ADA: Investigational Januvia Put Through Its Paces for Diabetes

WASHINGTON, June 11 ? Januvia (sitagliptin), an investigational oral agent for type 2 diabetes, appears to be effective when given as a monotherapy or as an adjunct to Glucophage (metformin) or Actos (pioglitazone), reported researchers here.

In several studies, investigators reported that the drug was associated with significant lowering of HbA1C levels, and that it helped to improve measures of beta-islet cell function.

"The data for Januvia presented today showed significant glucose lowering effects across a range of patients with type 2 diabetes, especially in those with more elevated baseline HbA1C levels," said Edward S. Horton, M.D., of the Joslin Diabetes Center in Boston, who was not involved in the studies.

Januvia is a member of a new class of diabetes drugs called dipetidyl peptidase-4 (DPP-4) inhibitors. These agents are part of the broader class of incretin mimetics, which includes Byetta (exenatide).

Incretin mimetics stimulate insulin secretion, protect beta cells, inhibit glucagon secretion, and help patients lose weight by delaying gastric emptying and inducing satiety.

Unlike Byetta, which is delivered by injection, Januvia is a once-daily oral agent.

In one study, Itamar Raz, M.D. of Hadassah University in Jerusalem, and colleagues, studied the efficacy and safety of Januvia in a randomized, double-blind, placebo -controlled study of 521 patients with type 2 diabetes.

After a washout period for patients already on an antihyperglycemic agent and a two-week single-blind placebo run-in, the patients, all with HbAIC levels between 7.0% and 10.0%, were randomized in a 1:2:2 ratio to placebo, Januvia at 100 mg daily, or Januvia at 200 mg daily for 18 weeks.

The mean HbA1C at baseline was 8.1%. The authors found that both doses of the drug significantly lowered HbA1C levels. The placebo-subtracted values were -0.60% for those in the 100-mg group, and -0.48% for those in the 200-mg group.

The biggest benefit was seen in patients with HbA1C levels at or above 9% at baseline. In these patients the placebo-subtracted difference was -1.20% for the 100-mg group, and -1.04% for the 200-mg group.

Januvia also significantly decreased fasting plasma glucose relative to placebo (difference from placebo, -19.7 mg/dL for 100 mg and -16.9 mg/dL for 200 mg).

The drug also appeared to have a positive effect on beta-cell function, as measured by HOMA-? (homeostasis model assessment of beta-cell function), which was significantly increased for both doses of the active drug. In addition, the fasting proinsulin ratio was significantly decreased with the 100-mg dose, but not the 200-mg dose, of Januvia.

The drug was well tolerated overall, with no significant differences in episodes of hypoglycemia or gastrointestinal adverse events compared with placebo.

Unlike Byetta, however, patients did not lose more weight on the drug than on placebo. In fact, weight loss was slightly greater in the placebo group (-0.7 kg/1.5 lbs, compared with -0.6 kg/1.3 lbs in the 100-mg group, or -0.2 kg/0.4lbs, for the 200-mg dose).

In a second large-scale study, endocrinologist Pablo Aschner, M.D., of Javeriana University School of Medicine in Bogota, Colombia, and colleagues, randomly assigned, in a double-blinded fashion, 741 patients to Januvia in the same doses as in the Jerusalem trial or to placebo on a 1:1:1 basis.

They found that after 24 weeks, Januvia at 100 mg and 200 mg produced significant (P

As was found in the Israeli study, patients with higher HbA1c levels at the outset fared the best on the drug. In a meal tolerance test, both doses of Januvia significantly decreased two-hour postprandial glucose compared with placebo (-46.7 mg/dL for the 100-mg dose, and -54.1 mg/dL for the 200-mg dose).

There were no significant differences in HbAIC, fasting plasma glucose or post-meal glucose reductions between the two active drug doses, the authors of this study found.

Beta-cell findings and safety findings were also similar to those seen in the Jerusalem study. In the Colombian study, body weight was significantly reduced on placebo (2.4 lbs) but not on either of the drug doses.

In other studies, Januvia at 100 mg as an add-on significantly reduced HbA1C and fasting plasma glucose levels in patients inadequately controlled on either Glucophage or Actos, with no significant differences in hypoglycemia or overall adverse events.

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