Ed Bryant Amylin Analog (Pramlintide) Studies Reveal Better Glycemic Control by Ed Bryant ********** From the Editor: The following article first appeared in Voice of the Diabetic, Volume 14, No. 2, April 1999, published quarterly by the NFB's Diabetes Action Network. Ed Bryant edits the publication and serves as President of the Diabetes Action Network. ********** For decades diabetes researchers thought the achievement of euglycemia (normal, stable blood sugars) was a balancing act between two hormones, pancreatic insulin and glucagon. All diabetes medications either stimulated, replaced, or augmented the action of one of these two. Such medications work, but people who use insulin know good control can be difficult, no matter how diligently the diabetic works at it. The blood sugars always seem to fluctuate, and the tightest control is never quite as good as that achieved by a healthy pancreas. There has always seemed to be a third element, another part of the puzzle, one we weren't getting.
We may now have the missing piece. Amylin Pharmaceuticals, Inc., a San Diego, California, company, has been researching the human hormone amylin, and their findings, while interim and incomplete, are fascinating.
About 100 years ago, researchers discovered white clumps of a substance in the pancreas while performing autopsies. They called it "amyloid," and no extensive research was done at that time. In 1987 Garth Cooper, Ph.D. a New Zealand researcher working in the U.K., and his co-workers published a paper describing the peptide he had sequenced from amyloid. This peptide was subsequently named "amylin."
The hormone amylin, like insulin, is produced in the beta cells of the pancreas. The two are co-secreted. A type 1 diabetic, deficient in insulin, is equally deficient in amylin. A type 2 diabetic may exhibit a lesser amylin deficit. The question: What is the role of amylin in blood glucose management?
Amylin Pharmaceuticals has completed thirty-seven clinical trials and is currently conducting phase 3 studies of its synthetic amylin analog, pramlintide, in the United States. Some studies were short and involved only a few people. Others lasted several years, and hundreds took part. Here's some of what they've found: ********** * Researchers believe that a deficiency of amylin contributes to excessive post-meal glucose elevation. Amylin appears to have a moderating effect on glucose absorption from the gut into the blood. It acts as a set of brakes, slowing and managing meal-derived glucose inflow and controlling pancreatic glucagon secretion, which in turn regulates hepatic (liver) glucose production. It also suppresses after-meal release of glucose from the liver. Both of these activities serve to smooth the peaks and valleys of blood sugar fluctuation and improve overall glycemic control.
* In studies where Hemoglobin A1c test results were compared between those who used both insulin and pramlintide and those who used insulin only, the A1c results of those who used the injectable amylin analog were significantly lower than those who did not. Major studies, such as the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study, have established the relationship between lower A1c results (for all diabetics) and a reduced risk of diabetes complications: kidney disease, blindness, neuropathy, and coronary artery disease.
* The clinical trials showed that many overweight diabetics who received pramlintide lost weight, while most lean diabetics, given the same medications, did not lose weight. Although the mechanism at work here is not yet clear, these results are exciting since achieving and maintaining ideal weight contributes to good health, a sense of well-being, and for some a reduction in the amount of insulin needed to maintain good control.
* Many diabetics have episodes of severe hypoglycemia (dangerously low blood sugar). If the diabetes is being kept under tight control by multiple tests and multiple insulin injections, the individual is more likely to experience hypoglycemia. Weight gain can follow as well. Studies in animals have shown that pramlintide, which normally retards release of the liver's glucose stores, suspends its action in the presence of hypoglycemia. This suggests that pramlintide helps lower the blood glucose without increasing the risk of hypoglycemia. Some test data appear to show a reduction in hypoglycemic episodes for the duration of amylin therapy.
* Although there are insufficient data to allow conclusions, test results from several phase 2 and phase 3 studies suggested that pramlintide use could lead to improvement in a diabetic's LDL/HDL cholesterol ratios. The company has stated that its test methodology was not clear enough to allow specific conclusions to be drawn, so this needs more investigation. But if borne out by further tests, it could suggest pramlintide might reduce the coronary artery disease that so often follows diabetes.
