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

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

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

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

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

Results: Statin Therapy  Results taken from 21 statin trials (2 with published data on pancreatitis and 19 with unpublished data)  309(134 assigned to statin, 175 assigned to control group) participants out of 113,800 developed pancreatitis in 16 placebo- and standard- controlled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

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, ],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

Results: Statin Therapy Fig. 2

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, ]; P=.053)  NNH: 935 over 5 years  Meta-analysis showed no relationship between risk of pancreatitis and reduction of triglycerides at 1 year

Results: Fibrate Therapy

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

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 ( mg/dL at baseline)

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):