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.
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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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