QuarterWatch is an ISMP surveillance program that monitors serious, disabling, and fatal adverse drug events (ADEs) reported to the US Food and Drug Administration (FDA) by manufacturers, health professionals, and the public. The goal of QuarterWatch is to improve patient safety through the identification of signals that may represent important drug safety issues. The term signal means evidence judged to be substantial enough to warrant publication but which usually requires further investigation to determine its frequency of occurrence and establish a causal relationship to the suspect drug. The latest QuarterWatch focuses on five widely prescribed glucagon-like peptide-1 based therapies referred to in this report as GLP-1 agents: exenatide (BYETTA), liraglutide (VICTOZA), sitaGLIPtin (JANUVIA), saxagliptin (ONGLYZA), and linagliptin (TRADJENTA).
GLP-1 Agents and Their Mechanisms
GLP-1, a hormone released from the gut when food is present, stimulates the release of insulin, slows gastric empting, reduces appetite, and has other effects on the regulation of blood glucose. Under normal conditions, the hormone is rapidly deactivated by the enzyme dipeptidyl peptidase-4 (DPP-4). The two injectable agents, exenatide and liraglutide, are GLP-1 receptor agonists (analogs) that are not inactivated by DPP-4. SitaGLIPtin, saxagliptin, and linagliptin are oral DPP-4 inhibitors that prevent the rapid breakdown of GLP-1.
Safety Questions Arise
Early in development of GLP-1 agents, some studies showed that the hormone stimulated cellular proliferation and inhibited programmed cell death.(1) Since then, concerns that these drugs may be associated with pancreatitis, pancreatic cancer, and thyroid cancer have arisen. A 2011 examination of ADEs reported to FDA for sitaGLIPtin and exenatide identified both pancreatitis and pancreatic cancer as reported adverse effects.(2) Pancreatitis was identified as a signal with liraglutide in the May 2011 QuarterWatch report.(3) In 2013, a population-based case-control study in a large health insurance plan database reported a 2-fold increase in the risk of pancreatitis when taking sitaGLIPtin or exenatide.(4) Pancreatitis, in turn, is a risk factor for pancreatic cancer. Also in 2013, a study of pancreatic tissue from age matched organ donors reported a 40% higher risk of a pancreatic mass in those taking GLP-1 agents compared to patients taking other diabetes drugs or non-diabetic patients.(5) The study also identified precancerous growths in the pancreas of those who had been treated with GLP-1 agents, and a 6-fold increase in beta cells. In the presence of these safety concerns, we investigated the safety profile of the five GLP-1 agents. (No data were available for a sixth agent, alogliptin [NESINA], which was approved in January 2013.)
Twelve months of data submitted between July 1, 2011, and June 30, 2012, were examined for signals associated with the five agents. Exposure to the drugs has risen steadily and accounts for 16.9 million prescriptions in the 4 quarters ending June 2012, according to IMS Health. The market thus far is dominated by sitaGLIPtin, with 11.2 million outpatient prescriptions (66%) in the same 4 quarters ending June 2012. For diabetes drug controls, reports for three second generation sulfonylurea drugs (glipiZIDE, glimepiride, glyBURIDE) were combined with reports for metFORMIN, the most widely used oral agent for diabetes. For random comparators, cases among all other drugs in patients within the same age range (20-85) were used. Suicides and deaths without a cause were excluded.
Report totals. We identified 1,723 serious ADEs for the five drugs in the 12-month study period, including 831 cases of pancreatitis, 105 cases of pancreatic cancer, 32 cases of thyroid cancer, and 101 cases indicating a hypersensitivity reaction.
Signals for pancreatitis. We observed a marked signal for pancreatitis in all five drugs compared to cases reported for the other diabetes drug controls. After adjusting for differences in report characteristics, the odds ratio (OR) for pancreatitis for the two injectable agents was 28.5 (95% CI 17.4-46.4) times higher than the diabetes drug controls; for the three oral agents, the OR for pancreatitis was 20.8 (95% CI 12.6-34.5) times higher. Examined individually in comparison to the other diabetes drug controls, the highest OR was for sitaGLIPtin and the lowest was for saxagliptin. Both the diabetes drug controls and the GLP-1 agents had higher odds of pancreatitis reports compared to the randomly selected cases, indicating a higher risk of pancreatitis across the diabetes patient population.
