The discovery of insulin approximately 80 years ago heralded hope for millions of people who have struggled with this devastating disease. As the 20th century progressed, significant advances occurred with the development of small molecules, as well as the long- and short-acting biologically modified insulin analogues. However, gaps still remain in the control of diabetes. The incidence of diabetes continues to climb — affecting 6.2 percent of the U.S. population, about 17 million people.
Although the number of choices to treat diabetes has risen, the disease still offers plenty of opportunity for improved outcomes. The complexity of maintaining glucose control encourages research efforts.
The pathophysiology of diabetes involves a relative or absolute deficiency of insulin, a relative excess of glucagon, insulin resistance, dysfunctional levels of glucagon-like peptide –1 (GLP-1), gastric inhibitory peptide (GIP), appetite dysregulation, and gastric emptying dysregulation. Merely correcting the insulin deficit is too simplistic a solution and does not correct all of the abnormalities.
Enter amylin, first described in 1987. It is a 37-amino acid polypeptide hormone located with insulin in the pancreatic beta-cells. Amylin is part of the complex interplay of glucose regulation. Thus, in addition to the relative or absolute deficiency of insulin, there is a similar deficiency of amylin.
The homeostasis of normal blood sugar occurs because of this interplay. These hormones balance the creation of glucose by the liver and the absorption of glucose from the gut. Amylin has been found to complement the effects of insulin in postprandial glucose control by affecting three pathways that contribute to the overall glycemic control in a way that the currently available agents, either oral or insulin, cannot mimic. The first is the suppression by amylin of postprandial glucagon secretion, which reduces the glucagon-induced hepatic glucose release. Second, amylin regulates gastric emptying of food into the small intestine. Third, amylin appears to suppress intake of food by causing the central nervous system to signal satiety.
Studies indicate that patients with type 1 diabetes lack amylin, while patients with type 2 have lower postprandial amylin concentrations than healthy people. Researchers note that the beta-cells are impaired in those with both type 1 and type 2 diabetes, leading to similar declines in both hormones in response to food intake.
Replacement of exogenous insulin is a partial solution, but does not create the balance that exists in normal people because the amylin deficiency still exists. In addition, subcutaneous administration of insulin does not mirror the natural release of insulin into the portal vein, where the liver is exposed to twice the concentration of insulin.
If high enough levels of insulin are administered to suppress hepatic glucose production, hypoglycemia results. Also, in both type 1 and type 2 diabetes, relative hyperglucagonemia exists. This is particularly troublesome in the postprandial times when glucagon is normally suppressed. Only recently was it discovered that the cause of the glucagon suppression in non-diabetic patients is amylin.
The native amylin hormone has a short half-life that limits its usefulness as an intermittent injectable. By modifying the native hormone's polypeptide content in a fashion similar to what several manufacturers have done to insulin to create the insulin analogues, the peak is reached at 20 minutes with a decline over three hours. This gives the analogue a 50-minute half-life. Amylin Pharmaceuticals has created this amylin analogue by altering the amino acids in locations 25, 28, and 29. This new compound, given the generic name of pramlintide acetate, will be marketed under the brand name Symlin. This new subcutaneous, synthetic amylin must be given before meals.
It is of interest that amylin has a neuroendocrine mode of action. A bilateral vagotomy abolishes the effect of amylin. Also of interest is that the decrease in gastric emptying caused by amylin is dependent upon the ambient glucose level. In other words, if the blood sugar is high, amylin slows gastric emptying. Hypoglycemia overrides this effect. This reinforces the importance of amylin, as insulin does not have a significant effect on gastric emptying.
Of note is that placebo-controlled crossover studies in both type 1 and type 2 diabetes have demonstrated almost total prevention of the initial surge of glucose levels in the first 30 to 60 minutes after a meal in people receiving pramlintide, thus limiting or preventing the postprandial hyperglycemia. The required dose appears not to be a pharmacologic dose, but simply a physiological effect. The studies have also demonstrated an almost total prevention of the postprandial glucagon rise in those patients receiving pramlintide.
Long term intervention trials such as the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study have clearly proven that control of ambient blood sugar as well as hemoglobin A1c (HbA1c) reduce the risk of microvascular and probably macrovascular complications in patients with type 1 or 2 diabetes. These trials also demonstrated the difficulty of attaining tight control even with insulin.
Patients may have difficulty with the social and lifestyle changes that accompany glucose control. Compounding the issue are the side effects of the aggressive therapy and the nearly inevitable hypoglycemia that accompanies tight glucose control. Hypoglycemia is a side effect of insulin therapy or combination therapy involving insulin and oral hypoglycemics. Nearly all people achieving tight control with the existing medication gain weight in response to the glucose being pushed into cells by the therapy.
The effects of pramlintide on weight are significant. Four double blinded, placebo-controlled, parallel-group, multi-center trials lasting 12 months have consistently demonstrated reduction of HbA1c levels of between 0.5 and 1.0. This resulted in a two- to three-fold increase in the number of patients able to reach the American Diabetes Association glycemic target of an HbA1c level of 7.0. The exciting part of the findings was that the reductions in HbA1c levels were generally associated with a weight loss.
The long term control of HbA1c was not associated with an increase in the overall event rate of severe hypoglycemia. In addition, pramlintide was generally well tolerated. No evidence of cardiac, hepatic, renal or other physiologic parameters was noted.
The primary target for Symlin will be type 1 diabetics and type 2 diabetics currently using insulin. This group includes 4.5 million Americans. Managed care directors would be interested to know that the FDA may approve very soon. It might even be available by the time of publication.
Managed care will quickly have to assess this hormone substitute. If it is priced on par with the insulin analogues, I expect little conflict with MCOs.
If it is priced as a typical biologic, I anticipate significant pushback. Of course, Symlin will add costs to the immediate treatment of diabetes, as it is used in addition to insulin.
Questions that remain are:
You have not heard the last from Amylin Pharmaceuticals. Exenatide, a peptide with anti-diabetic properties, is undergoing research by Amylin Pharmaceutical and Eli Lilly for the treatment of type 2 diabetes. But that is a topic for another Tomorrow's Medicine.