Lipid Modifying Therapies and Risk of Pancreatitis: A Meta-analysis

1. Lipid Modifying Therapies and Risk of Pancreatitis: A Meta-analysis Presented by: MaCie Rogers Pharm.d Candidate 2013

2. Background • Lipid-Modifying therapies (statins and fibrates specifically) have long been associated with pancreatitis through observational studies • Pancreatitis episodes can range from mild to life-threatening and are of particular concern to patients with hyperlipidemia • Hypertriglyceridemia is the third leading cause of pancreatitis, hence recommendations to commence triglyceride-lowering therapies when TGs>500mg/dL, usually with fibrates • Fibrates have been associated to increased risk for gallstones due to increased concentration of cholesterol in the bile • There are few large, randomized, controlled trials that have published associations between statins, fibrates, and pancreatitis

3. Objective • To investigate the association between statin or fibrate therapy and the incidence of pancreatitis in large, randomized, controlled trials

4. Methods • Relevant randomized controlled trials with cardiovascular endpoints investigating the effects of statins or fibrates were elucidated using MEDLINE, EMBASE, and Web of Science literature searches • Controls include placebo and standard of care. Intensive/moderate dose trials were also included • Inclusion criteria: 1000 or more participants exposed to randomized therapy with a minimum mean follow-up of 1 year, published from Jan 1,1994 to June 9, 2012 • Exclusion criteria: Trials conducted in patients with previous organ transplants or hemodialysis and trials comparing combination therapy to placebo • End Point: Development of pancreatitis was counted if pancreatitis was recorded as an adverse event or a serious adverse event • 28 studies included in meta-analysis: 27 statin and 7 fibrate

5. Statistical Analysis • Risk ratios were calculated as the ratio of cumulative incidence • 95% CIs were calculated from available data for all trial participants at baseline and for those who developed pancreatitis • P<.05 considered significant

6. Results: Statin Therapy • Results taken from 21 statin trials (2 with published data on pancreatitis and 19 with unpublished data) • 309(134 assigned to statin, 175 assigned to control group) participants out of 113,800 developed pancreatitis in 16 placebo-and standard- controlled trials (RR: 0.77; 95% CI, 0.62-0.97; P=.03) • NNT= 1175 over 5 years

7. Results: Statin Therapy • 156 participants (70 intensive dose, 84 moderate dose) out of 39,614 developed pancreatitis in 5 dose-comparison statin trials(RR: 0.82, [95% CI, .59-1.12],P=.21) • Combined data set (21 statin trials): 465 participants developed pancreatitis (204 assigned to statin or intensive-dose statin, 261 assigned to placebo or moderate-dose statin) • NNT=1187 over 5 years • Meta-regression analysis found no relationship between risk of pancreatitis and reduction of triglyceride levels at one year

8. Results: Statin Therapy Fig. 2

9. Results: Fibrate Therapy • Data provided from 7 randomized clinical trials of fibrate therapy (3 with unpublished data and 4 with published data regarding the incidence of pancreatitis) • 144 participants (84 assigned to fibrate therapy, 60 assigned to placebo) developed pancreatitis (RR: 1.39 [95% CI,1.00-1.95]; P= .053) • NNH: 935 over 5 years • Meta-analysis showed no relationship between risk of pancreatitis and reduction of triglycerides at 1 year

10. Results: Fibrate Therapy

11. Conclusions • This pooled data demonstrates that he use of statins is associated with a reduction in the incidence of pancreatitis • Dose comparison studies demonstrated that this effect is dose-dependent (intensive vs. moderate dosing) • An association between fibrate therapy and the risk of pancreatitis was NOT demonstrated

12. Study Limitations • Pancreatitis was not a pre-specified endpoint in any of the trials (primarily conducted to assess the effect of lipid-modifying therapy on CV events) • Occurrence of pancreatitis was recorded in a standardized way, resulting in variation between trials • Inability to access individual-participant data and specific causes of pancreatitis lead to ambiguity in regards to chronic vs. acute episodes and exact causes, such as gallstones • Study may have lacked power to show an increased risk of pancreatitis in participants with slightly elevated triglyceride levels (145-184mg/dL at baseline)

14. Reference • Preiss D, Tikkanen MJ, Welsh P, et al. Lipid-Modifying Therapies and Risk of Pancreatitis: A Meta-analysis. JAMA. 22 Aug 2012; 308(8): 804-810.