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The Food and Drug Administration (FDA) has approved a new adjunct injectable agent, shown to reduce postmeal blood glucose excursions and ward off weight gain for insulin-using patients with type 1 or type 2 diabetes.
Pramlintide (Symlin, Amylin) is an analog of the human pancreatic hormone amylin. In healthy individuals, amylin complements the actions of insulin and glucagon in maintaining normal blood glucose concentrations.
About 5,000 insulin-using patients with diabetes have received pramlintide in clinical studies. In the two most recent placebo-controlled, double-blind phase III clinical trials, Amylin Pharmaceuticals, Inc., reports that patients with type 2 diabetes receiving the recommended dosage of pramlintide—in addition to their regular insulin and other diabetes therapy—experienced statistically significant benefits over their regular therapies plus placebo. They achieved an average additional reduction in glycated hemoglobin (A1C) levels of 0.6% and lost an average 3.1 pounds during the 52-week study periods. A series of shorter-term clinical trials, each lasting 26 weeks, found similar weight-loss results and an average 0.4% additional reduction of A1C levels.1–3
Pramlintide is "a unique agent," says endocrinologist Bob Ratner, MD, vice president of scientific affairs at Medstar Research Institute in Washington, D.C., who studied the drug in clinical trials. "There are few drugs that really augment insulin. It's another tool in our armamentarium over and beyond insulin."
MECHANISM OF ACTION
The drug's mechanism of action appears to be twofold. First, it slows gastric emptying into the intestine. Second, it suppresses glucagon production by the liver during and after a meal. These, in turn, slow and reduce glucose entry into the circulation and apparently help to normalize post-meal fluctuations in circulating glucose more effectively than insulin treatment alone.
This is the aspect that interests many endocrinologists.
"[Pramlintide] is not particularly powerful in overall glucose lowering, but there's increasing interest in trying to sort out whether the gold standard A1C is the whole story in diabetes," says Paul Jellinger, MD, president of the American College of Endocrinology.
Growing evidence suggests that wide swings in blood glucose, particularly following meals, may have an independent detrimental effect in patients with diabetes that is not completely indicated by A1C measures alone, Jellinger explains.
"The diabetic patient who has exaggerated postmeal increases in glucose would be one of the better candidates for this drug," says Jellinger.
"The fact that it doesn't encourage weight gain is another beneficial effect, especially for patients with type 2 diabetes using insulin."
Amylin is a centrally acting hormone known to produce a satiating effect, which may explain the weight loss test subjects experienced, says company spokesperson Eric Shearin.
USING PRAMLINTIDE SAFELY
No significant adverse effects on patient blood pressure or lipid concentration were noted in 26- and 52-week studies of pramlintide. The most common side effect was transient mild-to-moderate nausea, which was generally dose-related.
Early double-blind studies had indicated an increase in episodes of severe hypoglycemia in patients who added pramlintide to their treatment regimen. These cases prompted Public Citizen, the consumer watchdog group, to object to the drug's approval during an FDA hearing in July 2001.4 Subsequently, the FDA called for further safety studies on pramlintide, which the company undertook.
The 7-month trial, which included 250 patients and an open-label use of pramlintide, indicated that a dosetitration protocol reduced the incidence of both severe hypoglycemia and nausea, says Shearin.
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According to Stephen Aronoff, MD, clinical endocrinologist and medical director of the Research Institute of Dallas, the original study design may have been at fault by not allowing for changes in insulin dosage when pramlintide was added. It was later recognized, says Aronoff, that insulin efficiency improved with the addition of pramlintide. When the insulin dosage was adjusted down accordingly, he says, the hypoglycemia rate in subsequently enrolled patients was reduced.
"Pramlintide itself does not cause hypoglycemia," Aronoff said at an industry-sponsored symposium held at the American Association of Clinical Endocrinologists' 13th Annual Meeting and Clinical Congress in Boston last May. "The addition of pramlintide to insulin therapy may affect the event rate of hypoglycemia by increasing insulin efficiency, which calls for a decrease in the insulin dosage."
The prescribing regimen for pramlintide also will call for a dose-titration approach, says Shearin, in which insulin dosage for selected patients initially will be dropped, pramlintide gradually introduced, and insulin added back as appropriate. The regimen will require close patient follow-up, and it "will generally be handled by endocrinologists rather than general practitioners," says Jellinger.
Despite the additional premeal injections required with this adjunct treatment, "it didn't seem to pose any barrier," says Shearin. "Well over 80% [of the blinded-study participants] stayed on the drug after their study concluded."
Pramlintide may best suit patients who are not adequately controlled on
insulin therapy, who have fluctuations in blood glucose, or who experience
excessive weight gain on insulin therapy, according to Ratner. 
References
2. Ratner RE, Want LL, Fineman MS, et al.: Adjunctive therapy with the amylin analogue pramlintide leads to a combined improvement in glycemic and weight control in insulin-treated subjects with type 2 diabetes. Diabetes Technol Ther 44:51–61, 2002.
3. Thompson RG, Pearson L, Schoenfeld SL, et al.: Pramlintide, a synthetic analog of human amylin, improves the metabolic profile of patients with type 2 diabetes using insulin: Diabetes Care 21: 987–993, 1998.[Abstract]
4. Testimony of Sidney M. Wolfe, MD, director, Public Citizen's Health Research Group, before the FDA; July 26, 2001 (www.citizen.org/publications/release.cfm?ID=6786).
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