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On April 29, the Food and Drug Administration (FDA) approved exenatide(Byetta, Amylin/Lilly), a drug derived from lizard saliva that is the first ina new class of medications called incretin mimetics being developed for thetreatment of type 2 diabetes.
The FDA approved exenatide as a twice-daily injectable adjunct therapy forpatients whose blood glucose is not well controlled with metformin and/or asulfonylurea. Exenatide may be approvable as a monotherapy pending a 6-monthFDA review of any additional data that support such an indication.
Amylin is on a hot streak with its diabetes drugs; the approval ofexenatide comes fast on the heels of the recent FDA sanction of pramlintide(Symlin, Amylin), an injectable adjunct for diabetes patients using insulin(DOC News, May 2005).
NATURAL HISTORY
Ongoing research on human gut hormones has identified intriguing compoundsin the intestinal tract that stimulate insulin secretion in response toglucose levels. One of these is glucagon-like peptide 1 (GLP-1), an incretinhormone secreted by the gut after food intake, which normalizes fasting plasmaglucose concentrations and inhibits glucagon secretion. It also slows gastricemptying, which reduces appetite and food consumption.
But the extremely short half-life of GLP-1 limits its use as a therapy fortype 2 diabetes. So research has focused on ways to create GLP-1 analogs thatwould replicate the activity of natural GLP-1 but have a much longerhalf-life.
Enter exenatide, one of a family of molecules that mimics the effects ofGLP-1, which has been probed by the pharmaceutical industry for about 15years. Exenatide owes its existence to the Gila monster; the drug is asynthetic derivation of exendin-4, a protein found in the salivary gland ofthis venomous lizard that resides in the deserts of the southwestern U.S.
GLP-1 drugs like exenatide are very attractive in a number of ways,explains Xavier Pi-Sunyer, MD, an endocrinologist specializing in diabetes atSt. Luke's-Roosevelt Hospital Center in New York City.
GLP-1 "seems to have a glucose-lowering effect and a weight-losseffect, whereas most antidiabetic drugs tend to increase weight,"Pi-Sunyer tells DOC News. These actions suggest that exenatide couldbe a therapeutic agent for type 2 diabetes without causing the weight gainassociated with oral antidiabetic agents.
One perceived barrier to exenatide is that it is an injectable drug,formulated for twice-daily, self-administered subcutaneous injections ofeither 5 or 10 µg.
"There is a reluctance in both doctors and patients to go oninjectables," Pi-Sunyer says.
THE EVIDENCE
In phase III clinical studies, exenatide was assessed as an adjunct therapyin patients with type 2 diabetes who were not yet taking insulin but in whomtreatment with either one or two standard oral antidiabetic medications hadfailed.
Among patients who did not benefit from maximally effective doses of asulfonylurea, one study showed that treatment with 30 weeks of twice-dailyexenatide resulted in significant reductions in glycated hemoglobin (A1C)compared withplacebo.1
Of 237 patients with A1C >7% at baseline (average 8.6%), 33% receiving 5µg exenatide and 41% receiving 10 µg achieved A1C 
7%, compared with9% taking placebo. Patients receiving the higher exenatide dose also haddecreased fasting plasma glucose concentrations and a mean weight loss of 1.6kg (3.5 lb).
Additional phase III research shows that exenatide has "a sustainedeffect to maintain glycemic control," according to investigator AlainBaron, MD, senior vice president of clinical research forAmylin.
One study assessed 336 patients taking metformin and exenatide or placebofor 30 weeks.2 Ofthose with A1C >7% at baseline (mean average 8.2 ± 1.1%), 32% in the5-µg exenatide group and 46% in the 10-µg group achieved A1C 7%,compared with 13% of the placebo group. Patients taking exenatide alsoexperienced progressive, dose-dependent weight loss. The researchers noted alow incidence of mild to moderate hypoglycemia that was similar acrosstreatment arms.
Another study looked at 733 patients taking the same doses of exenatide for30 weeks, in addition to metformin andsulfonylurea.3 Theresults showed 27% of the 5-µg and 34% of the 10-µg exenatide groupachieved A1C <7%, compared with 9% of those taking placebo. Significantweight loss (–1.6 ± 0.2 kg from baseline, or 3.5 ± 0.4 lb)was noted in both exenatide-treated groups.
As for adverse effects, investigators identified mild to moderatehypoglycemia in 19% of those taking 5 µg of exenatide, 28% of those taking10 µg, and 13% of those taking placebo. The incidence of hypoglycemiaappeared lower among patients taking the minimum rather than the maximum doseof sulfonylurea. All cases were resolved with oral administration ofcarbohydrate.
Amylin recommends that prescribing clinicians consider adjusting the doseof sulfonylurea to reduce the increased risk of hypoglycemia withexenatide.
Many patients treated with exenatide experienced transient mild andmoderate nausea. But nausea generally subsided as treatment continued.
Patients treated with exenatide showed low levels of antibodies, but theseantibodies did not appear to affect efficacy or be associated with adverseevents.1–3
Researchers remain excited about exenatide's prospects for controlling type2 diabetes.
"This therapy can get patients under good control relativelyrapidly," Baron tells DOC News. "The premise is exenatidecan prevent further deterioration of the disease." 
Footnotes
• For detailed exenatide prescribing information, read the packageinsert, available online as a downloadable file athttp://pi.lilly.com/us/byetta-pi.pdf.
• Primary care providers might consider exenatide for their patientswho are not achieving blood glucose targets with metformin or sulfonylurea orboth.
• Exenatide is an injection that comes in fixed-dose 5-µg and10-µg pens, but it is not an insulin.
• Amylin recommends initiating therapy at 5 µg and stepping up to10 µg based on the patient's clinical response.
• It is not yet approved for treatment with the use ofglucose-lowering thiazolidinediones (TZDs), such as pioglitazone (Actos,Takeda/Lilly) and rosiglitazone (Avandia, GlaxoSmithKline), although studiesfor this indication are under way.
• Amylin is conducting phase II trials on a long-acting version ofexenatide designed to work as a once-weekly injection.
References
2. Defronzo RA, Ratner RE, Han J, et al.: Effects of exenatide(exendin-4) on glycemic control and weight over 30 weeks in metformin-treatedpatients with type 2 diabetes. Diabetes Care 28: 1092–1100, 2005.
3. Kendall DM, Riddle MC, Rosenstock J, et al.: Effects of exenatide(exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetestreated with metformin and a sulfonylurea. DiabetesCare 28:1083–1091, 2005.
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