Exenatide, sitagliptin associated with doubled risk for acute pancreatitis

Patients with diabetes who take either sitagliptin or exenatide were twice as likely to experience acute pancreatitis as those who did not take the GLP-1 inhibitors, a large database review has determined.

The authors made no recommendations about using the drugs, instead saying that the findings call for confirmation by more rigorous studies.

"Further studies using new user designs should clarify the exact timing of these risks and determine whether susceptible subgroups, such as those with genetic mutations, or pancreatitis risks, such as obesity, may be at the highest risk," Dr. Sonal Singh and his colleagues wrote in the Feb. 25 online issue of JAMA Internal Medicine (formerly Archives of Internal Medicine) (doi: 10.1001/jamainternmed.2013.2720).

But the American Association of Clinical Endocrinologists (AACE), the American Diabetes Association, and the Endocrine Society are criticizing the study, saying that the risk of pancreatitis over a large population is very low, and that for most patients, the drugs’ benefits far outweigh that risk.

"This story is very simple," said Dr. Yehuda Handelsman, speaking for AACE. "Since day 1, we have been telling physicians there could be a bit of increase in the risk of pancreatitis with the drugs. But the risk is so minimal that we don’t believe anyone should change their practice based on this study."

The review included 1,269 controls and 1,269 patients who used the drugs and were hospitalized for acute pancreatitis during 2005-2008. Study subjects had a mean age of 52 years. Several comorbidities were significantly more common among the case patients than among controls, including elevated triglycerides (13% vs. 8%), alcohol use (3.2% vs. 0.2%), gallstones (9% vs. 1%), tobacco abuse (16% vs. 6%), obesity (20% vs. 10%), biliary and pancreatic cancer (3% vs. 0%), cystic fibrosis (1% vs. 0%), and any neoplasm (30% vs. 18%).

Photo courtesy of Dr. Yehuda Handelsman

Dr. Singh of Johns Hopkins University, Baltimore, and his associates controlled for all of these factors by using a multifactorial analysis, as well as an indicator of general morbidity level developed by the university.

After adjustment for these confounders and for metformin use, patients who had taking either sitagliptin or exenatide in the past 30 days were more than twice as likely to have experienced acute pancreatitis (odds ratio, 2.24). Those who had taken the drugs within the past 30 days to 2 years were twice as likely to have had the illness (OR, 2). Any use of the drugs – which included both 30-day and recent use – was associated with a doubling of the risk (OR, 2.1).

A sensitivity analysis excluded nine case-control pairs who were exposed to a combination of metformin and sitagliptin. After adjustment for the confounders, this subanalysis agreed with the primary findings. Current use of either drug within 30 days was associated with a doubled risk (OR, 2) as was recent use (OR, 1.95), and any use (OR, 2).

The study did not indicate the total number of patients in the database who were taking the drugs and who developed pancreatitis. This skewed the findings, said Dr. Handelsman, because it misrepresented the actual frequency of the illness in this group, which he said was very, very low. In an e-mail, Dr. Singh said, "Those numbers are not available in a case-control study."

And even though the study controlled for the significant baseline differences between the two groups, these also tainted the conclusions, said Dr. Handelsman, who is also the principal investigator at the Metabolic Institute of America in Tarzana, Calif. "Patients who are obese, who drink a lot and smoke a lot, who have gallstones – they are all more likely to get pancreatitis. We tell doctors, if you’re going to give the drugs to these patients, just watch them more carefully."

In a joint statement, AACE and ADA voiced concern that patients could stop taking their prescribed treatments. "We encourage patients to speak with their doctors to assess which treatments are best for them and not to stop therapy on their own without consulting their doctors."

A link between glucagonlike peptide–1(GLP-1) inhibitors and pancreatitis has never been firmly established. But, according to a recent review, questions remain – many centering around safety reviews performed by pharmaceutical companies, which were based on their own prospective studies (Gastroenterology 2011;141:20-3).

