Original Article
Gallbladder Disease as a Side Effect of Drugs Influencing Lipid Metabolism Experience in the Coronary Drug Project
N Engl J Med 1977; 296:1185-1190May 26, 1977DOI: 10.1056/NEJM197705262962101
- Abstract
- Abstract
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<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<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. (N Engl J Med 296:1185–1190, 1977)
Media in This Article
Figure 1
Life-Table Curves for the Development of New, Definite Cholecystitis or Cholelithiasis in the Groups Given Placebo, Clofibrate (CPIB) and Nicotinic Acid (NICA).Figure 2
Life-Table Curves for the Development of New, Definite Cholecystitis or Cholelithiasis in the Groups Given Placebo, 2.5 Mg of Estrogen (ESG1), 5.0 Mg of Estrogen (ESG2) and Dextrothyroxine (D-T4).Article Activity
- Article
The Coronary Drug Project was planned during the period 1961–1965 as a randomized, doubleblind, prospective, large-scale clinical trial.1 Two of its major objectives were "to evaluate the efficacy of cholesterol-lowering drugs in the long-term therapy of CHD [coronary heart disease]...." and "to obtain information on the natural history and clinical course of CHD." The cholesterol-lowering drugs to be tested were mixed conjugated equine estrogens in two dosage levels, 2.5 and 5.0 mg per day, clofibrate, 1.8 g per day, dextrothyroxine, 6.0 mg per day, and nicotinic acid, 3.0 g per day.
The Project established mechanisms for monitoring both beneficial and adverse effects of the several drugs from the outset. The possibility that drugs affecting serum lipid concentrations might also influence the formation or clinical manifestations of cholesterol gallstones was not foreseen at the time the study was planned, however. Indeed, recruitment of patients was more than half completed before the appearance of the work of Admirand and Small,2 calling attention to the relation of biliary lipid concentrations to the occurrence of gallstones.
In 1971, on the basis of experiments that showed that the administration of clofibrate to post-cholecystectomy patients with T-tubes in place caused an elevation of biliary cholesterol saturation, Pertsemlidis and his colleagues3 suggested that the Coronary Drug Project initiate an investigation of gallbladder disease. We summarize analyses of the resulting data for the effects of the several drugs on the diagnosis of gallbladder disease, and for demographic, clinical and biochemical variables measured at base line and their possible relation to the occurrence of gallbladder disease. A table indicating that gallbladder disease had a higher incidence in the clofibrate treatment group than in the control group has already appeared.4
Methods
The experimental design of the Coronary Drug Project and the status of all treatment groups at base line have already been described in detail.1 Likewise, detailed accounts of the findings culminating in the discontinuation of three of the treatment groups are to be found in previous papers 5 6 7; therefore, these aspects of the project are only summarized here.
Over a period of 3 1/2 years, 8341 patients were recruited by 53 cooperating clinical units. To qualify, a prospect had to be a man from 30 to 64 years of age and to have documentary evidence of a myocardial infarction occurring not less than three months previously. He had to be free of a number of conditions that might limit life expectancy or impair co-operation and had to show no more than slight limitation of physical activity. After extensive base-line evaluation, these patients were randomly assigned to one placebo and five treatment groups, the number assigned to placebo being 2.5 times as great as that assigned to any one of the five drug groups. Active drugs and the lactose placebo were administered in capsules of identical appearance. We followed patients with clinic visits and examinations every four months until the last recruited had had five years of observation.
Observations recorded at follow-up visits centered around the cardiovascular system, and special attention was paid to evidence indicating the level of continuing compliance with the prescribed treatment regimen. Side effects of the drugs that were foreseen were also looked for at each follow-up visit. Although none of the routine questions dealt specifically with gallbladder disorders, a number were pertinent to the present study. Any hospitalization was to be recorded, and the indication summarized. Examiners also inquired for several common gastrointestinal symptoms and indicated whether or not they believed that any noteworthy abnormality of the gastrointestinal system existed on the basis of historical, physical or laboratory evidence.
In early 1970, when the average follow-up period was 18 months, treatment with 5 mg of estrogen was discontinued for all patients assigned to it, but regular follow-up was maintained. At the same time, dextrothyroxine was discontinued in a small subgroup of patients. In the fall of 1971, dextrothyroxine was discontinued in all patients remaining on that treatment. Finally, in March, 1973, treatment with 2.5 mg of estrogen was discontinued. The Policy Board and Steering Committee made these decisions on the recommendation of the Data and Safety Monitoring Committee because of evidence that the adverse effects of treatment outweighed the possibility of benefit and that trends in overall mortality were unfavorable to the drugs. Thus, the only patients to complete the protocol as originally designed were those on placebo, nicotinic acid and clofibrate. The last two drugs, although effective in producing modest decreases in serum lipid levels, could not be shown to reduce total or cause-specific mortality.4
During the period 1972–1974, a total of 1529 surviving patients whose treatment had been discontinued were re-randomized and enrolled in a new double-blind study of the effect of aspirin, 324 mg three times daily, in the prevention of recurrent myocardial infarction. The schedule of follow-up visits in this second study (known as CDPA) and the list of data to be collected were almost identical to those used in the original Coronary Drug Project. One important exception was that the CDPA annual follow-up examination specifically requested information concerning the development of gallbladder disease. A full description of the methods and results of the CDPA has recently appeared.8
The study of gallbladder disease began in July, 1972, when each clinic in the Coronary Drug Project was sent a list of all its patients (including those known to have died) and asked to check off the names of all who were free of known gallbladder disorders. For each case not checked, a three-page questionnaire was to be completed covering the date of onset, the strength of diagnostic evidence, the type of gallbladder disease that had been diagnosed, whether or not operation had been performed, and, if so, whether or not gallstones had been obtained and analyzed. Gallbladder disease discovered only at autopsy was also to be reported. Each clinical unit was requested to update the form if, at any time before termination of the Coronary Drug Project on August 31, 1974, there was a change in any patient's initially reported status.
