Diabetes Drugs Affect Hearts of Men, Women Differently
Diabetes Drugs Affect Hearts of Men, Women Differently
Dec. 12, 2013 — Widely used treatments for type 2 diabetes
have different effects on the hearts of men and women, even as the drugs control blood sugar
equally well in both sexes, according to researchers at Washington
University School of Medicine in St. Louis.
In particular, the commonly prescribed diabetes drug metformin had positive effects
on heart function in women but not in men, who experienced a shift in
metabolism thought to increase the risk of heart failure.
"We saw dramatic sex differences in how the heart
responds to the different therapies," said senior author Robert J.
Gropler, MD, professor of radiology. "Our study suggests that we need to
better define which therapies are optimal for women with diabetes and which
ones are optimal for men."
The study appears in the December issue of the American
Journal of Physiology -- Heart and Circulatory Physiology.
To the researchers' knowledge, this is the first study to
investigate sex differences in the heart's response to diabetes treatments. In
type 2 diabetes, the pancreas continues to make insulin, but the body can't use
it effectively to move glucose out of the blood and into the tissues. And for
reasons that are not entirely clear, patients with diabetes are at higher risk for heart failure.
"It is imperative that we gain understanding of
diabetes medications and their impact on the heart in order to design optimal
treatment regimens for patients," said Janet B. McGill, MD, professor of
medicine and a study co-author who sees patients at Barnes-Jewish Hospital.
"This study is a step in that direction."
The investigators evaluated commonly prescribed diabetes
drugs in 78 patients, who were assigned to one of three groups. Under McGill's
supervision, the first group received
metformin alone; the second received metformin plus rosiglitazone (Avandia); and the
third received metformin
plus Lovaza, which is a kind of fish oil.
Metformin reduces
glucose production by the liver and helps the body become more sensitive to
insulin. Rosiglitazone
also improves insulin sensitivity and is known to move free fatty acids out of the
blood. Lovaza is
prescribed to lower blood levels of triglycerides, another type of fat.
Importantly, Gropler noted that when they compared the three
groups without separating men and women, no differences in heart metabolism
were seen. But when the patients were separated by sex, the drugs had very
different and sometimes opposite
effects on heart metabolism, even as blood sugar remained
well-controlled in all patients.
"The most dramatic difference between men and women is
with metformin alone," said Gropler, who also sees patients at
Barnes-Jewish Hospital. "Our data show it to have a favorable effect on
cardiac metabolism in women and an unfavorable one in men."
The research suggests that these divergent responses in men
and women may provide at least a partial explanation for the conflicting data
surrounding some diabetes drugs. Specifically, the proportion of men and women
participating in a clinical trial may play an unappreciated role in whether
drugs are found to be safe and effective.
There is particular controversy surrounding rosiglitazone. In 2010, the U.S. Food
and Drug Administration (FDA) restricted rosiglitazone's use because of questions about
cardiovascular safety. Based on a recent review of data, the FDA reversed its
2010 decision last month, lifting the restrictions.
In the current study, metformin caused the heart metabolism of men to move in
an undesirable direction -- burning less sugar and more fats. Chronic
burning of fat by the heart, according to Gropler, leads to detrimental changes
in the heart muscle, which can lead to heart failure.
"Instead of making heart metabolism more normal in men,
metformin alone made it worse, looking even more like a diabetic heart,"
Gropler said. "But in women, metformin had the desired effect -- lowering
fat metabolism and increasing glucose uptake by the heart."
Taking either rosiglitazone or Lovaza with metformin seemed
to mitigate some of the
negative heart effects of metformin alone in men. But women, already
benefiting from metformin, improved
heart metabolism further by adding rosiglitazone, with the desired
effect of reducing the heart's dependence on fat metabolism. Adding Lovaza did not have a
strong effect in either direction for men or women.
Gropler pointed out that he and his colleagues have shown in
previous work that even healthy men and women show differences in how their
hearts burn fuel. Healthy male hearts tend to burn more glucose, while in
women, healthy hearts tend to burn more fats. This difference may help explain
why women with diabetes tend to get more aggressive heart failure than men:
Women already burn more fats.
"We now know there are sex differences at baseline,
both in the metabolism of healthy hearts and in the hearts of patients with
diabetes," Gropler said. "We are adding the message that these sex
differences persist in how patients respond to drugs. For patients with
diabetes, we are going to have to be more attentive to sex differences when we
design therapies."
Further complicating matters, the researchers also noted
that the differences they observed in heart metabolism can't be measured with
conventional blood tests.
Unlike many heart studies that rely on blood sugar and
cholesterol tests that anyone might get at a doctor visit, the Washington
University researchers used positron emission tomography (PET) scans to image
the heart and measure blood flow, oxygen consumption and fatty acid and glucose
uptake by the heart, among other measures. They also took echocardiograms in
conjunction with the PET scans and used stable isotopes to monitor whole-body
metabolism and how this influences the heart.
Although the trial was relatively small in terms of the
number of patients, it was unusually rigorous in the methods used to analyze
heart metabolism, according to Gropler. He noted that only a handful of medical
centers worldwide have the resources to perform such a study.
"If you use standard measurements, you're going to miss
the sex differences we observed," Gropler said. "This may mean we have to do more complex imaging
of the heart to better understand which therapies are best for which patients."
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