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Clinical Review |

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

David Preiss, MD, PhD; Matti J. Tikkanen, MD, PhD; Paul Welsh, PhD; Ian Ford, PhD; Laura C. Lovato, MS; Marshall B. Elam, MD, PhD; John C. LaRosa, MD; David A. DeMicco, DPharm; Helen M. Colhoun, MD; Ilan Goldenberg, MD; Michael J. Murphy, MD, FRCP; Thomas M. MacDonald, MD, FRCP; Terje R. Pedersen, MD, PhD; Anthony C. Keech, MD, PhD; Paul M Ridker, MD; John Kjekshus, MD, PhD; Naveed Sattar, MD, PhD; John J. V. McMurray, MD
[+] Author Affiliations

Author Affiliations: BHF Glasgow Cardiovascular Research Centre (Drs Preiss, Welsh, Sattar, and McMurray) and Robertson Centre for Biostatistics (Dr Ford), University of Glasgow, Glasgow, United Kingdom; University of Helsinki and Division of Cardiology, Helsinki University Hospital, and Folkhalsan Research Center, Helsinki, Finland (Dr Tikkanen); Division of Public Health Sciences, Department of Biostatistical Science, Wake Forest University School of Medicine, Winston-Salem, North Carolina (Ms Lovato); Memphis Veterans Affairs Medical Center, Memphis, Tennessee (Dr Elam); SUNY Health Science Center at Brooklyn, New York, New York (Dr LaRosa); Pfizer Global Pharmaceuticals, New York, New York (Dr DeMicco); Medical Research Institute (Dr Colhoun), Department of Biochemical Medicine (Dr Murphy), and Medicines Monitoring Unit, Division of Medical Sciences (Dr MacDonald), University of Dundee, Dundee, United Kingdom; Cardiac Rehabilitation Institute and Israeli Society for the Prevention of Heart Attacks, Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Israel (Dr Goldenberg); University of Oslo and Centre for Preventative Medicine, Oslo University Hospital, Ulleval, Oslo, Norway (Dr Pedersen); NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia (Dr Keech); Harvard Medical School, Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts (Dr Ridker); and Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway (Dr Kjekshus).


Clinical Review Section Editor: Mary McGrae McDermott, MD, Contributing Editor. We encourage authors to submit papers for consideration as a Clinical Review. Please contact Mary McGrae McDermott, MD, at mdm608@northwestern.edu

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JAMA. 2012;308(8):804-811. doi:10.1001/jama.2012.8439.
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Published online

Context Statin therapy has been associated with pancreatitis in observational studies. Although lipid guidelines recommend fibrate therapy to reduce pancreatitis risk in persons with hypertriglyceridemia, fibrates may lead to the development of gallstones, a risk factor for pancreatitis.

Objective To investigate associations between statin or fibrate therapy and incident pancreatitis in large randomized trials.

Data Sources Relevant trials were identified in literature searches of MEDLINE, EMBASE, and Web of Science (January 1, 1994, for statin trials and January 1, 1972, for fibrate trials, through June 9, 2012). Published pancreatitis data were tabulated where available (6 trials). Unpublished data were obtained from investigators (22 trials).

Study Selection We included randomized controlled cardiovascular end-point trials investigating effects of statin therapy or fibrate therapy. Studies with more than 1000 participants followed up for more than 1 year were included.

Data Extraction Trial-specific data described numbers of participants developing pancreatitis and change in triglyceride levels at 1 year. Trial-specific risk ratios (RRs) were calculated and combined using random-effects model meta-analysis. Between-study heterogeneity was assessed using the I2 statistic.

Results In 16 placebo- and standard care–controlled statin trials with 113 800 participants conducted over a weighted mean follow-up of 4.1 (SD, 1.5) years, 309 participants developed pancreatitis (134 assigned to statin, 175 assigned to control) (RR, 0.77 [95% CI, 0.62-0.97; P = .03; I2 = 0%]). In 5 dose-comparison statin trials with 39 614 participants conducted over 4.8 (SD, 1.7) years, 156 participants developed pancreatitis (70 assigned to intensive dose, 86 assigned to moderate dose) (RR, 0.82 [95% CI, 0.59-1.12; P = .21; I2 = 0%]). Combined results for all 21 statin trials provided RR 0.79 (95% CI, 0.65-0.95; P = .01; I2 = 0%). In 7 fibrate trials with 40 162 participants conducted over 5.3 (SD, 0.5) years, 144 participants developed pancreatitis (84 assigned to fibrate therapy, 60 assigned to placebo) (RR, 1.39 [95% CI, 1.00-1.95; P = .053; I2 = 0%]).

Conclusion In a pooled analysis of randomized trial data, use of statin therapy was associated with a lower risk of pancreatitis in patients with normal or mildly elevated triglyceride levels.

Figures in this Article

Pancreatitis has a clinical spectrum ranging from a mild, self-limiting episode to a severe or fatal event. Case reports and pharmacoepidemiologic studies have claimed that statins may cause pancreatitis,14 although few of these studies comprehensively considered confounding factors. Very few large randomized trials of statin therapy have published data on incident pancreatitis. Recently reported data from the Study of Heart and Renal Protection (SHARP), a trial comparing combination therapy of simvastatin and ezetimibe with placebo on cardiovascular events in patients with chronic kidney disease, demonstrated a reduction in pancreatitis cases in patients receiving simvastatin and ezetimibe, suggesting a possible protective association.5 In addition, statins reduce bile cholesterol content,6 which may theoretically reduce the risk of developing gallstones, a risk factor for pancreatitis.

