NEW YORK–Incretin-based diabetes medications may not be as harmful to the pancreas as previously feared.
Emerging clinical data, combined with concerns about the accuracy of polyclonal GLP-1 receptor antibody staining, suggest that there may be little to no risk for either treatment-related pancreatitis or pancreatic cancer in patients with diabetes, Dr. Vanita R. Aroda said at the annual advanced postgraduate course held by the American Diabetes Association.
“No study has definitely concluded that there is a causal link, and but we should still keep the risk as something to at least be aware of,” said Dr. Aroda of the MedStar Research Institute, Hyattsville, Md. “Until we have more information, patients who have pancreatic risk factors probably shouldn’t receive the drugs.”
A number of confounders cast doubt on past studies showing a pathologic association between incretins and pancreatic adverse events. Although there are suggestive clinical data, preclinical data based on GLP-1 receptor staining is unreliable, because the polyclonal antibodies generally used don’t consistently stain GLP-1 transfected cells.
“In nontransfected cells, you would expect to see no uptake, but with two of the antibodies, you see quite a bit of uptake in nontransfected as well as transfected cells.”
A third polyclonal antibody has difficulty showing uptake in either type of cell. Only one, the monoclonal 3F52 antibody released in 2013, seems to reliably differentiate GLP1 receptors in these models.
In Dr. Aroda’s opinion, the more reliable results from the monoclonal antibody cast much doubt on all previous preclinical studies that used the polyclonal antibodies.
Nonrandomized data based on case reporting also add to the uncertainty, she said. Data in the Food and Drug Administration’s adverse events reporting system have shown a five- to six-time increased risk of incretin-associated pancreatitis and pancreatic cancer, but “even the FDA has said that spontaneous reports cannot be used to determine the true incidence rates of drug adverse events.” Issues of underreporting, lack of established background rates, and inadequate documentation of clinical details (comorbidities, concomitant medications, and medication errors) cloud the picture. Clarity will remain uncertain as long as decisions about safety are made based on such data.
Similar problems plague studies of discharge data, reflected in the fact that many of them have come to conflicting determinations. The most recent data, however, come from a meta-analysis comprising more than 1.3 million patients among nine insurance claims databases in North America and the European Union. The analysis found no increased risk of acute pancreatitis and any incretin-based therapy (Diabetes Obes. Metab. 2015;17:32-41).
Another recent meta-analysis showed that the adjusted risk of acute pancreatitis was not increased among Danes who had been treated with an incretin drug (Diabetes Care 2015 [doi:10.2337/dc13-2983])
A 2013 study of brain-dead organ donors did find a 40% increased pancreatic mass in diabetes patients treated with incretin therapy, compared to those who didn’t get it and to control patients. Treated patients also over-expressed both exocrine cell proliferation and pancreatic intraepithelial neoplasia (Diabetes 2013;62:2595-604).
“This study has been analyzed and reanalyzed,” Dr. Aroda said. “But it’s really comparing apples to oranges. Five patients with diabetes weren’t on any medication; four were on insulin and four on metformin only; and seven were on two or more agents. Age ranged from 40 to 58 years, and we know age is a big risk factor here.”
Dr. Aroda also examined individual drugs in her own extensive patient database. She found no differences in pancreatitis or cancer associated with liraglutide, exenatide, lixisenatide, or sitagliptin.
The European Medicines Agency is conducting a large evaluation of cardiovascular, cerebrovascular, renal and pancreatic events among diabetes patients taking noninsulin glucose-lowering agents.(SAFEGUARD). It will include combined data covering more than 240 million patient/years.
The National Institutes of Health is also looking at the issue with a consortium study of chronic pancreatitis and pancreatic cancer in diabetes patients.
These projects should result in a considerable amount of reliable data on the issue, Dr. Aroda said.
In the meantime, neither the American Diabetes Association, the Endocrine Society or any European agencies have changed their treatment guidelines with regard to incretin-based therapies.
Dr. Aroda had no financial disclosures.
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