|
||||||
|
|
|
|
|||||||||||
|
|||||||||||||
| ||||||||||||||||||||||||||||||||||||
With its marketing approval granted by the U.S. Food and Drug Administration (FDA) on October 17, sitagliptin (Januvia, Merck) became the latest weapon to combat type 2 diabetes.
|
The first of a new class of drug, dipeptidyl peptidase-4 (DPP-4) inhibitors, sitagliptin targets pancreatic islet cell dysfunction with a mechanism of action unlike that of other drugs on the market.
"Physicians and patients will now have another option with which to tackle a very challenging disease," says Daniel J. Drucker, MD, director of the Banting and Best Diabetes Centre at the University of Toronto.
DPP-4 is an enzyme that rapidly deactivates glucagon-like peptide 1 (GLP-1), an incretin that slows gastric emptying and stimulates the production of insulin in response to a meal. Inhibiting the action of DPP-4 allows levels of endogenous GLP-1 to rise, pushing the body's physiology toward more normal regulation of insulin and glucagon.
The FDA approved sitagliptin based on clinical studies showing that, in people with average baseline glycated hemoglobin (A1C) levels of 8%, the drug reduced A1C levels by an average of 0.6% in 18 weeks and 0.8% in 24 weeks, compared with placebo.1 When patients took sitagliptin along with metformin or pioglitazone (Actos, Takeda), about twice as many achieved A1C levels <7% as those who took the older drugs alone, according to Merck.2,3
The drug was approved for use in addition to diet and exercise for the treatment of type 2 diabetes, either alone or in combination with metformin or a perioxisome proliferator-activated receptor (PPAR)-gamma agonist, such as the thiazolidinediones (TZDs) pioglitazone or rosiglitazone. The 100-mg tablets, typically taken once daily with or without food, will retail for about $4.86 per tablet, according to Merck.
Sitagliptin is not effective for and should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Patients with renal impairment may require a reduction in dose to either 50 mg or 25 mg.
PRODUCT PIPELINE
Several other DPP-4–inhibitor compounds are in development. Vildagliptin (Galvus, Novartis) has completed phase III testing and is pending FDA approval, which could be granted by the end of the year. Other companies with DPP-4 products in development include Bristol Myers Squibb, GlaxoSmithKline, and Takeda.
At the European Association for the Study of Diabetes 42nd Annual Meeting, held September 14–17 in Copenhagen, Denmark, Novartis presented phase III data showing that vildagliptin as monotherapy reduced A1C levels an average of 1.8% more than placebo.
As a class, it is likely that the DPP-4 inhibitors will perform similarly, according to Drucker. "They're all different chemical entities, and they may have slightly different profiles," he says. "No head-to-head studies have been reported yet. At this point you'd have to say they are similar."
In general, the DPP-4 inhibitors appear to be effective, with few reported adverse events. The most commonly reported side effects were upper respiratory tract infection, sore throat, and diarrhea, and there appeared to be no effect on weight.
"This whole class of drugs appears to be remarkably well tolerated by patients," says Vivian Fonesca, MD, chief of endocrinology at Tulane University Health Sciences Center in New Orleans, who has been involved in vildagliptin trials.
"The side-effect profile to date is really excellent, probably better than any diabetes drug ever developed," says Drucker, who has served as an adviser or consultant to Merck, Novartis, and Takeda, among other companies.
The net effect of DPP-4 inhibitors on raising GLP-1 levels is similar to that of exenatide (Byetta, Amylin/Lilly), the GLP-1 agonist that the FDA approved in April 2005, but the drugs work in different ways that have particular clinical meaning, experts note.
DPP-4 inhibitors are glucose-dependent, stimulating the release of insulin when blood glucose levels are elevated. Unlike exenatide and several other drugs used to treat type 2 diabetes, DPP-4 inhibitors are less prone to cause hypoglycemia.
"There is virtually no hypoglycemia with these drugs, unless they're given with another drug" that affects blood glucose levels, such as metformin or a TZD, Drucker says.
PRESERVING BETA-CELLS
Some research suggests DPP-4 inhibitors and exenatide may increase beta-cell mass in the islets of Langerhans, potentially ameliorating diabetes. "There are intriguing animal studies that show DPP-4 inhibitors preserve beta-cell function and may even regenerate beta-cell mass," Fonesca says.
Research also suggests DPP-4 inhibitors have a more pronounced effect in
the elderly and patients who are not overly obese, he says. The drugs are
likely to be prescribed first in patients such as the elderly where
hypoglycemia is a serious concern. 
Footnotes
Sitagliptin label information is available on the FDA's Web site at www.fda.gov/cder/foi/label/2006/021995lbl.pdf.
References
2. Karasik A, Charbonnel B, Liu J, et al.: Sitagliptin added to ongoing metformin therapy enhanced glycemic control and beta-cell function in patients with type 2 diabetes (Abstract). Diabetes 55 (Suppl. 1):A119 –A120, 2006.
3. Rosenstock J, Brazg R, Andryuk PJ, et al.: Addition of sitagliptin to pioglitazone improved glycemic control with neutral weight effect over 24 weeks in inadequately controlled type 2 diabetes (Abstract). Diabetes 55 (Suppl. 1): A132–A133, 2006.
CiteULike 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
| ||||||||||||||||||||||||||||||||||||
|
||||||
|
| DOC News | Diabetes | Diabetes Care | Clinical Diabetes | Diabetes Spectrum |
