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Possible Cancer Link to Diabetes Drugs Stirs Controversy


 

FROM THE ANNUAL MEETING OF THE EUROPEAN ASSOCIATION FOR THE STUDY OF DIABETES

LISBON – The possibility that incretin-based therapies for type 2 diabetes can cause cancer warrants further investigation, a leading clinical diabetologist has said.

"Pancreatitis and pancreatic cancer are reported in excess with exenatide and sitagliptin therapy in the FDA AERS [Food and Drug Administration’s Adverse Events Reporting System database] in comparison to other diabetes medications," Dr. Peter Butler said at the annual meeting of the European Association for the Study of Diabetes.

Dr. Peter Butler

Using the database, Dr. Butler and his associates recently found that treatment with exenatide (Byetta) and sitagliptin (Januvia) significantly increased the risk of pancreatitis more than sixfold, with odds ratios (ORs) of 10.7 and 6.7, respectively, compared with four control drugs – rosiglitazone (Avandia), nateglinide (Starlix), repaglinide (Prandin), and glipizide (Glucotrol) – (P less than 10-16 for both comparisons) (Gastroenterology 2011;141:150-6). These data are somewhat alarming, as many experts now believe that pancreatitis may be a precursor to malignancy.

Furthermore, the risk of pancreatic cancer was more than doubled, compared with control treatments, with statistically significant odds ratios of 2.9 (P = 9 x 10-5) for exenatide and 2.7 for sitagliptin (P = .008). Thyroid cancer risk was also significantly elevated by exenatide, with an odds ratio of 4.7, (P = 4 x 10-16), but not by sitagliptin (OR = 1.5, P = .65).

The risk of other cancers did not seem to be elevated by the incretin-based therapies. Exenatide, a glucagon-like peptide–1 (GLP-1) receptor agonist, stimulates insulin secretion when glucose levels are high; sitagliptin, a dipeptidyl peptidase–4 (DPP-4) inhibitor, acts to lower glucose levels by prolonging the activity of GLP-1.

Dr. Butler, professor of medicine and chief of the division of endocrinology, diabetes, and hypertension at the University of California, Los Angeles, noted that there is also evidence that GLP-1–based therapy induces proliferative changes in the pancreatic ducts of rodents. GLP-1 receptors are also expressed in a very high percentage of premalignant and malignant pancreatic lesions in humans.

While he admitted that he would be happy to be proved wrong, Dr. Butler stated during a debate on GLP-1–based treatment and cancer that the association must be thoroughly investigated, as it was important to ensure the overall safety of patients using these drugs.

"For now, this analysis of the FDA database does not establish that pancreatitis, [and] pancreatic and thyroid cancer are caused by GLP-1–based therapy," Dr. Butler said, citing the concluding sentences of the recently published paper. "It simply raises the level of concern that they may be and that the appropriate prospective studies are required to rule them out."

Clinical Trials May Not Be Feasible

It might not be possible to conduct such studies because of the sheer number of patients that would need to be involved, suggested Dr. Michael Nuack of the Diabetes Center, Bad Lauterberg, Germany.

Dr. Michael Nuack

"In the case of pancreatitis ... we have around 5 cases per 1,000 patient years," Dr. Nuack observed. "If you want to exclude a rise in risk by 25% you would need to do a study with 80,000 patients per arm, and I think we are all pretty sure that this will never be tested in a prospective, randomized trial."

According to Dr. Nuack, there is not enough strong evidence for or against the notion that GLP-1–based therapy can cause cancer, and using the FDA AERS database to investigate any associated risk is significantly flawed for several reasons.

Severe adverse events are more likely to be reported than are less-severe events, he suggested, and newer drugs may receive more attention than older, more established medications. Overreporting could also occur because of rumors of a cancer link, and diagnoses may not be accurate or recorded in the same way by physicians.

More importantly, the FDA AERS review included years when exenatide and sitagliptin were not available and excluded data from 2010, when more adverse events associated with the two drugs would have been available.

"Talking about cancer and malignant disease in general, based on this analysis, some forms of cancer or malignant disease are reduced," Dr. Nuack observed. For exenatide this included reduced cases of lung cancer, prostate cancer, sarcoma, lymphoma, and multiple myeloma. For sitagliptin it included colon cancer and prostate cancer.

Change in Practice Not Necessary

There is no need to change current practice, Dr. Nuack advised. "I think we can say today that there is not a single case report of pancreatic cancer in patients treated with DPP-4 inhibitors or GLP-1 receptor agonists."

Dr. Ulf Smith

Reading a statement from the European Association for the Study of Diabetes on the matter, the society’s past president, Dr. Ulf Smith, agreed that for now, no changes to treatment should be made.

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