Quiz Ref IDHypertriglyceridemia has been reported to be the third most common cause of pancreatitis.7 This has led to major guidelines for lipid-modifying therapies, including advice to commence triglyceride-lowering therapy, usually fibrates, in persons with moderate and severe hypertriglyceridemia (above 400 to 500 mg/dL [to convert to mmol/L, multiply by 0.0113]).8,9 However, high-quality evidence for this approach is lacking, and only observational data exist.10,11 Indeed, there is concern that fibrates might increase the risk of pancreatitis in individuals with triglyceride levels lower than those mentioned in guidelines.12 Fibrates increase the cholesterol concentration in bile and may increase the risk of gallstones.13,14 However, few large randomized placebo-controlled trials of fibrate therapy have published data on pancreatitis.

Consequently, the associations between both types of lipid-modifying therapy and the risk of pancreatitis are uncertain. We therefore examined the associations between use of a statin or a fibrate and the incidence of pancreatitis by conducting collaborative meta-analyses of published and unpublished data from the relevant large randomized clinical trials.

We gathered data from large randomized end-point trials primarily designed to assess the effects of statin therapy (including both placebo- and standard care–controlled trials plus intensive-dose/moderate-dose trials) or fibrate therapy on cardiovascular events. Inclusion criteria were trials with 1000 or more participants exposed to randomized therapy with a minimum mean follow-up of 1 year, as in previous large meta-analyses of statin trials.15 We excluded trials conducted in patients with previous organ transplantation or those receiving hemodialysis as well as trials comparing combination therapy with placebo.

We searched MEDLINE, EMBASE, and Web of Science databases using the terms statin, HMG CoA reductase inhibitor, and fibrate and also names of individual statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) and fibrates (bezafibrate, ciprofibrate, clofibrate, fenofibrate, gemfibrozil) as title words and keywords, limited to studies defined as randomized controlled trials, to identify relevant studies performed in adult patients (initial search on October 28, 2011; search updated June 9, 2012) and published from January 1, 1972 (fibrate trials), or January 1, 1994 (statin trials), until June 9, 2012 (Figure 1), without language restrictions. Reference lists for the studies identified in the literature search were searched for additional studies. The US Food and Drug Administration website was also searched for trial reports containing relevant data. Abstracts, manuscripts, and reports were reviewed independently by 2 readers (D.P., P.W.) in an unblinded fashion. A third reviewer (N.S.) settled discrepancies. In the small number of trials in which published data regarding incident pancreatitis and change in triglyceride levels were available, these data were tabulated. In the majority of trials in which no relevant data were available, trial investigators were contacted with a request to provide the required information.

Place holder to copy figure label and caption
Figure 1. Literature Search
Graphic Jump Location

aMost records excluded for more than 1 reason, with only the strongest reason recorded.

After the full articles were reviewed and data were received from collaborators, 21 statin trials5,1636 (Table 1) and 7 fibrate trials12,3743 (Table 2) were included in the analyses. Because unpublished data were made available for both the Helsinki Heart Study40 and its smaller ancillary study44 conducted in similar groups of participants randomized to the same therapies over the same follow-up times, these results were combined as a single overall study.

Table Graphic Jump LocationTable 1. Baseline Data From 21 Large Statin Trials
Table Graphic Jump LocationTable 2. Baseline Data From Trials Comparing Fibrate Therapy With Placebo
Data Sources

Published data for incident pancreatitis were available from 2 statin trials5,22,36 and 4 fibrate trials.12,3739,41 Unpublished data were collected from 19 statin trials1621,2335 and 3 fibrate trials.40,42,43 To examine whether there was a relationship between the extent of triglyceride lowering between active and control therapy groups in the trials and risk of pancreatitis, we collected data on average change in triglyceride levels at 1 year. A PRISMA checklist was provided to the journal at the time of manuscript submission.45

Quality Assessment

Quiz Ref IDTwo authors (D.P., P.W.) used an established tool, the Jadad score, to independently evaluate the quality of each trial.46 The Jadad score is designed to assess trials with regard to method of randomization, whether the trial is double-blinded, and whether withdrawals/dropouts are described, resulting in a score of up to 5 points. A third reviewer (N.S.) was available to resolve any disagreement by consensus and discussion.

End Points

A patient was considered to have developed pancreatitis during the trial if this was recorded as an adverse event or serious adverse event. This information was identified using different approaches across the trials,1 namely text word searches of adverse event reports, including self-reported hospitalization data, for pancreatitis2; Medical Dictionary for Regulatory Activities event classification3; and International Classification of Diseases classifications (10th revision: K85, K86.0, K86.1; ninth revision: 577.0, 577.1), according to the preference of each trial's investigators. All reports of pancreatitis were included, regardless of suggested etiology (information regarding alcohol intake was not available) or whether the condition was described as acute, chronic, or neither, based on the rationale that such additional data may have been largely absent or variably reported across trials.

Statistical Analysis

To identify potential associations of lipid-modifying therapies with the risk of developing pancreatitis, we calculated risk ratios (RRs) as the ratio of cumulative incidence and 95% CIs from the available data for all trial participants at baseline and for those who developed pancreatitis during trial follow-up. Study-specific RRs were pooled using a random-effects model meta-analysis as the preferable approach to manage potential between-study heterogeneity that may have been introduced by the differing methods for identifying participants with incident pancreatitis available in the trials and different trial populations. For trials with no events with randomized or control therapy, a nominal amount (0.5 cases) was added to the results for both trial groups.

