliptin achieved a reduction of 0.6% compared with placebo, reports Tina Vilsboll, MD, Gentofte Hospital, University of Copenhagen, Denmark.

In addition, 13% of patients taking sitagliptin achieved ADA HbA_1c goals versus 5.0% of those in the placebo group (p<0.001).

However, the incidence of both hypoglycemia and severe hypoglycemic events doubled among patients receiving add-on sitagliptin. Body weight did not increase significantly among sitagliptin patients.

Combination therapy candidates

"The vast majority of patients require more than one agent to reach HbA_1c goals, and physicians wait too long to institute combination therapy," says Helena W. Rodbard, MD, past president of the American Society of Clinical Endocrinologists (pictured left).

"Initial combination therapy is very helpful when you need to reduce HbA_1c by more than 1.0%, so for patients with levels of 7.5% to 9.0%, the combination would be very good therapy, particularly for those who are treatment naive," Dr. Rodbard says. Patients who are diagnosed but who are very close to the HbA_1c goal of 7.0% would probably be adequately treated with monotherapy.

Initial combination treatment with sitagliptin and pioglitazone may be particularly helpful for patients who are not candidates for combination therapy with sitagliptin and metformin because of existing renal insufficiency or gastrointestinal side effects associated with metformin, Dr. Rodbard adds.

When adding therapy to insulin, hypoglycemia is always a concern, particularly in geriatric patients. "Often the insulin dose is not adjusted accordingly. When adding any insulin secretagogue, you have to adjust," says Dr. Rodbard. The insulin dose in the sitagliptin add-on trial was not adjusted and may have accounted for the increased rates of hypoglycemic events, she notes.

The Food and Drug Administration is currently reviewing Supplemental New Drug Applications for an agent combining 100 mg sitagliptin and 30 mg pioglitazone for initial treatment of type 2 diabetes, as well as for sitagliptin as add-on therapy in type 2 patients taking insulin with or without metformin.