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Research suggests
popular diabetes drugs can cause abnormal pancreatic growth in humans
March 26, 2013 Category: Health Sciences, Research
Individuals who had taken a type of drug commonly used to treat
Type 2 diabetes showed abnormalities in the pancreas, including cell
proliferation, that may be associated with an increased risk of neuroendocrine
tumors, according to a new study by researchers from UCLA and the University of
Florida. Their findings were published online March
22 in the journal Diabetes.
The researchers, from the Larry L. Hillblom Islet Research
Center at UCLA and the Diabetes Center at the University of Florida, found that
cell mass was increased approximately 40 percent in the pancreases of deceased
organ donors who had Type 2 diabetes and who had been treated with incretin
therapy. This widely used type of treatment takes advantage of the action
of a gut hormone known as glucagon-like peptide 1 (GLP-1) to lower blood sugar
in the body.
Although there have been conflicting reports on the effects of
the incretin class of drugs on the pancreas in animal studies, this is the
first study to note such changes in the human pancreas. The research was made
possible by a unique research consortium called nPOD
(Network for Pancreatic Organ Donors with Diabetes), led by Dr. Mark Atkinson,
a professor of pathology and pediatrics at the University of Florida. The
network, which is funded by the Juvenile Diabetes Research Foundation, obtains
pancreases from deceased organ donors, with permission of their next of kin, to
better understand diabetes by investigating tissues of those with the disease.
"There is an increasing appreciation that animal studies do
not always predict findings in humans," said Dr. Peter Butler, director of
UCLA's Hillblom Islet Research Center and chief of the endocrinology, diabetes
and hypertension unit. "The nPOD program is therefore a very precious
resource."
The researchers examined the pancreases of 20 deceased organ
donors with Type 2 diabetes. Eight had been treated for at least a year with
incretin therapy, while the other 12 had received therapies that didn't include
incretin-based drugs. The researchers also evaluated 14 pancreases from a
control group of non-diabetic individuals of similar age.
The pancreases of the individuals who had been on incretin
therapy were larger than those of patients on other types of diabetes
therapies, and this larger size was associated with increased cellular
proliferation. Incretin-treated individuals showed an increase in pancreas
dysplasia, an abnormal form of cell proliferation that is a risk factor for pancreatic cancer, as well as an
expansion of alpha cells, endocrine cells that make the hormone glucagon.
This latter finding is likely a consequence of GLP-1–based
therapies' suppression of the release of glucagon by alpha cells, since
decreasing the availability or action of the hormone glucagon has been shown in
a variety of prior studies to induce a proliferation of pancreatic alpha cells.
This alpha-cell expansion has been associated with the development of
pancreatic neuroendocrine tumors. Three of the eight incretin-treated
individuals had microadenomas and one has a neuroendocrine tumor composed of
alpha cells.
Of the eight donors who were on incretin therapy, seven had been
taking sitagliptin, sold in pill form as Januvia and marketed by Merck, and one
had been on exenatide, sold as Byetta by Bristol-Myers Squibb. These and
similar drugs are currently under investigation by the U.S. Food and Drug
Administration for their possible links to pancreatitis and pancreatic cancer.
"These findings lend additional weight to concerns
regarding the effects of long term GLP-1–related therapy, with respect to both
unintended proliferative actions on the exocrine pancreas and now also a
possible increased risk of neuroendocrine tumors," the researchers write.
"In addition to the surveillance previously recommended for the potential
association of GLP-1– based therapy and pancreatic cancer risk, the current
data imply that surveillance for a possible increased risk of pancreatic neuroendocrine tumors is
warranted."
Such surveillance approaches might include MRI imaging of the
pancreas and screening for neuroendocrine tumors, Butler said.
"The present studies are only from a small number of
individuals, and while the findings do raise concerns, it will be important
that other approaches are now used in a larger group of living individuals to
further investigate these findings," he said.
A recent study led by Dr. Sonal Singh of Johns Hopkins
University School of Medicine and Public Health and published in JAMA Internal
Medicine suggested a doubling in the risk of hospitalization for acute
pancreatitis with the GLP-1–based therapies and also recommended further
research.
"Since most risk factors for acute pancreatitis are
also linked to an increased risk of pancreatic cancer, these findings
of changes in the human pancreas are very concerning," said Singh, an
assistant professor of medicine and international health. "Now that
GLP-1–based therapies have been shown to increase the risk of
pancreatic inflammation and abnormal cell proliferation, further studies are
needed to urgently clarify whether these linkages lead to pancreatic
cancer with long-term use."
Study co-authors, in addition to Butler and Atkinson, are Alexandra
E. Butler, Tatyana Gurlo and David W. Dawson, all of UCLA, and Martha
Campbell-Thompson of the University of Florida.
Grants from National Institute of Diabetes and Digestive and
Kidney Diseases (DK059579, DK061539 and DK077967), the Hillblom Foundation, and
the Peter and Valerie Kompaniez Foundation funded this study. The Juvenile
Diabetes Research Foundation funds the nPOD program.
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