Statistical heterogeneity across studies was quantified using both the χ2 (or Cochran Q statistic) and I2 statistics, with P > .10 considered statistically nonsignificant. The I2 statistic is derived from the Q statistic ([Q − df /Q ] × 100) and provides a measure of the proportion of the overall variation attributable to between-study heterogeneity.47

Placebo- and standard care–controlled statin trials plus intensive-dose/moderate-dose statin trials were analyzed both separately (with comparison of analyses by fixed-effect inverse-variance method) and in a combined analysis. In sensitivity analyses, only trials with previously published pancreatitis data were examined; fixed-effects model meta-analyses were also performed. We assessed the potential for publication bias through formal statistical testing, namely, funnel plots and Egger tests. To evaluate the potential relationship between the associations of lipid-modifying agents with incident pancreatitis and relative reductions in triglyceride levels achieved at 1 year using statins and fibrates, respectively, random-effects meta-regression analyses were performed.

All P values were 2-sided, and P < .05 was considered statistically significant for the meta-analyses and meta-regression analyses. Analyses were conducted using Stata version 10.1 (StataCorp).

Statin Therapy and Pancreatitis

Twenty-one randomized clinical trials of statin therapy, 2 with published data regarding incident pancreatitis and 19 with unpublished data, provided data on 153 414 participants over a weighted mean follow-up period of 4.3 (SD, 1.6) years. Baseline average triglyceride levels in the trials varied from 118 mg/dL to 187 mg/dL. Trials were of high quality, with a median Jadad score of 5 (range, 3-5) and 100% agreement between reviewers.

In 16 placebo- and standard care–controlled statin trials with 113 800 participants conducted over 4.1 (SD, 1.5) years, 309 participants (0.27%) developed pancreatitis (134 assigned to statin, 175 assigned to control) (RR, 0.77 [95% CI, 0.62-0.97; P = .03]) (Table 1, Figure 2). This represents a number needed to treat of 1175 (95% CI, 693-9195) over 5 years. There was limited heterogeneity between trials for incident pancreatitis (χ2 = 9.11; I2 = 0%).

Place holder to copy figure label and caption
Figure 2. Meta-analysis of Incident Pancreatitis in 21 Large Statin Trials
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For abbreviations, see Table 1. Size of data markers indicates relative weight of the study (from random-effects analysis).

In 5 dose-comparison statin trials with 39 614 participants conducted over 4.8 (SD, 1.7) years, 156 participants (0.39%) developed pancreatitis (70 assigned to intensive dose, 86 assigned to moderate dose) (RR, 0.82 [95% CI, 0.59-1.12; P = .21]) (Table 1, Figure 2). There was again limited heterogeneity between these trials for incident pancreatitis (χ2 = 1.29; I2 = 0%).

There was no evidence of statistical heterogeneity between the analyses of placebo-controlled trials and intensive-dose/moderate-dose trials (P = .79 for interaction).

In the combined data set of 21 trials, 465 participants (0.30%) developed pancreatitis (of whom 204 were assigned to statin therapy or intensive-dose statin therapy and 261 were assigned to placebo, standard care, or moderate-dose statin therapy, respectively) (RR, 0.79 [95% CI, 0.65-0.95; P = .01; χ2 = 10.48; I2 = 0%]) (Table 1, Figure 2). This represents a number needed to treat of 1187 (95% CI, 731-4768) over 5 years. There was no evidence of publication bias (P = .83) (eFigure 1A. Meta-regression analysis found no relationship across the trials between risk of pancreatitis and reduction in triglyceride levels at 1 year, although this analysis was of limited value given the limited statistical heterogeneity between trial-specific RRs (P = .23) (eFigure 2A).

Using a fixed-effects model approach produced results (RR, 0.79 [95% CI 0.65-0.95; P = .01]) identical to those of the random-effects model. In a sensitivity analysis of only the 2 trials with published data,22,36 122 participants (0.37%) developed pancreatitis (52/16 300 assigned to statin therapy or intensive-dose therapy, 70/16 300 assigned to placebo or moderate-dose statin therapy) (RR, 0.74 [95% CI, 0.52-1.07; P = .11; χ2 = 0.30; I2 = 0%]).

Fibrate Therapy and Pancreatitis

Seven randomized clinical trials of fibrate therapy (4 with published data and 3 with unpublished data regarding incident pancreatitis) provided data on 40 162 participants over a weighted mean follow-up period of 5.3 (SD, 0.5) years. Baseline average triglyceride levels in the trials varied from 145 mg/dL to 184 mg/dL. Trials were of high quality, with a median Jadad score of 5 (range, 5-5) and 100% agreement between reviewers. During this time, 144 participants (0.36%) developed pancreatitis (84 assigned to fibrate therapy, 60 assigned to placebo) (RR, 1.39 [95% CI, 1.00-1.95; P = .053]) (Table 2, Figure 3). This represents a number needed to harm of 935 (95% CI, 388 to >50 000) over 5 years. There was limited heterogeneity between trials for incident pancreatitis (χ2 = 4.48; I2 = 0%). Likewise, there was no evidence of publication bias (P = .59) (eFigure 1B). Meta-regression analysis found no relationship across the trials between risk of pancreatitis and reduction in triglyceride levels at 1 year across the trials (P = .81) (eFigure 2B), although this analysis was of limited value given the limited statistical heterogeneity between trial-specific RRs and the similar relative reductions in triglyceride levels achieved across the trials.

Place holder to copy figure label and caption
Figure 3. Meta-analysis of Incident Pancreatitis in 7 Large Fibrate Trials
Graphic Jump Location

For abbreviations, see Table 2. Size of data markers indicates relative weight of the study (from random-effects analysis).

Using a fixed-effects model approach produced results identical to those achieved using the random-effects model (RR, 1.39 [95% CI, 1.00-1.95; P = .053]). In a sensitivity analysis of only the 4 trials with published data,12,37,39,41 69 participants (0.26%) developed pancreatitis (44/12 593 assigned to fibrate therapy, 25/14 252 assigned to placebo) (RR, 1.75 [95% CI, 1.07-2.86; P = .03; χ2 = 1.19; I2 = 0%]).