* Davida Kruger's paper, "Amylin: The Clinical Impact of Restoring Both Beta Cell Hormones Insulin and Amylin," states: "Amylin controls the rate of glucose inflow into the bloodstream by restraining the rate of gastric emptying and suppressing glucagon secretion, which in turn suppresses post-prandial glucose production." Simply, pramlintide appears to slow gastric emptying, which would more closely mimic the way our system is supposed to work, certainly helping to stabilize glycemic control. Some diabetics have gastroparesis, delayed gastric emptying. Although the effect of pramlintide in the presence of this complication has not yet been studied, the company plans to do so before the drug is marketed. ********** Because natural amylin is too viscous to inject, Amylin Pharmaceuticals developed its synthetic analog, pramlintide, which is injected subcutaneously using an insulin syringe. Although the use of an insulin/amylin mix was not tested in this round of clinicals and test participants were specifically instructed not to mix their insulin with their pramlintide, the company did carry out a safety check, and it found no acute (or short-term) hazard would be created if such mixing did occur (both Humulin and Novolin insulins were tested, though quick- acting Humalog insulin was excluded from study at that time). Still the company has no plans at this time to offer a mixed insulin/amylin product when it first markets pramlintide.
Test volunteers, unable to mix their pramlintide with their insulin, were faced with the need for many more injections. Almost none of them dropped out of the study, and the consensus was that they perceived the benefits to outweigh the irritation of the extra injections. A few study participants were insulin pump users. Use of pramlintide in conjunction with the insulin pump may become possible.
Amylin Pharmaceuticals has been testing this product for years and is currently engaged in phase 3 clinicals in several locations. As of March, 1999, over 1,700 people have received the drug. Both type 1 and insulin-using type 2 diabetics received pramlintide in different concentrations and frequencies. Only among type 1 diabetics receiving the highest dosage were there any noticeable side effects--in this case nausea and an increase in hypoglycemic events. All other dosage and frequency levels featured no increase in side effects (except transient nausea) over that seen with placebos, and in most cases there were significant reductions in hemoglobin A1c numbers--the kind of result known to cut risk of complications.
"Research shows that aggressive treatment...will prevent or delay much of the illness and death," says Dr. Phillip Gorden, Director of the NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in a June 23, 1998, news release. "Scientific studies provide compelling evidence that maintaining blood sugar levels at less than 7 percent, as measured by the HbA1c blood test, may reduce risk of complications by 50 percent to 80 percent," says Dr. Frank Vinicor, director of the CDC's Division of Diabetes Translation, quoted in the same document.
The process of winning approval from the Food and Drug Administration (FDA) for a new medication and permission to market it to consumers is long, expensive, and complex. To win approval, a company must prove, not only that its product works and doesn't imperil the safety of its users, but that its results are regular, consistent, and predictable. Unexpected results, surprise findings, or blind alleys can delay or prevent FDA approval. Before permission to market is granted, all such questions must be answered.
Amylin Pharmaceuticals has reported some unexpected results. Two six-month European/Canadian studies yielded, for the highest dosages, less than the hypothesized drug effect, thus failing the exam. (Other dosages showed positive effects.) The company must now reexamine its testing strategy in light of the new findings. As a recent news release stated: "The company plans to reassess its regulatory timelines for pramlintide...." It is hoped FDA filing requirements will be completed by the middle of year 2000.
Much work is still underway to determine amylin's exact role in helping to treat diabetes. If pramlintide can be successfully retested, if the company can answer the questions its high-dosage results exposed, if it can locate sufficient funding to weather the storm, we may see approval by the FDA. If not, it will go into the books as one more idea that didn't quite make it. For the sake of all diabetics, I hope we see this one happen.
For further information visit Amylin Pharmaceuticals' Web site: <http://www.amylin.com>.
See American Association of Diabetes Educators conference tapes for 1998 (AADE 25th Annual Meeting and Educational Program) #S23, "Amylin, the Other Beta Cell Hormone," by Davida Kruger, MSN, RN CS, CDE, and Patricia Gatcomb, BSN, RN, CDE, and #T15, "Amylin, the Clinical Impact of Restoring Both Beta Cell Hormones, Insulin and Amylin," by Davida Kruger. Get these tapes and others from the 1998 AADE meeting by calling Landes Slezak Group at (800) 776-5454. Tapes cost $11 each. **********