Lipid-Modifying Therapies Lower Risk of Pancreatitis

The intensity of pancreatitis can range from a mild, self-limiting episode to a severe or even fatal event. There have been case reports and studies suggesting that pancreatitis may be caused by statin use. According to researchers, few of these studies have considered confounding factors and there are few large randomized trials of statin therapy that include data on incident pancreatitis.

The SHARP (Study of Heart and Renal Protection) trial that compared combination therapy of simvastatin and ezetimibe with placebo on cardiovascular events in patients with chronic kidney disease found a reduction in cases of incident pancreatitis in patients in the simvastatin and ezetimibe group, findings that suggest a possible protective association. Statins reduce bile cholesterol content, which may reduce the risk of gallstones, a risk factor for pancreatitis.

The third most common cause of pancreatitis has been reported to be hypertriglyceridemia, leading to guidelines for lipid-modifying therapies that advise beginning therapy to lower triglycerides (usually with fibrates) in persons with moderate and severe hypertriglyceridemia (.400-500 md/dL). However, there is concern that fibrates may increase the risk of pancreatitis in persons with triglycerides lower than in the guidelines.

Noting the uncertainty of the associations between both types of lipid-modifying therapy and the risks of pancreatitis, researchers recently conducted collaborative meta-analyses of published and unpublished data from relevant large randomized trials to identify the connections. They reported results of the analyses in the Journal of the American Medical Association [2012;308(8):804-811].

The researchers performed literature searches of MEDLINE, EMBASE, and Thomson Reuters Web of Science^® (January 1, 1994, for statin trials, and January 1, 1972, for fibrate trials, through June 9, 2012). Published pancreatitis data from 6 trials were tabulated; unpublished data from 22 unpublished trials were obtained from investigators. Of the 28 trials, 21 were statin trials and 7 were fibrate trials.

Participants were identified as developing pancreatitis during the trial when pancreatitis was recorded as an adverse event or a serious adverse event.

In 16 trials (placebo and standard-care controlled) with 113,800 participants conducted over 4.1 years, 0.27% of participants (n=309) developed pancreatitis; of those, 134 were assigned to statin and 175 were assigned to control (relative risk [RR], 0.77; 95% confidence interval [CI], 0.62-0.97; P=.03). In 5 dose-comparison statin trials with 39,614 patients conducted over 4.8 years, 0.39% of participants (n=156) developed pancreatitis (70 assigned to intensive dose, 86 assigned to moderate dose; RR, 0.82; 95% CI, 0.59-1.12; P=.211).

In the combined data set of the 21 statin trials, 0.30% of participants (n=465) developed pancreatitis. Using a fixed-effects model approach produced results (RR, 0.79; 95% CI, 0.65-0.95; P=.011) identical to those of the random-effects model.

The 7 randomized clinical trials of fibrate therapy provided data on 40,162 participants over 5.3 years. During the mean follow-up period, 0.36% (n=144) of participants developed pancreatitis (84 assigned to fibrate therapy and 60 assigned to placebo; RR, 1.39; 95% CI, 1.00-1.95; P=.053).

Limitations cited by the researchers included pancreatitis not being a prespecified end point in the trials, the lack of standardization in the way in which pancreatitis was recorded, the inability to examine specific causes of pancreatitis such as gallstones, and lack of access to individual-participant data, which may have reduced the ability to identify any relationship with the extent of triglyceride lowering. In addition, because exclusion criteria in the trials tended to include patients with marked hypertriglyceridemia, the findings may not be generalizable to that specific  group of patients.

In summary, the researchers stated, “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.”