Signals for pancreatic cancer. The GLP-1 agents had increased adjusted odds of reported pancreatic cancer cases compared to the diabetes drug controls. For the injectables, the adjusted OR was 23.3 (95% CI 5.7-95.1), and for the combined oral agents, the adjusted OR was 13.5 (95% CI 3.1-58.5). However, examined individually, both linagliptin and saxagliptin had just a single reported case each, with an increased OR that was not statistically significant. These two drugs also had the fewest number of overall serious case reports of the group of five drugs.
Signals for thyroid cancer. The reported thyroid cancer cases were largely limited to the two injectable GLP-1 analogs, with 14 cases for exenatide and 17 cases for liraglutide. Grouped together, the two injectable agents had an adjusted OR of 15.2 times greater than the diabetes drug controls, and while statistically significant, the confidence intervals were wide (95% CI 2.0-111.7). One case of thyroid cancer was reported for saxagliptin, and one case was reported with the diabetes drug controls. Thyroid cancer is a biologically plausible adverse effect given the fact that thyroid tissues have GLP-1 receptors.
Signal for hypersensitivity. The newest of these oral agents, linagliptin, was associated with a marked signal for hypersensitivity reactions that included angioedema, urticaria, rash, blisters, and skin exfoliation. The adjusted OR for linagliptin was 7.7 (95% CI 4.2-13.8) times higher than the diabetes drug controls and was the only drug of five with a statistically significant difference.
Higher reporting rates for three drugs. Given that patient exposures varied widely among the five drugs, notable differences emerged when we compared the total serious adverse event reports for the five GLP-1 agents with dispensed prescription volume over the 12-month study period (see Figure 1 on page 2 in the PDF version of the newsletter). The adverse event reporting rate per 100,000 prescriptions for exenatide, liraglutide, and linagliptin was about 10-fold higher than for sitaGLIPtin and saxagliptin. The overall results suggest that the toxicity of the injectable GLP-1 analogs may be higher than all but one oral agent—linagliptin.
Responses from manufacturers. We shared preliminary results of QuarterWatch with manufacturers of the five drugs. Three companies, Bristol-Myers Squibb, Boehringer Ingelheim, and Merck & Co. said that a causal relationship between drug treatment and pancreatic cancer was unproven, and noted weaknesses in using adverse event reports to assess this risk. Some companies also sponsored and cited animal and epidemiological studies, and meta-analysis of human studies that did not detect the risks explored here.
These results add scientific weight to the association of all five drugs with reports of pancreatitis. However, the marked association in adverse event data does not indicate how frequently this adverse event might occur. While available studies suggest that severe cases of pancreatitis are relatively rare, they do not address the incidence of cumulative or subclinical injury suggested in studies of pancreatic tissue.
Considered as a group, these data provide a signal for pancreatic cancer substantial enough to warrant further investigation. The two injectable agents had a signal for thyroid cancer. One, liraglutide, has a Boxed Warning about this possible risk. However, the number of cases reported over 12 months was modest, and as we have previously reported, links between drug treatments and increased cancer risk are difficult to measure in adverse event data. A relationship, however, is biologically plausible.
These data also provide preliminary evidence that the toxicity of the injectable agents may be higher than the oral agents. It is also clear from the data that linagliptin has a higher risk of reported hypersensitivity reactions. Better information about the incidence of more severe hypersensitivity reactions should guide judgments about its place in diabetes treatment.
This report and other recent studies establish the need to reassess the safety of this class of drugs and conduct further studies of their long-term effects on human pancreatic and thyroid tissues. Meanwhile, we recommend updating the prescribing information to include stronger warnings based on the adverse event data now available.
To view the full QuarterWatch report, please visit: www.ismp.org/QuarterWatch/.
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2) Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011;141:150–6.
3) Moore TJ, Cohen MR, Furberg CD. Quarter-Watch: 2010 Quarter 3: New signals for liraglutide, quetiapine and varenicline. Institute for Safe Medication Practices. 2011. www.ismp.org/sc?id=177
4) Singh S, Chang HY, Richards TM, Weiner JP, Clark JM, et al. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med. 2013;173(7):534-9.
5) Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, et al. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes [epub ahead of print]. March 22, 2013. www.ismp.org/sc?id=178