Quiz Ref IDThis report of pooled randomized trial data demonstrates that use of statin therapy was associated with a reduction in the number of patients developing pancreatitis. Broadly similar results were obtained for statin compared with placebo as well as for intensive-dose statin therapy compared with moderate-dose therapy, in keeping with a dose-dependent association. However, we did not demonstrate an association between use of fibrate therapy and risk of pancreatitis.

Previously published case reports and observational pharmacoepidemiologic studies have demonstrated an association between statin therapy and increased risk of pancreatitis.14 However, such analyses are susceptible to bias by unmeasured confounders and to confounding by indication. The present analysis, however, indicates that statin therapy may be associated with a reduced risk of pancreatitis overall. Although we cannot completely exclude the possibility that statin therapy may lead to very occasional idiosyncratic cases of pancreatitis, the randomized trial data appear reassuring. Unlike fibrates, statins are not known to increase the risk of developing gallstones.48 Studies showing both a reduction in bile cholesterol levels and an association with reduced risk of gallstones with statin therapy suggest the possibility of a protective effect.6,49 Furthermore, studies conducted in animal models suggest that statin therapy may be beneficial in both established acute pancreatitis and chronic pancreatitis.5052

Major guidelines of lipid-modifying therapy such as the National Cholesterol Education Program Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP ATP III)8 and the National Institute for Health and Clinical Excellence (NICE) Type 2 Diabetes guideline9 suggest the addition of fibrate therapy in patients with moderately elevated triglyceride levels and above (>400 mg/dL and >500 mg/dL, respectively). This is based on the rationale that hypertriglyceridemia is a well-recognized cause of pancreatitis and that lowering of triglyceride levels should be clinically beneficial.7 However, no convincing trial data exist to support use of any agents for prevention of pancreatitis in this clinical situation. Participants in the Coronary Drug Project assigned to clofibrate were at 50% higher risk of developing cholelithiasis or cholecystitis than those receiving placebo,13 and gallstones are a well-recognized cause of pancreatitis. In addition, it has been demonstrated in small clinical studies that both fenofibrate—a fibrate thought less likely to cause gallstones—and bezafibrate increase the cholesterol content of bile, thereby theoretically increasing the risk of developing gallstones.14,53 Following the Coronary Drug Project, other large fibrate trials did not find a significant increase in the incidence of gallbladder disease, although the total number of cases was small.40,41,43 Our analysis did not demonstrate an association between fibrate therapy and risk of pancreatitis, although the analysis may have lacked statistical power to show an increased risk in patients with slightly elevated triglyceride levels (the range at baseline in the trials we examined was 145-184 mg/dL). It remains possible, however, that fibrates might have a different net effect in patients with higher triglyceride levels.

Although the present results for both statins and fibrates should be considered hypothesis-generating and the number of pancreatitis cases was small in this trial population at low risk of pancreatitis, the analysis raises questions regarding the choice of lipid-modifying agents in patients with hypertriglyceridemia. Quiz Ref IDIn those with slightly elevated triglyceride levels, statins appear better supported by the available data than fibrates for preventing pancreatitis. Lifestyle modifications also remain important to improve lipid profiles in such individuals. In patients with severe hypertriglyceridemia, a trial comparing fibrates and statins for preventing pancreatitis would be clinically valuable.

Strengths of this meta-analysis are that the analysis was conducted using data from randomized trials, which avoids most of the potential bias of unmeasured confounders encountered in observational studies, and that we were able to include data from almost all of the relevant trials, both published and unpublished, thereby maximizing power and providing the best answer possible with existing data.

This meta-analysis also has several limitations. First, pancreatitis was not a prespecified end point in the trials, which were primarily designed to assess the effect of lipid-modifying therapy on cardiovascular events. However, limited statistical heterogeneity between trial results for statins and fibrates, plus evidence of a dose-dependent association for statins, provides confidence in the findings. Second, the occurrence of pancreatitis was not recorded in a standardized way, with resultant variation between trials. Therefore these results, especially for fibrate therapy when there were relatively few events dominated by 2 trials,12,43 should be interpreted with caution.

Quiz Ref IDThird, because it was felt unlikely that the cause of pancreatitis would have been consistently recorded in an accurate way across trials, we were unable to examine specific causes such as gallstones. Likewise, we were unable to separate reports of pancreatitis into acute and chronic cases. However, given that the majority of trials used the presence of hepatobiliary disease as an exclusion criterion, it is highly likely that the majority of cases included in this report represent de novo acute pancreatitis. This is supported by evidence from SHARP.5 Fourth, we did not have access to individual-participant data, which may have reduced our ability to identify any relationship with the extent of triglyceride lowering. Fifth, because the trials tended to exclude participants with marked hypertriglyceridemia, these findings may not necessarily be generalizable to that specific group of patients.

In summary, pooled analyses of randomized trial data suggest that statin therapy is associated with a reduction in the risk of pancreatitis in patients with normal or mildly elevated triglyceride levels.

Corresponding Author: David Preiss, MD, PhD, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Pl, Glasgow G12 8TA, United Kingdom (david.preiss@glasgow.ac.uk).

Author Contributions: Dr Preiss had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Preiss, Tikkanen, McMurray.

Acquisition of data: Preiss, Tikkanen, Ford, Lovato, Elam, LaRosa, Demicco, Colhoun, Goldenberg, Pedersen, Keech, Ridker, Kjekshus, McMurray.

Analysis and interpretation of data: Preiss, Tikkanen, Welsh, LaRosa, Demicco, Colhoun, Goldenberg, Murphy, MacDonald, Keech, Ridker, Sattar, McMurray.

