ADA: Topiramate
Relieves Peripheral Neuropathy, Improves Metabolic
Syndromes and Causes Weight Loss
Dr. Aaron I. Vinik, reported at the American Diabetes
Association 63rd Annual Scientific Sessions, that
a pharmacologic intervention may effectively target
the underlying abnormalities that lead to the development
of type 2 diabetes.
In a small pilot study, the anticonvulsant topiramate
appeared to induce the growth of new nerve fibers
and relieve symptoms of peripheral neuropathy while
also improving components of metabolic syndrome,
reported Aaron I. Vinik, MD, PhD, director of the
Strelitz Diabetes Research Institutes at Eastern
Virginia Medical School in Norfolk.
"Topiramate improves both symptoms and objective
measurements of peripheral neuropathy while also
lowering levels of total cholesterol, blood glucose,
and blood pressure and promoting significant weight
loss," bottom line, he stated that "this
has given us the first opportunity to change the
underlying biology of the disease as opposed to
treating its symptoms."
The There's still a long way to go, Dr. Vinik stressed,
noting that he has so far only studied 11 patients
in an open-label trial. "But all the patients
in the study improved, so even though the numbers
are small, the findings are powerful," he said.
In a previous trial, Dr. Vinik's team found that
topiramate appeared to relieve both symptoms and
electrophysiological measures of peripheral neuropathy.
But what was even more striking, he said, is that
all the patients unexpectedly lost weight and experienced
a drop in cholesterol, triglyceride, and blood pressure
levels.
"There was something much more interesting
happening to these patients than relief of pain,"
he said. "It seemed like topiramate would possibly
address both insulin resistance and changes in function."
Reporting his study results at the American Diabetes
Association 63rd Scientific Sessions, Dr. Vinik
said that he undertook a hypothesis-seeking trial
in 11 patients with type 2 diabetes (average age,
59 years). All of the patients suffered from C-fiber
neuropathy, as diagnosed by total neuropathy scores,
nerve symptom scores, and quantitative sensory tests.
Intra-epidermal nerve fiber density was determined
by immunohistochemical staining. All of the patients
were stabilized using standard antidiabetes therapy
and weaned off pain medication.
Because previous trials had shown that high starting
doses of topiramate can be toxic, the patients were
administered 25 mg/day, titrated over 42 days to
the maximum tolerated dose or 100 mg/day. The patients
received the anticonvulsant for 84 more days. By
the end of trial, dendrite length and peroneal nerve
amplitude had increased, and total neuropathy scores
had decreased from 14 to 11.8, Dr. Vinik reported.
More important, "intra-epidermal nerve fibers
actually grew back," he said. "That was
the most dramatic observation."
In addition, total cholesterol dropped by about
10% and diastolic blood pressure decreased by 10
mm Hg, "more than you can expect with an [angiotensin-converting
enzyme] inhibitor," Dr. Vinik said. Median
hemoglobin A1c levels decreased by 0.75% to 7.1%.
Because there was no significant change in body
mass index from baseline, Dr. Vinik said that the
improvements in glucose appear to be independent
of the body weight changes observed in animal studies.
Dr. Vinik agrees that longer and larger trials are
needed. He said he plans to proceed with a double-blind
randomized trial after testing topiramate on 10
more patients in the open-label design to "make
sure we didn't just get lucky."
In a separate international trial presented at the
meeting, topiramate was shown to help patients who
had lost weight to keep the pounds off. For the
study, 300 diabetic patients who had lost weight
while on a low-calorie diet were randomized to 96
mg/day or 192 mg/day of topiramate or placebo. At
44-week follow-up, patients receiving topiramate
had lost 15% to 16% of their body weight compared
with 9% for those receiving placebo. Also, 72% to
75% of those receiving topiramate maintained their
weight loss compared with 30% in the placebo group.
Dr. Vinik, who was not involved with the trial,
pointed out that the weight loss seen with topiramate
is as good as, if not better than, that of other
weight loss drugs, and it persists without recidivism
for at least two years.
"Basically, this is the first time that anyone
has seen a reduction in weight that persists for
16 months to 18 months in diabetic patients and
the first time that any drug in addition to a low-calorie
diet results in long-term weight reduction. I'm
very impressed," Dr. Vinik said.
But, he added, the trial had to be halted prematurely
due to drug-related adverse effects, including parathesia
in 59% of patients, fatigue in 24%, and dizziness
in 20%. "Now the findings have to be revisited
with a lower dose of topiramate," Dr. Vinik
said.
Researchers of both studies acknowledged a relationship
with Johnson & Johnson, manufacturer of topiramate.
ADA 63rd Scientific Sessions: Abstract 66, presented
June 13, 2003; poster 1702, presented June 14, 2003.
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