“Glucagonlike Peptide 1–Based Therapies and Risk of Hospitalization for Acute Pancreatitis in T2DM”
April 8, 2013
Glucagonlike Peptide 1–Based Therapies and Risk of Hospitalization for Acute Pancreatitis in Type 2 Diabetes MellitusA Population-Based Matched Case-Control Study
Sonal Singh, MD, MPH; Hsien-Yen Chang, PhD; Thomas M. Richards, MS; et al Jonathan P. Weiner, DrPH; Jeanne M. Clark, MD, MPH; Jodi B. Segal, MD, MPH
Author Affiliations Article Information
JAMA Intern Med. 2013;173(7):534-539. doi:10.1001/jamainternmed.2013.2720”
Importance Acute pancreatitis has significant morbidity and mortality. Previous studies have raised the possibility that glucagonlike peptide 1 (GLP-1)–based therapies, including a GLP-1 mimetic (exenatide) and a dipeptidyl peptidase 4 inhibitor (sitagliptin phosphate), may increase the risk of acute pancreatitis.
Objective To test whether GLP-1–based therapies such as exenatide and sitagliptin are associated with an increased risk of acute pancreatitis. We used conditional logistic regression to analyze the data.”
“Design Population-based case-control study.
Setting A large administrative database in the United States from February 1, 2005, through December 31, 2008.
Participants Adults with type 2 diabetes mellitus aged 18 to 64 years. We identified 1269 hospitalized cases with acute pancreatitis using a validated algorithm and 1269 control subjects matched for age category, sex, enrollment pattern, and diabetes complications.”
“Main Outcome Measure Hospitalization for acute pancreatitis.
Results The mean age of included individuals was 52 years, and 57.45% were male. Cases were significantly more likely than controls to have hypertriglyceridemia (12.92% vs 8.35%), alcohol use (3.23% vs 0.24%), gallstones (9.06% vs 1.34), tobacco abuse (16.39% vs 5.52%), obesity (19.62% vs 9.77%), biliary and pancreatic cancer (2.84% vs 0%), cystic fibrosis (0.79% vs 0%), and any neoplasm (29.94% vs 18.05%). After adjusting for available confounders and metformin hydrochloride use, current use of GLP-1–based therapies within 30 days (adjusted odds ratio, 2.24 [95% CI, 1.36-3.68]) and recent use past 30 days and less than 2 years (2.01 [1.37-3.18]) were associated with significantly increased odds of acute pancreatitis relative to the odds in nonusers.
Conclusions and Relevance In this administrative database study of US adults with type 2 diabetes mellitus, treatment with the GLP-1–based therapies sitagliptin and exenatide was associated with increased odds of hospitalization for acute pancreatitis.”
Our findings suggest a significantly increased risk of hospitalization for acute pancreatitis associated with the use of sitagliptin or exenatide among adult patients with type 2 diabetes mellitus. Our results support findings from mechanistic studies and spontaneous reports submitted to the US Food and Drug Association that such an association may be causal.”
“Unanswered questions and future research:
We suggest that a self-controlled case series design that allows control for individual-level confounding by disease severity may offer additional insight. 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. A recent study noted elevation of serum lipase and serum amylase levels in patients with GLP-1–based therapies. Future studies should determine whether monitoring of serum enzyme levels can be used to predict the occurrence of acute pancreatitis among patients using GLP-1–based therapies. Long-term prospective studies should examine other outcomes, such as chronic pancreatitis and pancreatic cancer.
In summary, acute pancreatitis has significant morbidity and mortality. In this administrative database study of US adults with type 2 diabetes mellitus, treatment with the GLP-1–based therapies sitagliptin and exenatide was associated with an increased risk of hospitalization for acute pancreatitis.”
“Accepted for Publication: October 13, 2012.”
“Glucagonlike Peptide 1–Based Drugs and Pancreatitis
Clarity at Last, but What About Pancreatic Cancer?
The worldwide prevalence of type 2 diabetes mellitus (T2DM) is approaching 100 million.
Most affected individuals are treated for decades. Not surprisingly, the market for drug treatment of T2DM is
worth more than $20 billion per year. The most lucrative drugs are those still protected by patent and deemed
worthy of selection despite high expense because of clear advantages over cheaper drugs no longer covered by pat-
ent protection. The glucagonlike peptide 1 (GLP-1)–based drugs are the most recently launched drug class for treatment of T2DM. Proponents of these drugs claim they are safe and offer advantages over existing drugs. Glucagonlike peptide 1 is a hormone released by endocrine cells in the gut after meal ingestion, and one of its best characterized actions is amplification of glucose-mediated insulin secretion, a property that is of course desirable in T2DM. The first drug in this class approved in the United States was a peptide agonist of the GLP-1 receptor, exenatide (Byetta), followed by sitagliptin (Januvia), an inhibitor of the enzyme that degrades endogenously secreted GLP-1, dipeptidyl peptidase 4. Singh and colleagues3 report that treatment with either of these GLP-1 mimetic drugs is associated with an increased risk of hospital admission for acute pancreatitis compared with other diabetes medica tions. The many strengths of this study include the large size of the sample, the ability to adjust for confounders, and the independence of the authors from the companies
marketing the drugs. Because both drugs already carry US Food and Drug Administration (FDA) warnings for
the risk of pancreatitis, why is this study important? Pancreatitis associated with exenatide treatment was
first described in case reports, followed by adverse event reports by the FDA for sitagliptin and other drugs in this class. Vendors and supporters of GLP-1 treatment refuted the reported association of pancreatitis as being an
artifact of the increased risk of pancreatitis in T2DM and pointed to a myriad of negative findings of animal and
clinical studies, most performed by and/or sponsored by the marketing companies. We appreciate why an increased risk of pancreatitis associated with drug treatment, even if rare, would be unwelcome.
JAMA INTERN MED/ VOL 173 (NO. 7), APR 8, 2013 WWW.JAMAINTERNALMED.COM”
“The rising burden of type 2 diabetes is a major concern in healthcare worldwide. This research aimed to analyze the global epidemiology of type 2 diabetes. We analyzed the incidence, prevalence, and burden of suffering of diabetes mellitus based on epidemiological data from the Global Burden of Disease (GBD) current dataset from the Institute of Health Metrics, Seattle. Global and regional trends from 1990 to 2017 of type 2 diabetes for all ages were compiled. Forecast estimates were obtained using the SPSS Time Series Modeler. In 2017, approximately 462 million individuals were affected by type 2 diabetes corresponding to 6.28% of the world’s population (4.4% of those aged 15–49 years, 15% of those aged 50–69, and 22% of those aged 70+), or a prevalence rate of 6059 cases per 100,000. Over 1 million deaths per year can be attributed to diabetes alone, making it the ninth leading cause of mortality. The burden of diabetes mellitus is rising globally, and at a much faster rate in developed regions, such as Western Europe. The gender distribution is equal, and the incidence peaks at around 55 years of age. Global prevalence of type 2 diabetes is projected to increase to 7079 individuals per 100,000 by 2030, reflecting a continued rise across all regions of the world. There are concerning trends of rising prevalence in lower-income countries. Urgent public health and clinical preventive measures are warranted.
Keywords: Diabetes mellitus type 2, epidemiology, disease pattern, prevalence