Drafting of the manuscript: Preiss, Elam, LaRosa, Sattar, McMurray.

Critical revision of the manuscript for important intellectual content: Preiss, Tikkanen, Welsh, Ford, Lovato, Elam, LaRosa, Demicco, Colhoun, Goldenberg, Murphy, MacDonald, Pedersen, Keech, Ridker, Kjekshus, McMurray.

Statistical analysis: Preiss.

Obtained funding: Pedersen.

Administrative, technical, or material support: Welsh, Ford, Demicco, Goldenberg, Keech, Ridker.

Study supervision: Ford, LaRosa, Pedersen, Sattar, McMurray.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. The majority of trials discussed in this article were funded partly or wholly by industry, and Drs Tikkanen, Ford, Elam, LaRosa, DeMicco, Colhoun, Goldenberg, Pedersen, Keech, Ridker, Kjekshus, and McMurray and Ms Lovato each reported serving as an investigator in at least 1 of the trials. Dr Tikkanen reported receiving honoraria from Pfizer and consultant fees from Amgen Inc. Dr Elam reporting serving as a consultant, speaker, or both for Abbott/Solvay, Merck Schering Plough, and Pfizer Canada. Dr LaRosa reported receiving consultancy fees from Pfizer and AstraZeneca and participating in clinical trials funded by Pfizer. Dr Colhoun reported receiving honoraria for advisory board participation and speaker fees from Pfizer. Dr Pedersen reported receiving speakers honoraria, consulting fees, or research grants from Merck, AstraZeneca, AMGEN, Roche, and Novartis. Dr Keech reported receiving honoraria and research or travel grants from Abbott, Merck Sharpe & Dohme, Bristol-Myers Squibb, Novartis, Eli Lilly, Pfizer, Roche Diagnostics, Solvay, and AstraZeneca. Dr Ridker reported receiving research grant support from AstraZeneca and Novartis; receiving consultancy fees from Merck, Genzyme, Vascular Biogenics, ISIS, and Boston Diagnostics; and being listed as a co-inventor on patents held by the Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to AstraZeneca and Siemens. Dr Sattar reported consulting for and receiving lecture fees from Merck, Pfizer, and AstraZeneca and receiving research grant support from Pfizer. No other authors reported disclosures.

Funding/Support: This project was not supported by external funding. Dr Welsh is supported by British Heart Foundation fellowship grant FS/10/005/28147.

Role of the Sponsor: The British Heart Foundation had no role in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.

Additional Contributions: We are grateful to the investigators from the following trials for providing unpublished data: Helsinki Heart Study, Bezafibrate Infarction Prevention Study, Action to Control Cardiovascular Risk in Diabetes Lipid Study, Scandinavian Simvastatin Survival Study, West of Scotland Coronary Prevention Study, Air Force/Texas Coronary Atherosclerosis Prevention Study, Long-term Intervention With Pravastatin in Ischaemic Disease Study, Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza cardiaca (GISSI) Prevenzione, Prospective Study of Pravastatin in the Elderly at Risk, Greek Atorvastatin and Coronary Heart Disease Evaluation Study, Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm, Collaborative Atorvastatin Diabetes Study, Pravastatin or Atorvastatin Evaluation and Infection Therapy Study, Aggrastat to Zocor Study, Treating to New Targets Study, Incremental Decrease in Events Through Aggressive Lipid Lowering Study, Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non–Insulin-Dependent Diabetes Mellitus, Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese Study Group, Controlled Rosuvastatin Multinational Trial in Heart Failure, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin, and GISSI-Heart Failure. Bristol-Myers Squibb provided data for the Cholesterol and Recurrent Events Trial.

