Incretin Hormones Poised For Better Control of Diabetes


Enhanced management continues due to a greater understanding of the intricate glucose balance and the shortfalls of existing medications.

Thomas Morrow, MD

The United States is facing an unprecedented challenge from type 2 diabetes, a disease characterized by a combination of insulin resistance and progressive pancreatic beta cell dysfunction. The glucose balance is a complex interplay of numerous neuroendocrine control mechanisms, hepatic glucose production, energy expenditure, and peripheral insulin sensitivity. When this system becomes unbalanced, the resulting rise in glucose results in a widespread vasculitis affecting all organs of the body.

Traditional pharmacological therapy targets both postprandial and fasting hyperglycemia and the surrounding metabolic derangements such as hyperlipidemia and hypertension.

Incretin hormones

But all of the existing medications have shortfalls for this progressive disease and are associated with side effects such as weight gain, edema, gastrointestinal intolerance, and hypoglycemia.

Recently, a new source of hope has been discovered — incretin hormones. These hormones are polypeptides released by the intestine. Their role in the regulation of glucose and insulin secretion after a meal was postulated after observing a greater insulin effect after the administration of an oral load of glucose as compared to an equivalent intravenous load. This effect was termed the “incretin effect” and has been mainly defined in animals.

Gastric inhibitory polypeptide (GIP) and glucagons like peptide-1 (GLP-1) are two incretins. GIP and GLP-1 are rapidly released by cells lining the GI tract after a meal and stimulate a decrease in the secretion of glucagon and an increase in the release of insulin. Interestingly, the release of glucagon to a hypoglycemic episode is not blunted. These effects use pathways that may include both neural and endocrine mediators. The GLP-1 insulinotrophic responses remain present in type 2 diabetes although those of GIP are blunted, making the GLP-1 compound a target for pharmaceutical development. GLP-1 is produced through the cleavage of proglucagon into several smaller peptides. This production is reduced in patients with diabetes, but the GLP-1 insulin and GI response remains intact if exogenous GLP-1 is administered.

Of great interest to clinicians is the finding that the insulin secretion effect appears to be strictly dependent upon the serum glucose level, resulting in less potential for hypoglycemia. Additionally, GLP-1 slows gastric emptying, thus decreasing the rate of glucose absorption and further enhancing diabetic control. Appetite suppression and reductions in food intake also appear to be a beneficial effect of this class of hormones in both humans and animals.

Incretin analogs gain a foothold

The natural GLP-1 substance is rapidly degraded, and to be useful, must be infused. Two strategies have been used to take advantage of the GLP-1 effects. The first is to produce substances that increase the half life of endogenous GLP-1. Several medications are under investigation using this strategy.

Another strategy is to look for what have been termed incretin mimetics — incretin analogs that mimic the effect of incretin hormones but are resistant to the degradation processes that limit the half life of natural GLP-1. There are a variety of these compounds in various phases of development including liraglutide (Novo Nordisk), CJC-1311 (ConjuChem, Montreal, Canada) and, exenatide, the synthetic version of exendin-4 (Amylin Pharmaceuticals, San Diego, Calif.) This was recently released by the FDA.

Exendin-4 is a naturally occurring substance found in the salivary secretions of the lizard Heloderma suspectun — the gila monster. This animal eats only every several months, which poses a considerable challenge to any organism attempting to regulate its glucose level. Exendin-4 shares about 50 percent of the amino acid sequence of the mammalian GLP-1. In humans, Exendin-4 has a half life of 2.4 hours when administered subcutaneously. Marketed under the brand name Byetta, this 39 amino acid is available in a pen-injector and is administered subcutaneously in a dose of 5 mcg BID at any time within the 60 minute period before the morning and evening meal. It should not be administered after a meal. The dose can be increased, based upon clinical response after one month, to a dose of 10 mcg BID. It is indicated for use in patients with type 2 diabetes mellitus who are already receiving either metformin or a sulfonylurea or both and have suboptimal glycemic control. A reduction in the dose of the sulfonylurea may be considered to reduce the risk of hypoglycemia.

Beta-cell mass

Exenatide also appears to augment beta-cell mass, which is a distinct contrast to other available treatments. This effect involves the regulation of beta-cell genes but is an area of continued study. Another effect needing study is an insulin sensitizing effect. This may be an indirect consequence of improved metabolic control.

Diabetes is one of the greatest, if not the greatest, public health concerns of the next decade. The introduction of the incretin class of drugs offers much to the control of this disease.

Limited uptake

Since this product is indicated in poorly controlled patients and is administered by injection, the uptake of this drug is likely to be limited. Debate over the use of Byetta versus insulin should occur, as the cost of this product is several times higher than another injectable alternative. The weight loss potential offers a significant advantage over other treatment regimens and will probably be a focus of patient interest. Reduction in hypoglycemia is also going to be attractive to physicians and patients alike.

The retail price is $190 to $225 depending upon dose. Byetta is administered through a 30-day prefilled pen. Patients reported mild to moderate nausea, which generally subsides after continued exposure to the hormone. In addition, diarrhea and vomiting occurred two to three times more often in patients treated.

Clinical trials demonstrated an immunogenicity rate of 38 percent, with patients developing low levels of antiexenatide antibodies at 30 weeks. An additional 6 percent of patients developed higher levels of antibody production that did appear to attenuate the hypoglycemic effects of the drug.

Based upon the renal clearance, hepatic disease is not expected to affect blood concentrations. There were no significant differences in race, gender, or obese populations.

Clinical outcomes were based upon primary endpoints of HgA1c levels. HgA1c reductions of 0.46 (5 mcg BID) to 0.86 (10 mcg BID) with a corresponding increase in the placebo arm of 0.12 were reported.

Understanding of the intricacies of the peptide and genetic pathways is offering exciting advances for a large population. The others in this class will offer numerous opportunities for future editions of Tomorrow’s Medicine!

Thomas Morrow, MD, is president of the National Association of Managed Care Physicians and vice president and medical director of Matria Health Care. He has 20 years of managed care experience at the payer or health plan level.
Dr. Morrow discloses that he has received honoraria or other financial benefit during the last three years from the following commercial companies: Amgen, Amylin Pharmaceuticals, AstraZeneca, Biogen Idec, Centocor, Galderma, Genentech, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Novo Nordisk, Pfizer, Procter & Gamble, Q-Med, Sanofi-Aventis, Teva Pharmaceuticals Industries, UCB, and Wyeth.

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