DPP-IV inhibitors effectively reduce levels of HbA1c as monotherapy or in combination with other agents

News
Article

New incretin-based therapies will soon enter the therapeutic armamentarium for type 2 diabetes. Two dipeptidyl peptidase (DPP)-IV inhibitors in phase 3 clinical trials, vildagliptin and sitagliptin, are oral agents that can be used once daily as monotherapy or in combination with other oral antidiabetic agents to reduce levels of hemoglobin A1c (HbA1c) with few side effects, little risk of hypoglycemia, and no promotion of weight gain, researchers reported at the 66th scientific sessions of the American Diabetes Association (ADA) in Washington, DC.

New incretin-based therapies will soon enter the therapeutic armamentarium for type 2 diabetes. Two dipeptidyl peptidase (DPP)-IV inhibitors in phase 3 clinical trials, vildagliptin and sitagliptin, are oral agents that can be used once daily as monotherapy or in combination with other oral antidiabetic agents to reduce levels of hemoglobin A1c (HbA1c) with few side effects, little risk of hypoglycemia, and no promotion of weight gain, researchers reported at the 66th scientific sessions of the American Diabetes Association (ADA) in Washington, DC.

Glucagon-like peptide-1 (GLP-1) is a naturally occurring peptide hormone that stimulates insulin secretion and promotes expansion of beta cell mass. It also reduces the secretion of glucagon, a hormone that signals the liver to produce excess glucose.

Vildagliptin and sitagliptin act to inhibit DPP-IV, an enzyme that inactivates GLP-1. Preventing GLP-1 breakdown with a DPP-IV inhibitor reduces glucose production and increases insulin production. The magnitude of reduction in HbA1c levels with these 2 agents is greatest in patients with the highest baseline HbA1c levels.

Both vildagliptin and sitagliptin demonstrated efficacy in several clinical trials when used alone or with agents such as metformin and pioglitazone.

Vildagliptin was studied in combination with pioglitazone in 592 treatment-näive patients with type 2 diabetes who had uncontrolled blood glucose levels (baseline HbA1c of 7.5%–11.0%).

Patients were randomly assigned to 1 of 4 treatment groups:

Patients assigned to vildagliptin 100 mg/d plus pioglitazone 30 mg/d experienced a statistically significant reduction in HbA1c levels compared with patients assigned to pioglitazone alone (1.9% vs 1.4%; P<.001), said Ameet Nathwani, MD, global therapy head for cardiovascular, metabolism, and atherosclerosis, Novartis Pharmaceuticals, Basel, Switzerland. Among patients with the worst glycemic control (baseline HbA1c values ≥9%), the combination of vildagliptin and pioglitazone was associated with a reduction in HbA1c of 2.8%.

"Two of three patients on vildagliptin and pioglitazone achieved the American Diabetes Association HbA1c target of ≤7%," Dr Nathwani said. In contrast, only 42% achieved this goal while on either monotherapy.

In patients aged >65 years, the combination of vildagliptin and pioglitazone resulted in a decrease in HbA1c of 2.3% from baseline without causing hypoglycemia. As in previous clinical studies, vildagliptin did not cause weight gain.

VILDAGLIPTIN EFFICACY WITH METFORMIN

Similar efficacy in improving HbA1c values was demonstrated when vildagliptin was used with metformin, again without inducing weight gain, according to Alan J. Garber, MD, PhD, professor of medicine, biochemistry, and molecular biology, and molecular and cellular biology, Baylor College of Medicine, Houston, Texas.

In the study, vildagliptin was evaluated in combination with metformin in a double-blind, randomized fashion over 24 weeks in 416 patients whose diabetes was poorly controlled despite being on metformin for at least 3 months (mean HbA1c of 7.5%–11.0%). Patients were randomized to vilda-gliptin, 50 mg once- or twice-daily, or placebo. All patients received metformin 1,500 mg/d.

The incidence of adverse effects in the various groups did not differ and ranged from 63.3% to 65.0%. The rate of gastrointestinal (GI) adverse effects was significantly greater (P=.022) in the placebo recipients (18.2%) compared with those receiving vildagliptin 50 mg once daily (9.6%) and vildagliptin 50 mg BID (14.8%), Dr Garber said.

One hypoglycemic event occurred in each of the 3 groups.

Improvements in indices of beta-cell function were observed during the study, a finding consistent with animal studies, Dr Garber stated.

SITAGLIPTIN EFFICACY

Much like vildagliptin, sitagliptin also significantly lowered HbA1c levels when used as monotherapy or with metformin or pioglitazone, and it, too, had a greater effect on HbA1c levels when they were highest at baseline.

Sitagliptin proved noninferior to glipizide in reducing HbA1c levels at 52 weeks when used in patients who had inadequate glycemic control with metformin monotherapy, reported Peter Stein, MD, senior director of clinical research at Merck & Co.

In the double-blind study, 793 patients with HbA1c values of 6.5% to 10% were randomized to sitagliptin 100 mg/d or glipizide up to 20 mg/d. At 52 weeks, sitagliptin and glipizide each reduced HbA1c by 0.67% from baseline (P<.001). Prespecified bounds for noninferiority were achieved with sitagliptin, Dr Stein said.

An HbA1c goal of <7% was achieved by 63% of the sitagliptin group and 59% of the glipizide group. Patients treated with sitagliptin experienced a mean weight loss of 1.5 kg from baseline, whereas glipizide recipients experienced a mean weight gain of 1.1 kg (P<.001 for between-group difference).

In 3 monotherapy studies presented at the ADA scientific sessions in patients with mean baseline HbA1c levels ranging from 7.5% to 8.1%, 100 mg/d of sitagliptin was associated with reductions in HbA1c of 0.60% to 1.05% relative to placebo. In patients with baseline HbA1c levels >9%, reductions in HbA1c with sitagliptin relative to placebo were 1.2% to 1.5%.

"In these studies, a low rate of hypoglycemia was observed, and sitagliptin was generally weight neutral," said Dr Horton.

In a pooled analysis of monotherapy and add-on studies, there was no excess level of hypoglycemia in the sitagliptin groups compared with the placebo groups and no clinically meaningful changes in body weight with sitagliptin.

EXENATIDE EFFICACY

A new once-weekly formulation of the GLP-1-like peptide exenatide showed efficacy in reducing HbA1c levels in a study of 45 patients who could not achieve glycemic control on metformin or diet and exercise. In the study, a once-weekly subcutaneous injection of 0.8 or 2.0 mg of exenatide long-acting release reduced HbA1c by an average of 1.4% or 1.7%, respectively, after 15 weeks, compared with an increase of 0.4% in placebo recipients.

Related Videos
Related Content
© 2024 MJH Life Sciences

All rights reserved.