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More drug classes, complexity for diabetes care.

SAN FRANCISCO -- Diabetes treatment is about to acquire several more layers of complexity as new classes of drugs become available, Dr. David M. Kendall said at a conference sponsored by the American Diabetes Association.

Incretin mimetics, dipeptidyl peptidase IV (DPP-IV) inhibitors, dual peroxisome proliferator-activated receptor (PPAR) activators, amylin analogues, and cannabinoid receptor blockers--not to mention inhaled forms of insulin--are all wending their way through clinical trials.

Some drugs in these classes already have been approved, most notably the incretin mimetic exenatide (Byetta), an inhaled insulin (Exubera), and the amylin analogue pramlintide (Symlin). Others are in the late stages of clinical trials and may be approved later this year.

A cookbook approach to using these new drugs is unlikely to emerge, said Dr. Kendall, a diabetologist currently serving as executive director for medical affairs at Amylin Pharmaceuticals, San Diego. Instead, clinicians will have to consider which classes of compounds, and which drugs within those classes, are likely to benefit individual patients, depending on their clinical characteristics.

"A number of outcome trials both in type 1 and type 2 diabetes will help guide where our therapies play their most important roles in years ahead," Dr. Kendall said.

In his talk, Dr. Kendall commented on how these compounds work and what clinical evidence is available to assist in matching the drug to the patient.

The "incretin effect" refers to gut-related factors that increase insulin levels rapidly in response to oral glucose. Several drugs are being developed that are analogues of one of the two incretins known--glucagon-like peptide 1 (GLP-1).

In addition to their direct effect on pancreatic islet cells, GLP-1 analogues can help restore appropriate suppression of glucagon secretion, and by so doing limit hepatic glucose output after a meal. Furthermore, these drugs slow the rate of gastric emptying and increase satiety, leading to moderate weight loss.

Several GLP-1 analogues are under development. Exenatide already has been approved for patients with type 2 diabetes who fail to achieve glycemic control with metformin or a sulfonylurea. Similar compounds are not far behind, including liraglutide and a compound currently designated CJC-1134.

Dr. Kendall referred to exenatide and other incretin mimetics as "smart bombs for diabetes," since they lead to a "profound restoration of phasic insulin secretion," a decrease in postmeal glucose excursions, and reductions in hemoglobin [A.sub.1c] (Hb[A.sub.1c]) along with weight loss. About 75%-80% of patients respond to these compounds.

The main disadvantages of current incretin mimetics is that they must be kept refrigerated, and must be administered by injection, twice daily in the case of exenatide and once daily in the case of liraglutide. They can also cause nausea and vomiting.

DPP-IV rapidly degrades incretins, and Dr. Kendall mentioned at least four DPP-IV inhibitors under development. Several, including vildagliptin and sitagliptin, have reached phase III clinical trials. Orally administered, these compounds lead to sustained glucose control, and Hb[A.sub.1c] reductions of about 0.7%. They appear to be weight neutral, and they're well tolerated, but the response rate is not yet known.

Dual PPAR activators are agonists for both PPAR-[alpha] and PPAR-[gamma], and so may have beneficial effects on both insulin sensitivity and lipid metabolism. Several are under development, including muraglitazar, tesaglitazar, and naveglitazar.

Dr. Kendall mentioned a head-to-head study comparing muraglitazar and pioglitazone. They appear to have similar efficacy in improving insulin sensitivity, but muraglitazar was significantly better at reducing Hb[A.sub.1c] and improving levels of triglycerides and HDL cholesterol.

"This is a two for one," Dr. Kendall said, that's particularly suited for "anyone with type 2 diabetes and insulin resistance who's at higher risk for cardiovascular disease, particularly those who have a specific need to target abnormalities in HDL cholesterol and triglycerides."

Unfortunately, questions have been raised regarding long-term safety and tolerability because of hints that these compounds increase rates of fluid retention.

Amylin is a pancreatic islet hormone that's cosecreted with insulin. It's been demonstrated to lower plasma glucagon levels in patients with both type 1 and type 2 diabetes, to regulate rates of gastric emptying, and to be associated with reductions in food intake and moderate weight loss. Amylin levels are deficient in patients with type 1 and type 2 diabetes.

Pramlintide, the first amylin analogue, was approved by the Food and Drug Administration in 2005 as an adjunct to insulin in patients with type 1 or type 2 diabetes.

It appears to lower the dose of bolus insulin required for glycemic control by 50%, leads to a stabilization of plasma glucose, decreases Hb[A.sub.1c] by 0.4%-0.7%, and decreases food intake, leading to weight loss of 2 kg or more over 26 weeks.

Pramlintide must be injected, its dose must be titrated, and it can cause nausea. In addition, Dr. Kendall advised, "anytime you're improving postmeal blood glucose control, careful attention to current insulin doses and the consistency of carbohydrate intake must be taken under advisement to limit hypoglycemia risk."

While not directed specifically at diabetes, cannabinoid receptor blockers are likely to have a use in this population, since they may be useful as an adjunct to diet and exercise for the management of obesity. Rimonabant (Acomplia) is the furthest along in clinical development, although it has not yet been approved by the FDA.

In clinical trials in patients with type 2 diabetes, rimonabant was associated with weight loss of about 4 kg more than placebo over 1 year, along with significant reductions in waist circumference and reductions in Hb[A.sub.1c] of about 0.6%.

BY ROBERT FINN

San Francisco Bureau
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Author:Finn, Robert
Publication:Internal Medicine News
Geographic Code:1USA
Date:Apr 15, 2006
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