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 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).  Lancet. 1994;344(8934):1383-1389
PubMed
Shepherd J, Cobbe SM, Ford I,  et al; West of Scotland Coronary Prevention Study Group.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.  N Engl J Med. 1995;333(20):1301-1307
PubMed   |  Link to Article
Sacks FM, Pfeffer MA, Moye LA,  et al; Cholesterol and Recurrent Events Trial Investigators.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.  N Engl J Med. 1996;335(14):1001-1009
PubMed   |  Link to Article
Downs JR, Clearfield M, Weis S,  et al; Air Force/Texas Coronary Atherosclerosis Prevention Study.  Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS.  JAMA. 1998;279(20):1615-1622
PubMed   |  Link to Article
Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.  Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.  N Engl J Med. 1998;339(19):1349-1357
PubMed   |  Link to Article
GISSI Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico).  Results of the low-dose (20 mg) pravastatin GISSI Prevenzione trial in 4271 patients with recent myocardial infarction: do stopped trials contribute to overall knowledge?  Ital Heart J. 2000;1(12):810-820
PubMed
Heart Protection Study Collaborative Group.  MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.  Lancet. 2002;360(9326):7-22
PubMed   |  Link to Article
Shepherd J, Blauw GJ, Murphy MB,  et al;  PROSPER Study Group.  Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.  Lancet. 2002;360(9346):1623-1630
PubMed   |  Link to Article
Athyros VG, Papageorgiou AA, Mercouris BR,  et al.  Treatment with atorvastatin to the National Cholesterol Educational Program goal versus “usual” care in secondary coronary heart disease prevention: the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study.  Curr Med Res Opin. 2002;18(4):220-228
PubMed   |  Link to Article
Sever PS, Dahlöf B, Poulter NR,  et al; ASCOT Investigators.  Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.  Lancet. 2003;361(9364):1149-1158
PubMed   |  Link to Article
Colhoun HM, Betteridge DJ, Durrington PN,  et al; CARDS Investigators.  Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.  Lancet. 2004;364(9435):685-696
PubMed   |  Link to Article
Knopp RH, d’Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of coronary heart disease Endpoints in Non-insulin-dependent diabetes mellitus (ASPEN).  Diabetes Care. 2006;29(7):1478-1485
PubMed   |  Link to Article
Nakamura H, Arakawa K, Itakura H,  et al; MEGA Study Group.  Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial.  Lancet. 2006;368(9542):1155-1163
PubMed   |  Link to Article
Kjekshus J, Apetrei E, Barrios V,  et al; CORONA Group.  Rosuvastatin in older patients with systolic heart failure.  N Engl J Med. 2007;357(22):2248-2261
PubMed   |  Link to Article
Ridker PM, Danielson E, Fonseca FA,  et al;  JUPITER Study Group.  Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.  N Engl J Med. 2008;359(21):2195-2207
PubMed   |  Link to Article
Tavazzi L, Maggioni AP, Marchioli R,  et al; Gissi-HF Investigators.  Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.  Lancet. 2008;372(9645):1231-1239
PubMed   |  Link to Article
Cannon CP, Braunwald E, McCabe CH,  et al; Pravastatin or Atorvastatin Evaluation and Infection Therapy−Thrombolysis in Myocardial Infarction 22 Investigators.  Intensive versus moderate lipid lowering with statins after acute coronary syndromes.  N Engl J Med. 2004;350(15):1495-1504
PubMed   |  Link to Article
de Lemos JA, Blazing MA, Wiviott SD,  et al; A to Z Investigators.  Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial.  JAMA. 2004;292(11):1307-1316
PubMed   |  Link to Article
LaRosa JC, Grundy SM, Waters DD,  et al; Treating to New Targets (TNT) Investigators.  Intensive lipid lowering with atorvastatin in patients with stable coronary disease.  N Engl J Med. 2005;352(14):1425-1435
PubMed   |  Link to Article
Pedersen TR, Faergeman O, Kastelein JJ,  et al; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group.  High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.  JAMA. 2005;294(19):2437-2445
PubMed   |  Link to Article
Armitage J, Bowman L, Wallendszus K,  et al; Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group.  Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial.  Lancet. 2010;376(9753):1658-1669
PubMed   |  Link to Article
 Clofibrate and niacin in coronary heart disease.  JAMA. 1975;231(4):360-381
PubMed   |  Link to Article
Canner PL, Berge KG, Wenger NK,  et al.  Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin.  J Am Coll Cardiol. 1986;8(6):1245-1255
PubMed   |  Link to Article
Report From the Committee of Principal Investigators.  A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate.  Br Heart J. 1978;40(10):1069-1118
PubMed   |  Link to Article
Frick MH, Elo O, Haapa K,  et al.  Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease.  N Engl J Med. 1987;317(20):1237-1245
PubMed   |  Link to Article
Rubins HB, Robins SJ, Collins D,  et al; Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.  Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol.  N Engl J Med. 1999;341(6):410-418
PubMed   |  Link to Article
 Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study.  Circulation. 2000;102(1):21-27
PubMed   |  Link to Article
Ginsberg HN, Elam MB, Lovato LC,  et al; ACCORD Study Group.  Effects of combination lipid therapy in type 2 diabetes mellitus.  N Engl J Med. 2010;362(17):1563-1574
PubMed   |  Link to Article
Frick MH, Heinonen OP, Huttunen JK, Koskinen P, Mänttäri M, Manninen V. Efficacy of gemfibrozil in dyslipidaemic subjects with suspected heart disease: an ancillary study in the Helsinki Heart Study frame population.  Ann Med. 1993;25(1):41-45
PubMed   |  Link to Article
Moher D, Liberati A, Tetzlaff J, Altman DG.PRISMA Group.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.  BMJ. 2009;339:b2535
PubMed   |  Link to Article
Jadad AR, Moore RA, Carroll D,  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary?  Control Clin Trials. 1996;17(1):1-12
PubMed   |  Link to Article
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
Baigent C, Landray MJ, Reith C,  et al; SHARP Investigators.  The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial.  Lancet. 2011;377(9784):2181-2192
PubMed   |  Link to Article
Bodmer M, Brauchli YB, Krähenbühl S, Jick SS, Meier CR. Statin use and risk of gallstone disease followed by cholecystectomy.  JAMA. 2009;302(18):2001-2007
PubMed   |  Link to Article
Choi OS, Park SJ, Seo SW, Park CS, Cho JJ, Ahn HJ. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, lovastatin (statin) ameliorates CCK-induced acute pancreatitis in rats.  Biol Pharm Bull. 2005;28(8):1394-1397
PubMed   |  Link to Article
Almeida JL, Sampietre SN, Mendonça Coelho AM,  et al.  Statin pretreatment in experimental acute pancreatitis.  JOP. 2008;9(4):431-439
PubMed
Wei L, Yamamoto M, Harada M, Otsuki M. Treatment with pravastatin attenuates progression of chronic pancreatitis in rat.  Lab Invest. 2011;91(6):872-884
PubMed   |  Link to Article
von Bergmann K, Leiss O. Effect of short-term treatment with bezafibrate and fenofibrate on biliary lipid metabolism in patients with hyperlipoproteinaemia.  Eur J Clin Invest. 1984;14(2):150-154
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Literature Search
Graphic Jump Location

aMost records excluded for more than 1 reason, with only the strongest reason recorded.

Place holder to copy figure label and caption
Figure 2. Meta-analysis of Incident Pancreatitis in 21 Large Statin Trials
Graphic Jump Location

For abbreviations, see Table 1. Size of data markers indicates relative weight of the study (from random-effects analysis).

Place holder to copy figure label and caption
Figure 3. Meta-analysis of Incident Pancreatitis in 7 Large Fibrate Trials
Graphic Jump Location

For abbreviations, see Table 2. Size of data markers indicates relative weight of the study (from random-effects analysis).

