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                         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 



	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 

	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.