New Diabetes Drugs Add to Tx Complexity

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.

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 thus 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_1c (HbA_1c) along with weight loss. About 75%–80% of patients respond to these compounds.

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 HbA_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-a and PPAR-g, 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 HbA_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.”

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 insulin adjunct in patients with either type 1 or type 2 diabetes.

It appears to lower the dose of bolus insulin required for glycemic control by 50%, it leads to a stabilization of plasma glucose, it decreases HbA_1c by 0.4%–0.7%, and it decreases food intake, leading to weight loss of 2 kg or more.

While not directed specifically at diabetes, cannabinoid receptor blockers are likely to be useful in this population as an adjunct to diet and exercise for the management of obesity. Rimonabant (Acomplia) is the furthest along in clinical development.