Animal studies have suggested a physiological link, wrote Dr. Joachim Spranger of the German Medical Association. "Exocrine pancreatic cells express the GLP-1 receptor [GLP-1R], and administering GLP-1 has biological effects on these cells. In animal experiments (Diabetes 2009;58:2148-61), 1 week of GLP-1R activation with liraglutide or exenatide increased pancreatic weight and changed pancreatitis-associated gene expression, although the DPP-4 [dipeptidyl peptidase–4] inhibitor sitagliptin had no such effects. Theoretically, the increased pancreatic weight may reflect edema or similar changes, although the underlying cause of the weight increase was not further analyzed and histopathology results were not reported."

Any pancreatic effect of the drugs could be directly related to the beneficial physiological changes they induce in the pancreas, Dr. Spranger wrote. GLP-1 agonists increase beta-cell mass in rodents, by enhancing beta-cell proliferation, inhibiting apoptosis, and enhancing stem cell differentiation in the ductal pancreatic epithelium.

"Although beta-cell proliferation may be beneficial with regard to progression of type 2 diabetes, similar trophic mechanisms in other cell types might be detrimental. Thus, the epidermal growth factor receptor system and the Src kinase have been implicated in the pathogenesis and progression of numerous malignant tumors, including pancreatic cancer; mechanisms increasing the activity of these pathways could promote tumor development or progression."

The observations raise safety concerns which should be heeded until proven unfounded, Dr. Spranger wrote.

More detailed data about the link between incretin-based therapies and pancreatitis should be forthcoming, as long-term prospective studies continue to collect a wide range of safety information.

"There are at least nine prospective trials looking at cardiovascular outcomes which are capturing a lot of other outcomes data as well – including pancreatitis," Dr. Handelsman said. "In a few years we might be able to identify the true risk. But a scare based on an observational study from one insurance database, from years ago, is not enough to change practice."

The Endocrine Society’s response to Dr. Singh’s study echoed that of AACE and ADA, and added that "an important but unanswered question is whether or not the morbidity and mortality from incretin-associated pancreatitis is the same as that of other causes of pancreatitis," in particular whether such cases would lead to an increased incidence of pancreatic cancer similar to that seen in some other causes of acute pancreatitis. The statement suggested that some of the ongoing trials "may also help elucidate the conflict between Singh’s finding of increased incidence of acute pancreatitis with these drugs and the four recent retrospective database analyses and 1 meta-analysis cited in Singh’s paper which found no such association."

Dr. Singh’s study was sponsored by Johns Hopkins University and the National Institutes of Health. He had no financial disclosures. Dr. Handelsman has been a consultant to numerous drug companies developing diabetes treatments. Dr. Spranger has lectured for or received consultant honoraria from Eli Lilly and NovoNordisk.

michele.sullivan@elsevier.com

Patients with diabetes who take either sitagliptin or exenatide were twice as likely to experience acute pancreatitis as those who did not take the GLP-1 inhibitors, a large database review has determined.

The authors made no recommendations about using the drugs, instead saying that the findings call for confirmation by more rigorous studies.

"Further studies using new user designs should clarify the exact timing of these risks and determine whether susceptible subgroups, such as those with genetic mutations, or pancreatitis risks, such as obesity, may be at the highest risk," Dr. Sonal Singh and his colleagues wrote in the Feb. 25 online issue of JAMA Internal Medicine (formerly Archives of Internal Medicine) (doi: 10.1001/jamainternmed.2013.2720).

But the American Association of Clinical Endocrinologists (AACE), the American Diabetes Association, and the Endocrine Society are criticizing the study, saying that the risk of pancreatitis over a large population is very low, and that for most patients, the drugs’ benefits far outweigh that risk.

"This story is very simple," said Dr. Yehuda Handelsman, speaking for AACE. "Since day 1, we have been telling physicians there could be a bit of increase in the risk of pancreatitis with the drugs. But the risk is so minimal that we don’t believe anyone should change their practice based on this study."