Tables

Table Graphic Jump LocationTable 1. Baseline Data From 21 Large Statin Trials
Table Graphic Jump LocationTable 2. Baseline Data From Trials Comparing Fibrate Therapy With Placebo

References

Van Woerkom RC, Adler DG. Report of simultaneous acute pancreatitis and acute hepatitis in a patient taking ezetimibe/simvastatin.  J Clin Lipidol. 2010;4(4):314-315
PubMed   |  Link to Article
Badalov N, Baradarian R, Iswara K, Li J, Steinberg W, Tenner S. Drug-induced acute pancreatitis: an evidence-based review.  Clin Gastroenterol Hepatol. 2007;5(6):648-661
PubMed   |  Link to Article
Singh S, Loke YK. Statins and pancreatitis: a systematic review of observational studies and spontaneous case reports.  Drug Saf. 2006;29(12):1123-1132
PubMed   |  Link to Article
Tsigrelis C, Pitchumoni CS. Pravastatin: a potential cause for acute pancreatitis.  World J Gastroenterol. 2006;12(43):7055-7057
PubMed
US Food and Drug Administration (FDA).  Endocrinologic and Metabolic Drugs Advisory Committee Briefing Document: SHARP (Study of Heart and Renal Protection). FDA website. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM277652.pdf. 2011. Accessed June 6, 2012
Duane WC, Hunninghake DB, Freeman ML, Pooler PA, Schlasner LA, Gebhard RL. Simvastatin, a competitive inhibitor of HMG-CoA reductase, lowers cholesterol saturation index of gallbladder bile.  Hepatology. 1988;8(5):1147-1150
PubMed   |  Link to Article
Ewald N, Hardt PD, Kloer HU. Severe hypertriglyceridemia and pancreatitis: presentation and management.  Curr Opin Lipidol. 2009;20(6):497-504
PubMed   |  Link to Article
National Cholesterol Education Program.  Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). http://www.nhlbi.nih.gov/guidelines/cholesterol/. 2004. Accessed June 6, 2012
National Institute for Health and Clinical Excellence.  The management of type 2 diabetes. http://www.nice.org.uk/nicemedia/live/12165/44320/44320.pdf. 2009. Accessed June 6, 2012
Athyros VG, Giouleme OI, Nikolaidis NL,  et al.  Long-term follow-up of patients with acute hypertriglyceridemia-induced pancreatitis.  J Clin Gastroenterol. 2002;34(4):472-475
PubMed   |  Link to Article
Sandhu S, Al-Sarraf A, Taraboanta C, Frohlich J, Francis GA. Incidence of pancreatitis, secondary causes, and treatment of patients referred to a specialty lipid clinic with severe hypertriglyceridemia: a retrospective cohort study.  Lipids Health Dis. 2011;10:157
PubMed   |  Link to Article
Keech A, Simes RJ, Barter P,  et al; FIELD Study Investigators.  Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.  Lancet. 2005;366(9500):1849-1861
PubMed   |  Link to Article
Experience in the Coronary Drug Project.  Gallbladder disease as a side effect of drugs influencing lipid metabolism.  N Engl J Med. 1977;296(21):1185-1190
PubMed   |  Link to Article
Palmer RH. Effects of fenofibrate on bile lipid composition.  Arteriosclerosis. 1985;5(6):631-638
PubMed   |  Link to Article
Baigent C, Blackwell L, Emberson J,  et al; Cholesterol Treatment Trialists' (CTT) Collaboration.  Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.  Lancet. 2010;376(9753):1670-1681
PubMed   |  Link to Article
 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).  Lancet. 1994;344(8934):1383-1389
PubMed
Shepherd J, Cobbe SM, Ford I,  et al; West of Scotland Coronary Prevention Study Group.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.  N Engl J Med. 1995;333(20):1301-1307
PubMed   |  Link to Article
Sacks FM, Pfeffer MA, Moye LA,  et al; Cholesterol and Recurrent Events Trial Investigators.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.  N Engl J Med. 1996;335(14):1001-1009
PubMed   |  Link to Article
Downs JR, Clearfield M, Weis S,  et al; Air Force/Texas Coronary Atherosclerosis Prevention Study.  Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS.  JAMA. 1998;279(20):1615-1622
PubMed   |  Link to Article
Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.  Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.  N Engl J Med. 1998;339(19):1349-1357
PubMed   |  Link to Article
GISSI Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico).  Results of the low-dose (20 mg) pravastatin GISSI Prevenzione trial in 4271 patients with recent myocardial infarction: do stopped trials contribute to overall knowledge?  Ital Heart J. 2000;1(12):810-820
PubMed
Heart Protection Study Collaborative Group.  MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.  Lancet. 2002;360(9326):7-22
PubMed   |  Link to Article
Shepherd J, Blauw GJ, Murphy MB,  et al;  PROSPER Study Group.  Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.  Lancet. 2002;360(9346):1623-1630
PubMed   |  Link to Article
Athyros VG, Papageorgiou AA, Mercouris BR,  et al.  Treatment with atorvastatin to the National Cholesterol Educational Program goal versus “usual” care in secondary coronary heart disease prevention: the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study.  Curr Med Res Opin. 2002;18(4):220-228
PubMed   |  Link to Article
Sever PS, Dahlöf B, Poulter NR,  et al; ASCOT Investigators.  Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.  Lancet. 2003;361(9364):1149-1158
PubMed   |  Link to Article
Colhoun HM, Betteridge DJ, Durrington PN,  et al; CARDS Investigators.  Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.  Lancet. 2004;364(9435):685-696
PubMed   |  Link to Article
Knopp RH, d’Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of coronary heart disease Endpoints in Non-insulin-dependent diabetes mellitus (ASPEN).  Diabetes Care. 2006;29(7):1478-1485
