On February 27, 2014, The New England Journal of Medicine published an article online summarizing U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) findings concerning the safety of incretin-based diabetic medications. The agencies determined that no causal connection could be identified between incretin mimetic drugs and pancreatic side effects.
Incretin mimetic is a broad term for drugs belonging to the glucagon-like peptide-1 (GLP-1) agonist and dipeptidyl peptidase-4 (DPP-4) inhibitor classes of drugs. GLP-1 agonists include the brand name drugs Byetta and Bydureon, while the DPP-4 inhibitors include the drugs Janumet and Januvia. FDA posted a Drug Safety Communication in March 2013 stating the agency would investigate the potential link between pancreatic disorders and incretin mimetics. After another study supported the association between these drugs and pancreatic risks, the FDA and EMA joined together to evaluate existing clinical and nonclinical trial data GLP-1 agonists and DPP-4 inhibitors.
Findings revealed inconsistent results due to varying shortcomings of the studies included in the analysis. The FDA and EMA evaluated clinical safety databases, data from the SAVOR and EXAMINE trials, as well as postmarketing reports of adverse events. Results from the SAVOR and EXAMINE trial yielded similar rates of acute pancreatitis in patients treated with incretin mimetics compared to those in placebo groups (SAVOR 22 vs 16, EXAMINE 12 vs 8, respectively). Officials stated:
A pooled analysis of data from 14,611 patients with type 2 diabetes from 25 clinical trials in the sitagliptin database provided no compelling evidence of an increased risk of pancreatitis or pancreatic cancer.
The FDA and EMA were in agreement that previous allegations regarding the causal link between incretin mimetics and pancreatic adverse events were not in line with the agencies’ findings. The agencies stated that they have not reached a final conclusion on this matter, though both expressed that the current safety labeling for these drugs accurately reflects potential pancreatic risks. Both agencies will continue to examine safety information as it becomes available.
Exenatide (Bydureon, Byetta) is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Byetta was approved in April 2005, and Bydureon, an extended-release version of exenatide, was approved in January 2012. Both drugs are co-marketed by Bristol-Myers Squibb and AstraZeneca.
Sitagliptin (Januvia, Janumet) is an oral blood glucose lowering agent indicated for the treatment of type 2 diabetes. Januvia prolongs the activity of proteins that increase the release of insulin after blood sugar rises, such as after a meal, by blocking an enzyme (dipeptidyl peptidase 4 or DPP-4) which breaks down these proteins, leading to better blood sugar control. Januvia was FDA approved in October 2006, and Janumet was approved March 2007. Janumet is a DPP-4 and biguanide combination medication, containing both sitagliptin and metformin. Both Janumet and Januvia are marketed by Merck.
Of the six drugs evaluated by AdverseEvents that belong to the “other blood glucose lowering drugs, excl. insulins” class of drugs, Victoza (liraglutide [rDNA origin] injection) has the highest RxScore. Of the seven drugs evaluated by AdverseEvents that belong to the “didpeptidyl peptidate 4 (DPP-4) inhibitors” class of drugs, Janumet (sitagliptin, metformin hydrochloride) has the highest RxScore. These scores signify both medications have an above average level of risk compared to the other drugs within each of their respective drug classes.
To see the RxScores for all of the drugs in the “other blood glucose lowering drugs, excl. insulins” drug class, the “didpeptidyl peptidate 4 (DPP-4) inhibitors” drug class, or to learn more about how RxScore supports comparative drug safety analysis, please login to AdverseEvents Explorer or sign up for a complimentary trial.
AdverseEvents uses a proprietary disproportionality analysis tool called RxSignal to track and predict pending FDA safety actions.
To see the RxSignals for all of the drugs in the “other blood glucose lowering drugs, excl. insulins” drug class, the “didpeptidyl peptidate 4 (DPP-4) inhibitors” drug class, or to learn more about how RxSignal supports comparative drug safety analysis, please login to AdverseEvents Explorer or sign up for a complimentary trial.
In our RxSignal analysis, we identified the adverse events listed below as serious safety issues that have not been identified on the drug’s label in either the Warnings & Precautions or Adverse Reactions from Clinical Trial Experience sections. Any of these adverse reactions may trigger further FDA safety reviews.
Using FAERS data (from 11/01/1997 to 12/31/2012), aggregated and standardized by the AdverseEvent RxFilter process, we identified 41,150 serious adverse events which listed exenatide as the primary suspect drug. Of these cases, we identified 2,487 cases of pancreatitis. We identified 5,093 hospitalizations and 579 patient deaths where exenatide was indicated as the primary suspect.
Using FAERS data (from 11/01/1997 to 12/31/2012), aggregated and standardized by the AdverseEvent RxFilter process, we identified 11,829 serious adverse events which listed sitagliptin or sitagliptin/metformin as the primary suspect drug. Of these cases, we identified 997 cases of pancreatitis. We identified 2,599 hospitalizations and 369 patient deaths where sitagliptin or sitagliptin/metformin was indicated as the primary suspect.
Note: This analysis does not take into account the total number of patients taking each medication. In order to calculate the number of cases of pancreatitis, we aggregated reports listing the following adverse events: MedDRA Preferred Terms: Pancreatitis, pancreatitis acute.
RxScore is a proprietary algorithmic scoring model based predominantly on post-marketed safety data from over five million FAERS reports. RxScore is presented on a 100-point scale meant to reflect both the breadth and seriousness of side effect(s) by incorporating nine differentially weighted categories including FAERS fields such as “Outcome,” “Event Seriousness,” “Report Type,” and “Event Reporter,” a disproportionality measure, and existing FDA warnings and DEA risk classifications. The score is also negatively adjusted by factoring in both “Condition Seriousness” and a patient’s existing comorbidities. A score of 100 indicates the highest potential adverse event risks.