The review included 1,269 controls and 1,269 patients who used the drugs and were hospitalized for acute pancreatitis during 2005-2008. Study subjects had a mean age of 52 years. Several comorbidities were significantly more common among the case patients than among controls, including elevated triglycerides (13% vs. 8%), alcohol use (3.2% vs. 0.2%), gallstones (9% vs. 1%), tobacco abuse (16% vs. 6%), obesity (20% vs. 10%), biliary and pancreatic cancer (3% vs. 0%), cystic fibrosis (1% vs. 0%), and any neoplasm (30% vs. 18%).

Photo courtesy of Dr. Yehuda Handelsman

Dr. Singh of Johns Hopkins University, Baltimore, and his associates controlled for all of these factors by using a multifactorial analysis, as well as an indicator of general morbidity level developed by the university.

After adjustment for these confounders and for metformin use, patients who had taking either sitagliptin or exenatide in the past 30 days were more than twice as likely to have experienced acute pancreatitis (odds ratio, 2.24). Those who had taken the drugs within the past 30 days to 2 years were twice as likely to have had the illness (OR, 2). Any use of the drugs – which included both 30-day and recent use – was associated with a doubling of the risk (OR, 2.1).

A sensitivity analysis excluded nine case-control pairs who were exposed to a combination of metformin and sitagliptin. After adjustment for the confounders, this subanalysis agreed with the primary findings. Current use of either drug within 30 days was associated with a doubled risk (OR, 2) as was recent use (OR, 1.95), and any use (OR, 2).

The study did not indicate the total number of patients in the database who were taking the drugs and who developed pancreatitis. This skewed the findings, said Dr. Handelsman, because it misrepresented the actual frequency of the illness in this group, which he said was very, very low. In an e-mail, Dr. Singh said, "Those numbers are not available in a case-control study."

And even though the study controlled for the significant baseline differences between the two groups, these also tainted the conclusions, said Dr. Handelsman, who is also the principal investigator at the Metabolic Institute of America in Tarzana, Calif. "Patients who are obese, who drink a lot and smoke a lot, who have gallstones – they are all more likely to get pancreatitis. We tell doctors, if you’re going to give the drugs to these patients, just watch them more carefully."

In a joint statement, AACE and ADA voiced concern that patients could stop taking their prescribed treatments. "We encourage patients to speak with their doctors to assess which treatments are best for them and not to stop therapy on their own without consulting their doctors."

A link between glucagonlike peptide–1(GLP-1) inhibitors and pancreatitis has never been firmly established. But, according to a recent review, questions remain – many centering around safety reviews performed by pharmaceutical companies, which were based on their own prospective studies (Gastroenterology 2011;141:20-3).

Animal studies have suggested a physiological link, wrote Dr. Joachim Spranger of the German Medical Association. "Exocrine pancreatic cells express the GLP-1 receptor [GLP-1R], and administering GLP-1 has biological effects on these cells. In animal experiments (Diabetes 2009;58:2148-61), 1 week of GLP-1R activation with liraglutide or exenatide increased pancreatic weight and changed pancreatitis-associated gene expression, although the DPP-4 [dipeptidyl peptidase–4] inhibitor sitagliptin had no such effects. Theoretically, the increased pancreatic weight may reflect edema or similar changes, although the underlying cause of the weight increase was not further analyzed and histopathology results were not reported."

Any pancreatic effect of the drugs could be directly related to the beneficial physiological changes they induce in the pancreas, Dr. Spranger wrote. GLP-1 agonists increase beta-cell mass in rodents, by enhancing beta-cell proliferation, inhibiting apoptosis, and enhancing stem cell differentiation in the ductal pancreatic epithelium.

"Although beta-cell proliferation may be beneficial with regard to progression of type 2 diabetes, similar trophic mechanisms in other cell types might be detrimental. Thus, the epidermal growth factor receptor system and the Src kinase have been implicated in the pathogenesis and progression of numerous malignant tumors, including pancreatic cancer; mechanisms increasing the activity of these pathways could promote tumor development or progression."

The observations raise safety concerns which should be heeded until proven unfounded, Dr. Spranger wrote.

