Gallbladder disease as a side effect of drugs influencing lipid metabolism. Experience in the Coronary Drug Project

N Engl J Med. 1977 May 26;296(21):1185-90. doi: 10.1056/NEJM197705262962101.


We analyzed data obtained during the Coronary Drug Project to discover the influence of the drugs used on the frequency of gallbladder disease. Of 2680 placebo-treated men who had had myocardial infarction, gallbladder disease developed in 69. Corresponding figures for those given 2.5 mg of estrogen, 5.0 mg of estrogen and 1.8 g of clofibrate per day were 46 of 1061, 47 of 1081 and 42 of 1051, respectively. Each treatment group differed from placebo by over twice the standard error of the difference, life-table analysis yielding P less than 0.05 for each drug-placebo comparison. Forty-five variables, including age, body weight, blood pressure, serum lipids and blood sugar, were evaluated as risk factors. Age significantly correlated with prevalence of known gallbladder disease at entry (r = 0.066, P less than 0.001). No variable yielded a strong and consistent correlation with the incidence of subsequent new gallbladder disease. Gallstone formation is a risk whenever clofibrate or estrogen is prescribed.

PIP: Data obtained during the Coronary Drug Project were analyzed to determine the influence of drugs on the frequency of gall bladder disease. All subjects were males with a history of myocardial infarction. The cholesterol-lowering drugs tester were mixed conjugated equine estrogens in doses of 2.5 and 5 mg/day, clofibrate 1.8 gm/day, dextrothyroxine 6 mg/day, nicotinic acid 3 gm/day, and placebos. The observation period was over 5 years. Patients receiving clofibrate and both estrogen dosage groups had the highest incidence of cholecystitis or cholelithiasis. Each treatment group, except those taking dextrothyroxine, exceeded the placebo-taking group in incidence of gallbladder disease (p .05). Of 45 variables evaluated as risk factors, only age of the subject correlated with incidence of gallbladder disease prior to the tests (p .001). None of these variables gave a constant correlation with the incidence of subsequent new gallbladder disease. The development of gallstones must be accepted as an anticipated risk whenever estrogens or clofibrate are prescribed.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Age Factors
  • Anticholesteremic Agents / adverse effects*
  • Body Height
  • Body Weight
  • Cholecystitis / chemically induced
  • Cholelithiasis / chemically induced
  • Cholesterol / blood
  • Clinical Trials as Topic
  • Clofibrate / adverse effects*
  • Coronary Disease / prevention & control
  • Estrogens / adverse effects*
  • Gallbladder Diseases / chemically induced*
  • Gallbladder Diseases / epidemiology
  • Humans
  • Male
  • Middle Aged
  • Risk


  • Anticholesteremic Agents
  • Estrogens
  • Cholesterol
  • Clofibrate