Pancreatitis, Pancreatic, and Thyroid Cancer With Glucagon-like Peptide-1–Based Therapies

Michael Elashoff; Aleksey V. Matveyenko; Belinda Gier; Robert Elashoff; Peter C. Butler

Disclosures

Gastroenterology. 2011;141(1):150-156. 

In This Article

Results

Control Events

The validity of the analysis is predicated on a similar rate of reported control events for each drug in the analysis. For the 2 test drugs and 4 control drugs, this was found to be the case. However, one drug initially chosen for the analysis (pioglitazone) had an elevated control event reporting rate compared to the other drugs, which were otherwise similar in their control event rate. This was not driven by any one of the controls, but rather was an overall elevation in reported control events. This means that either pioglitazone truly has an increased frequency of these events, or some reporting bias exists with pioglitazone relative to the other drugs. In either case, its inclusion in the analysis would be suspect. As a practical issue, despite the higher control event rate (control reports/total reports), the actual number of control reports was relatively low, and dropping it from the analysis resulted in only a modest reduction in the power of the analysis. The similarity of the control event rates for the remaining drugs supported the validity of this 2-level control analysis approach.

Pancreatitis. Exenatide and sitagliptin had similar patterns of reported pancreatitis events relative to the controls events. Pancreatitis has been reported >6-fold more frequently as an adverse event for patients administered exenatide (OR = 10.68; 95% confidence interval [CI]: 7.75–15.1; P < 10−16 ) or sitagliptin (OR = 6.74; 95% CI: 4.61–10.0; P < 10−16) when compared with other therapies (Table 1, Figure 1). When the adverse reporting events of the GLP-1 class of drugs (exenatide and sitagliptin) were considered together, the reported event rate of pancreatitis was approximately 10-fold greater than that of other therapies (OR = 9.99; 95% CI: 7.26–14.1; P < 10−16).

Figure 1.

Odds ratio of test vs control events for exenatide, sitagliptin, and other therapies. The odds ratio of an adverse report of pancreatitis, pancreatic and thyroid cancer, or any cancer associated with exenatide and/or sitagliptin therapy vs other therapies.

Because of recent attention to the potential link between use of GLP-1 mimetic drugs and pancreatitis after the FDA's first warning in 2007[11] that pancreatitis appeared to be an adverse effect of exenatide treatment, the analysis was repeated using only events reported to have occured in 2006 or earlier. Because sitagliptin had only recently been made available at that time, there were insufficient reports to consider sitagliptin alone, so the event rates for the combined GLP-1 mimetic therapies of sitagliptin and exenatide were considered together. The reported event rate for pancreatitis for the GLP-1 mimetic drugs was still >2.5-fold increased compared to other therapies (OR = 2.55; 95% CI: 1.70–3.94; P < 1 × 10−6 ).

Collectively, these data imply that there is an increased risk of pancreatitis in patients treated with either exenatide or sitagliptin vs the other therapies.

Pancreatic Cancer. Because pancreatitis is a known risk factor for pancreatic cancer,[17] we evaluated the reported rates of pancreatic cancer with exenatide and sitagliptin compared to control events relative to rosiglitazone.

The reported event rate for pancreatic cancer was 2.9-fold greater in patients treated with exenatide compared to other therapies P = 9 × 10−5 ). The reported event rate for pancreatic cancer was 2.7-fold greater with sitagliptin than other therapies P = .008).

Thyroid Cancer. Because thyroid tumors were reported to be increased in rodents treated with liraglutide in a filing to the FDA,[20] we examined the frequency of reported adverse events of thyroid cancer with the GLP-1 mimetic therapies vs rosiglitazone. The reported event rate for thyroid cancer in patients treated with GLP-1 mimetic therapy was increased and reached statistical significance in the exenatide group (OR = 4.73; P = 4 × 10−3 ), but not in the sitagliptin group (OR = 1.48; P = .65).

All Other Cancers. There has been a suggestion that DPP-4 inhibition may lead to impaired immune function and increased risk for cancers.[18,19] Therefore, we also examined the reported event rate for all other cancers (excluding pancreas and thyroid) associated with sitagliptin, exenatide, or the control therapies. Neither sitagliptin or exenatide were associated with a higher reported rate of other cancers. The risk for cancer increases with age but age was not different between the individuals in whom cancer (mean age, 61 years other therapies, 61 years exenatide, 64 years sitagliptin) or a control event (mean age, 62 years other therapies, 60 years exenatide, 63 years sitagliptin) was reported for the drugs included in this analysis.

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