More detailed data about the link between incretin-based therapies and pancreatitis should be forthcoming, as long-term prospective studies continue to collect a wide range of safety information.

"There are at least nine prospective trials looking at cardiovascular outcomes which are capturing a lot of other outcomes data as well – including pancreatitis," Dr. Handelsman said. "In a few years we might be able to identify the true risk. But a scare based on an observational study from one insurance database, from years ago, is not enough to change practice."

The Endocrine Society’s response to Dr. Singh’s study echoed that of AACE and ADA, and added that "an important but unanswered question is whether or not the morbidity and mortality from incretin-associated pancreatitis is the same as that of other causes of pancreatitis," in particular whether such cases would lead to an increased incidence of pancreatic cancer similar to that seen in some other causes of acute pancreatitis. The statement suggested that some of the ongoing trials "may also help elucidate the conflict between Singh’s finding of increased incidence of acute pancreatitis with these drugs and the four recent retrospective database analyses and 1 meta-analysis cited in Singh’s paper which found no such association."

Dr. Singh’s study was sponsored by Johns Hopkins University and the National Institutes of Health. He had no financial disclosures. Dr. Handelsman has been a consultant to numerous drug companies developing diabetes treatments. Dr. Spranger has lectured for or received consultant honoraria from Eli Lilly and NovoNordisk.

michele.sullivan@elsevier.com

Patients with diabetes who take either sitagliptin or exenatide were twice as likely to experience acute pancreatitis as those who did not take the GLP-1 inhibitors, a large database review has determined.

The authors made no recommendations about using the drugs, instead saying that the findings call for confirmation by more rigorous studies.

"Further studies using new user designs should clarify the exact timing of these risks and determine whether susceptible subgroups, such as those with genetic mutations, or pancreatitis risks, such as obesity, may be at the highest risk," Dr. Sonal Singh and his colleagues wrote in the Feb. 25 online issue of JAMA Internal Medicine (formerly Archives of Internal Medicine) (doi: 10.1001/jamainternmed.2013.2720).

But the American Association of Clinical Endocrinologists (AACE), the American Diabetes Association, and the Endocrine Society are criticizing the study, saying that the risk of pancreatitis over a large population is very low, and that for most patients, the drugs’ benefits far outweigh that risk.

"This story is very simple," said Dr. Yehuda Handelsman, speaking for AACE. "Since day 1, we have been telling physicians there could be a bit of increase in the risk of pancreatitis with the drugs. But the risk is so minimal that we don’t believe anyone should change their practice based on this study."

The review included 1,269 controls and 1,269 patients who used the drugs and were hospitalized for acute pancreatitis during 2005-2008. Study subjects had a mean age of 52 years. Several comorbidities were significantly more common among the case patients than among controls, including elevated triglycerides (13% vs. 8%), alcohol use (3.2% vs. 0.2%), gallstones (9% vs. 1%), tobacco abuse (16% vs. 6%), obesity (20% vs. 10%), biliary and pancreatic cancer (3% vs. 0%), cystic fibrosis (1% vs. 0%), and any neoplasm (30% vs. 18%).

Photo courtesy of Dr. Yehuda Handelsman

Dr. Singh of Johns Hopkins University, Baltimore, and his associates controlled for all of these factors by using a multifactorial analysis, as well as an indicator of general morbidity level developed by the university.

After adjustment for these confounders and for metformin use, patients who had taking either sitagliptin or exenatide in the past 30 days were more than twice as likely to have experienced acute pancreatitis (odds ratio, 2.24). Those who had taken the drugs within the past 30 days to 2 years were twice as likely to have had the illness (OR, 2). Any use of the drugs – which included both 30-day and recent use – was associated with a doubling of the risk (OR, 2.1).

A sensitivity analysis excluded nine case-control pairs who were exposed to a combination of metformin and sitagliptin. After adjustment for the confounders, this subanalysis agreed with the primary findings. Current use of either drug within 30 days was associated with a doubled risk (OR, 2) as was recent use (OR, 1.95), and any use (OR, 2).

