AMYLIN ANALOG (PRAMLINTIDE) STUDIES
REVEAL BETTER GLYCEMIC CONTROL

by Ed Bryant

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, PhD, 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 consecrated. 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 37 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:

• 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, controlling pancreatic glucagon secretion, which in turn regulates hepatic (liver) glucose production. (It is believed that a deficiency of Amylin contributes to excessive post-meal glucose elevation.) 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, the A1c results of those who used the injectable Amylin analog were significantly lower than those who did not. NOTE: 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. Although the "ideal" HbA1c reading is 7.0% or less, any reduction in Hemoglobin A1c helps reduce the risk of complications.

• 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, I find it is exciting, as 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" (as defined by the CDC, multiple tests and multiple insulin injections, to keep the blood glucose test numbers down in the non-diabetic "normal" or "euglycemic" range), 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. What this suggests is 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 is 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 their 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, MSN, RN, CS, CDE, a diabetes researcher, delivered a paper titled "Amylin: The Clinical Impact of Restoring Both Beta Cell Hormones Insulin and Amylin" at the 25th annual convention of the American Association of Diabetes Educators, held August 19-23, 1998, in Minneapolis, Minnesota. In her presentation she stated: "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. (Note: Some diabetics have gastroparesis, delayed gastric emptying.) Although the effect of pramlintide in the presence of this complication has not been yet studied, the company plans to do so before the drug is marketed.

Because natural Amylin is too viscous (thick) to inject, Amylin Pharmaceuticals developed its synthetic analog, pramlintide. Pramlintide is injected subcutaneously, with 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 they first market pramlintide.

Interestingly, 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 consensus was 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 their product for years, and is currently engaged in phase 3 clinicals in several locations. As of March, 1999, over 1700 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 the placebo, 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%, as measured by the HbA1c blood test, may reduce risk of complications by 50%-80%," says Dr. Frank Vinicor, director of the CDC's Division of Diabetes Translation, quoted in the same document.

The process of winning approval for a new medication, permission to market it to consumers, from the Food and Drug Administration (FDA), is long, expensive, and complex. To pass, 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, in effect "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 time lines 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 they 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' website: http://www.amylin.com

Resources:

See American Association of Diabetes Educators conference tapes for 1998 (AADE "25th annual meeting and educational program") Numbers #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" #T15, by Davida Kruger, MSN, RN, CS, CDE. Get these tapes and others from the 1998 AADE meeting by calling Landes Slezak Group at 1-800-776-5454. Tapes cost $11 each.

SIDEBAR

The December 1997 issue of "Practical Diabetology" carried an article titled "A New Look at Glucose Control: The Case for Therapy with Insulin and an Amylin Analog," by Steven V. Edelman, MD, and Davida F. Kruger, MSN, RN, CS, CDE. The text contained a very useful definition of type 1 and type 2 diabetes:

Although type 1 and type 2 diabetes have strikingly different pathophysiologies, the final manifestations of the disease are similar: insulin secretory defects and hyperglycemia. In type 1 diabetes, autoimmune destruction of the pancreatic beta cells virtually eliminates insulin production. In contrast, people with type 2 diabetes develop beta-cell exhaustion due to chronic overstimulation of insulin production by the pancreas in response to increasing insulin resistance. The final result of both pathophysiologic processes is that the plasma glucose profiles of these two forms of diabetes are similar, typified by elevated fasting and excessive postprandial glucose concentrations.