Combination treatments: More patients reach goal, achieve lower HbA1c

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

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

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

The magnitude of reduction was similar regardless of baseline HbA_1clevel, 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% forpioglitazone 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 significantlygreater 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 insulinwith or without metformin who were randomized to receive 100 mg sitagliptin daily orplacebo for 24 weeks. Patients had a mean baseline HbA_1c of 8.7%, and theaddition of sitagliptin achieved a reduction of 0.6% compared with placebo, reportsTina Vilsboll, MD, Gentofte Hospital, University of Copenhagen, Denmark.

In addition, 13% of patients taking sitagliptin achieved ADA HbA_1cgoals versus 5.0% of those in the placebo group (p<0.001).

However, the incidence of both hypoglycemia and severe hypoglycemic eventsdoubled among patients receiving add-on sitagliptin. Body weight did not increasesignificantly 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 combinationtherapy," 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 beparticularly helpful for patients who are not candidates for combination therapywith sitagliptin and metformin because of existing renal insufficiency orgastrointestinal side effects associated with metformin, Dr. Rodbard adds.

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

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