Amylin Analog (Pramlintide)

Amylin Analog (Pramlintide)

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.