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Sitagliptin Role As Monotherapy, Adjunct

Posted: Thursday, November 30, 2006

The newly licensed glucose-lowering agent sitagliptin phosphate (Januvia) appears safe and somewhat effective. It could become a replacement for sulfonylurea, due to its ability to control blood sugars without weight gain and hypoglycemia.

Sitagliptin, manufactured by Merck & Co. under the name Januvia, is a once-daily oral agent that will cost $4.86 per tablet. The first of the new class known as dipeptidyl peptidase-4 (DPP-IV) inhibitors, it was approved by the Food and Drug Administration in October as monotherapy or in combination with metformin or a thiazolidinedione.

The DPP-IV inhibitors work by blocking the enzyme that breaks down the two incretin hormones glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide, which help regulate glucose metabolism via increased insulin release, suppressed glucagon release, and delayed gastric emptying.

“Despite the numerous therapies already available, many people are not adequately controlled in their blood sugar. So a new treatment option for type 2 diabetes, particularly one in a new class, is always a useful addition,” Dr. Robert Meyer, director of the FDA's Office of Drug Evaluation II, said in a telephone press briefing.

Another DPP-IV inhibitor, Novartis' vildagliptin (Galvus), was expected to be approved by the end of the year, but it now seems that it will be delayed.

Whether or not sitagliptin represents a distinct advantage over other available glucose-lowering agents is a matter of debate. Dr. Priscilla Hollander, who conducted clinical trials on sitagliptin for Merck, envisions use of the drug as a replacement for sulfonylureas in patients who don't achieve glucose targets with metformin or a thiazolidinedione (TZD) alone.

Metformin and TZDs address the insulin resistance component of type 2 diabetes, and sitagliptin's ability to promote ß-cell insulin secretion without causing hypoglycemia or weight gain might make it an attractive substitute. “One place sitagliptin could probably play a very major role is where we currently use the sulfonylureas,” Dr. Hollander said in an interview.

It might also benefit elderly patients who need a “push” to their ß cells but are sensitive to the hypoglycemia induced by sulfonylureas and perhaps are intolerant to the side effects of metformin or TZDs, she added.

Data from three phase III studies on sitagliptin were presented at the annual meeting of the European Association for the Study of Diabetes, in Copenhagen.

Dr. Pablo Aschner of the Colombian Diabetes Association, Bogota, presented data from a 24-week monotherapy trial in which 741 patients aged 18–75 years were randomized to daily placebo, 100 mg sitagliptin, or 200 mg sitagliptin. The study population began with a mean hemoglobin A1c of 8.0% and fasting plasma glucose of 9.6 mmol/L. At 24 weeks, the two sitagliptin doses produced significant, placebo-adjusted reductions in A1c of 0.79% with 100 mg and 0.94% with 200 mg, and in fasting plasma glucose of 1.0 mmol/L and 1.2 mmol/L, respectively.

Patients who started at an A1c of 9% or higher had a mean reduction of 1.52% with 100 mg sitagliptin and 1.5% with 200 mg, vs. 0.8% and 1.13%, respectively, among those with baseline A1c levels of 8.0%–8.9%, and 0.57% and 0.65% among those with baseline A1c of less than 8%. The proportion of patients achieving an A1c level of less than 7% were 41% with 100 mg sitagliptin and 45% with 200 mg, while 18% and 20%, respectively, reached an A1c below 6.5%.

Placebo-adjusted reductions in 2-hour postmeal glucose values were 47mg/dL (2.6 mmol/L) with 100 mg and 54mg/dl (3.0 mmol/L) with 200 mg sitagliptin. Improvements with sitagliptin relative to placebo also were seen in postmeal insulin and C-peptide concentrations, as well as in homeostasis model assessment-ß and the ratios of insulin to glucose areas under the curve and proinsulin/insulin, suggesting improved ß-cell function, Dr. Aschner said.

Neither hypoglycemia nor gastrointestinal events were increased with sitagliptin, compared with placebo. Small reductions in body weight were seen with sitagliptin (0.2 kg with 100 mg and 0.1 kg with 200 mg), but placebo subjects lost more weight (1.1 kg).

A second study, presented by Dr. Avraham Karasik, of Chaim Sheba Medical Centre, Tel Hashomer, Israel, randomized 701 type 2 diabetic patients who were inadequately controlled on 1,500 mg/day or more of metformin alone to receive placebo or 100 mg/day of sitagliptin for 24 weeks. Adjunctive sitagliptin led to significant mean placebo-subtracted reductions from baseline in hemoglobin A1c (0.65%), fasting glucose (25mg/dl [1.4 mmol/L]) and 2-hour postprandial glucose (50mg/dL [2.8 mmol/L]).
The proportions achieving a hemoglobin A1c value of less than 7% were 47% with sitagliptin plus metformin vs. 18% with metformin; 17% and 5%, respectively, reached an A1c level below 6.5%. Adding sitagliptin to metformin had no effect on body weight, nor did it increase the risk for hypoglycemia or gastrointestinal adverse events, compared with placebo, Dr. Karasik said.
Dr. Julio Rosenstock, of the Dallas Diabetes and Endocrine Center and the University of Texas Southwestern Medical Center, Dallas, reported on 353 patients who had hemoglobin A1c values between 7% and 10% while taking 30 mg or 45 mg/day of pioglitazone. At 24 weeks after randomization to receive the addition of placebo or 100 mg/day of sitagliptin, mean A1c was 7.2% with sitagliptin and 7.8% with placebo, a significant difference.

Nearly half those receiving sitagliptin achieved an A1c level of less than 7%, compared with 23% of those who received placebo. Also, 24% of the sitagliptin group and 5% of the placebo group reached the lower A1c target of 6.5%.

Source: Diabetes In Control: Internal Medicine: Volume 39, Issue 22, Page 1,4 (15 November 2006)