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Ed Bryant
Amylin Analog (Pramlintide) Studies
Reveal Better Glycemic Control
by Ed Bryant
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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.
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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:
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* 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.
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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>.
Resources:
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.
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