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with published data on pancreatitis and 19 with unpublished data)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, 0.62-0.97; 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, .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

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,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

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 (145-184mg/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): 804-810.