PubMed   |  Link to Article
Nakamura H, Arakawa K, Itakura H,  et al; MEGA Study Group.  Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial.  Lancet. 2006;368(9542):1155-1163
PubMed   |  Link to Article
Kjekshus J, Apetrei E, Barrios V,  et al; CORONA Group.  Rosuvastatin in older patients with systolic heart failure.  N Engl J Med. 2007;357(22):2248-2261
PubMed   |  Link to Article
Ridker PM, Danielson E, Fonseca FA,  et al;  JUPITER Study Group.  Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.  N Engl J Med. 2008;359(21):2195-2207
PubMed   |  Link to Article
Tavazzi L, Maggioni AP, Marchioli R,  et al; Gissi-HF Investigators.  Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial.  Lancet. 2008;372(9645):1231-1239
PubMed   |  Link to Article
Cannon CP, Braunwald E, McCabe CH,  et al; Pravastatin or Atorvastatin Evaluation and Infection Therapy−Thrombolysis in Myocardial Infarction 22 Investigators.  Intensive versus moderate lipid lowering with statins after acute coronary syndromes.  N Engl J Med. 2004;350(15):1495-1504
PubMed   |  Link to Article
de Lemos JA, Blazing MA, Wiviott SD,  et al; A to Z Investigators.  Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial.  JAMA. 2004;292(11):1307-1316
PubMed   |  Link to Article
LaRosa JC, Grundy SM, Waters DD,  et al; Treating to New Targets (TNT) Investigators.  Intensive lipid lowering with atorvastatin in patients with stable coronary disease.  N Engl J Med. 2005;352(14):1425-1435
PubMed   |  Link to Article
Pedersen TR, Faergeman O, Kastelein JJ,  et al; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group.  High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.  JAMA. 2005;294(19):2437-2445
PubMed   |  Link to Article
Armitage J, Bowman L, Wallendszus K,  et al; Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group.  Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial.  Lancet. 2010;376(9753):1658-1669
PubMed   |  Link to Article
 Clofibrate and niacin in coronary heart disease.  JAMA. 1975;231(4):360-381
PubMed   |  Link to Article
Canner PL, Berge KG, Wenger NK,  et al.  Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin.  J Am Coll Cardiol. 1986;8(6):1245-1255
PubMed   |  Link to Article
Report From the Committee of Principal Investigators.  A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate.  Br Heart J. 1978;40(10):1069-1118
PubMed   |  Link to Article
Frick MH, Elo O, Haapa K,  et al.  Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease.  N Engl J Med. 1987;317(20):1237-1245
PubMed   |  Link to Article
Rubins HB, Robins SJ, Collins D,  et al; Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.  Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol.  N Engl J Med. 1999;341(6):410-418
PubMed   |  Link to Article
 Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study.  Circulation. 2000;102(1):21-27
PubMed   |  Link to Article
Ginsberg HN, Elam MB, Lovato LC,  et al; ACCORD Study Group.  Effects of combination lipid therapy in type 2 diabetes mellitus.  N Engl J Med. 2010;362(17):1563-1574
PubMed   |  Link to Article
Frick MH, Heinonen OP, Huttunen JK, Koskinen P, Mänttäri M, Manninen V. Efficacy of gemfibrozil in dyslipidaemic subjects with suspected heart disease: an ancillary study in the Helsinki Heart Study frame population.  Ann Med. 1993;25(1):41-45
PubMed   |  Link to Article
Moher D, Liberati A, Tetzlaff J, Altman DG.PRISMA Group.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.  BMJ. 2009;339:b2535
PubMed   |  Link to Article
Jadad AR, Moore RA, Carroll D,  et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary?  Control Clin Trials. 1996;17(1):1-12
PubMed   |  Link to Article
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
Baigent C, Landray MJ, Reith C,  et al; SHARP Investigators.  The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial.  Lancet. 2011;377(9784):2181-2192
PubMed   |  Link to Article
Bodmer M, Brauchli YB, Krähenbühl S, Jick SS, Meier CR. Statin use and risk of gallstone disease followed by cholecystectomy.  JAMA. 2009;302(18):2001-2007
PubMed   |  Link to Article
Choi OS, Park SJ, Seo SW, Park CS, Cho JJ, Ahn HJ. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, lovastatin (statin) ameliorates CCK-induced acute pancreatitis in rats.  Biol Pharm Bull. 2005;28(8):1394-1397
PubMed   |  Link to Article
Almeida JL, Sampietre SN, Mendonça Coelho AM,  et al.  Statin pretreatment in experimental acute pancreatitis.  JOP. 2008;9(4):431-439
PubMed
Wei L, Yamamoto M, Harada M, Otsuki M. Treatment with pravastatin attenuates progression of chronic pancreatitis in rat.  Lab Invest. 2011;91(6):872-884
PubMed   |  Link to Article
von Bergmann K, Leiss O. Effect of short-term treatment with bezafibrate and fenofibrate on biliary lipid metabolism in patients with hyperlipoproteinaemia.  Eur J Clin Invest. 1984;14(2):150-154
PubMed   |  Link to Article
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Supplemental Content

Preiss D, Tikkanen MJ, Welsh P, et al. Lipid-modifying therapies and risk of pancreatitis: a meta-analysis. JAMA. doi:10.1001/jama.2012.8439.

eFigure 1A-B. Funnel Plots for Statin Trials and Fibrate Trials

eFigure 2A-B. Meta-Regression Plots of Incident Pancreatitis and the Percentage Magnitude of Triglyceride-Lowering at 1 Year in (A) Statin Trials and (B) Fibrate Trials

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