The study did not indicate the total number of patients in the database who were taking the drugs and who developed pancreatitis. This skewed the findings, said Dr. Handelsman, because it misrepresented the actual frequency of the illness in this group, which he said was very, very low. In an e-mail, Dr. Singh said, "Those numbers are not available in a case-control study."

And even though the study controlled for the significant baseline differences between the two groups, these also tainted the conclusions, said Dr. Handelsman, who is also the principal investigator at the Metabolic Institute of America in Tarzana, Calif. "Patients who are obese, who drink a lot and smoke a lot, who have gallstones – they are all more likely to get pancreatitis. We tell doctors, if you’re going to give the drugs to these patients, just watch them more carefully."

In a joint statement, AACE and ADA voiced concern that patients could stop taking their prescribed treatments. "We encourage patients to speak with their doctors to assess which treatments are best for them and not to stop therapy on their own without consulting their doctors."

A link between glucagonlike peptide–1(GLP-1) inhibitors and pancreatitis has never been firmly established. But, according to a recent review, questions remain – many centering around safety reviews performed by pharmaceutical companies, which were based on their own prospective studies (Gastroenterology 2011;141:20-3).

Animal studies have suggested a physiological link, wrote Dr. Joachim Spranger of the German Medical Association. "Exocrine pancreatic cells express the GLP-1 receptor [GLP-1R], and administering GLP-1 has biological effects on these cells. In animal experiments (Diabetes 2009;58:2148-61), 1 week of GLP-1R activation with liraglutide or exenatide increased pancreatic weight and changed pancreatitis-associated gene expression, although the DPP-4 [dipeptidyl peptidase–4] inhibitor sitagliptin had no such effects. Theoretically, the increased pancreatic weight may reflect edema or similar changes, although the underlying cause of the weight increase was not further analyzed and histopathology results were not reported."

Any pancreatic effect of the drugs could be directly related to the beneficial physiological changes they induce in the pancreas, Dr. Spranger wrote. GLP-1 agonists increase beta-cell mass in rodents, by enhancing beta-cell proliferation, inhibiting apoptosis, and enhancing stem cell differentiation in the ductal pancreatic epithelium.

"Although beta-cell proliferation may be beneficial with regard to progression of type 2 diabetes, similar trophic mechanisms in other cell types might be detrimental. Thus, the epidermal growth factor receptor system and the Src kinase have been implicated in the pathogenesis and progression of numerous malignant tumors, including pancreatic cancer; mechanisms increasing the activity of these pathways could promote tumor development or progression."

The observations raise safety concerns which should be heeded until proven unfounded, Dr. Spranger wrote.

More detailed data about the link between incretin-based therapies and pancreatitis should be forthcoming, as long-term prospective studies continue to collect a wide range of safety information.

"There are at least nine prospective trials looking at cardiovascular outcomes which are capturing a lot of other outcomes data as well – including pancreatitis," Dr. Handelsman said. "In a few years we might be able to identify the true risk. But a scare based on an observational study from one insurance database, from years ago, is not enough to change practice."

The Endocrine Society’s response to Dr. Singh’s study echoed that of AACE and ADA, and added that "an important but unanswered question is whether or not the morbidity and mortality from incretin-associated pancreatitis is the same as that of other causes of pancreatitis," in particular whether such cases would lead to an increased incidence of pancreatic cancer similar to that seen in some other causes of acute pancreatitis. The statement suggested that some of the ongoing trials "may also help elucidate the conflict between Singh’s finding of increased incidence of acute pancreatitis with these drugs and the four recent retrospective database analyses and 1 meta-analysis cited in Singh’s paper which found no such association."

Dr. Singh’s study was sponsored by Johns Hopkins University and the National Institutes of Health. He had no financial disclosures. Dr. Handelsman has been a consultant to numerous drug companies developing diabetes treatments. Dr. Spranger has lectured for or received consultant honoraria from Eli Lilly and NovoNordisk.

michele.sullivan@elsevier.com