The collected forms were not extensively edited during the study, although clinics were queried by co-ordinating-center clerical personnel about obvious omissions. Further editing was done after the Coronary Drug Project and CDPA had discontinued data collection by one of us (R.S.G.), an internist who was at the time unaware of the treatment groups to which individual patients belonged. During this editing, information recorded in narrative form by the clinics was coded for computer processing, and internal inconsistencies, where detected, were resolved so far as possible with the aid of other study forms.
A patient was assigned to the class of definite cholecystitis or cholelithiasis if a cholecystectomy was required for either or both of these conditions or, in the absence of operation, on the basis of x-ray evidence. A case was considered definite if cholecystography showed stones or nonfunction. (We cannot be certain that second doses of dye were given in every case.) A case was also considered definite if a calcified gallstone was identified on another abdominal x-ray examination, if a surgeon reported palpating gallstones during a laparotomy done for a purpose other than cholecystectomy, or if gallstones were discovered at autopsy. The category of suspect cholecystitis or cholelithiasis included all cases with the clinical diagnosis, but evidence less firm than that stated above. Poor function on a cholecystogram was taken as evidence of suspect gallbladder disease. "Other gallbladder disease" included miscellaneous, less common entities such as cholesterolosis, adenomyoma and one case of carcinoma of the gallbladder.
For every case, the reporting physician assigned a month and year of incidence in answer to a query concerning the "approximate date of first symptoms of gallbladder disease." For patients in whom gallbladder disease was discovered only at autopsy, the date of death was considered the date of incidence.
Only a few of the questionnaires returned contained definite information on the chemical composition of gallstones that had been removed. In most of the remainder, the gross description did not permit a confident distinction between cholesterol and pigment stones; therefore, we made no attempt to analyze incidence of cholesterol and bile pigment stone separately.
Excluding from the population at risk any patient who had had a prior cholecystectomy or had a prior diagnosis of any gallbladder disease, the incidence of new cases of clinically manifest, definite cholecystitis or cholelithiasis was compared among the several treatment groups by a life-table technic — a statistical procedure for determining the rate of occurrence of an event over time when patients have varying lengths of follow-up period — based on the method of Littell.9 Suspect cases and other gallbladder disease were treated as noncases for this analysis. We computed the z value for a drug-placebo comparison of life-table incidence curves by finding the difference in estimated "forces of mortality" for the two groups and dividing by the standard error of this difference.
Simple and multiple linear-regression analyses10 were performed to relate the development of definite, new cholecystitis or cholelithiasis (omitting 15 suspect cases and six cases of other gallbladder disease from the analysis) among patients in the whole population and in each separate treatment group to the 45 base-line variables that were considered to be of possible interest. These variables included age, race, height, relative body weight, systolic blood pressure, diastolic blood pressure, region of the country, type of clinic (accounting for two regression variables), leisure-time physical activity habits and smoking status; prior history of congestive heart failure, angina pectoris, acute coronary insufficiency, intermittent cerebral ischemic attacks, stroke, intermittent claudication, peripheral arterial occlusion or gout; treatment during the base-line period with oral hypoglycemic agents, digitalis, anti-arrhythmic drugs, diuretics, antihypertensive drugs, nitroglycerin or medications for gout; the reported number of previous myocardial infarctions, length of the interval since the most recent episode of infarction, and the patient's New York Heart Association functional class, the cardiac "risk group" as defined by the Coronary Drug Project; and serum glutamic oxalacetic transaminase, total bilirubin, cholesterol, triglycerides, uric acid, alkaline phosphatase, urea nitrogen, plasma glucose, both fasting and one hour after a glucose load, protein-bound iodine, urinary glucose, urinary protein, hematocrit, total white-cell count and absolute neutrophil count. A complete description of each of these variables and of the laboratory methods used has been given in previous Coronary Drug Project publications.1 , 11
Finally, the presence or absence of definite cholecystitis or cholelithiasis at entry into the Coronary Drug Project (considering previous cholecystectomy as definite evidence of cholecystitis or cholelithiasis, though in many cases details of operations done in the past were lacking) was related to the same 45 base-line variables by means of the multiple linear-regression analysis. Twenty-eight cases of suspect cholecystitis or cholelithiasis or of other gallbladder disease were omitted from the analysis. This analysis was done for the whole population and separately for two subpopulations — those randomized to the placebo group and those randomized into any drug treatment group.
It might be added here that a conscious decision was made to use the linear-regression rather than the logistic-regression model. Experience with data from the Coronary Drug Project indicates that the linear-regression model provides nearly as good a fit to the data as the logistic model, and is more convenient and economical to use than the logistic model.11
Results
Table 1Table 1
Incidence of Definite Cholecystitis or Cholelithiasis. and Figures 1Figure 1Life-Table Curves for the Development of New, Definite Cholecystitis or Cholelithiasis in the Groups Given Placebo, Clofibrate (CPIB) and Nicotinic Acid (NICA). and 2Figure 2Life-Table Curves for the Development of New, Definite Cholecystitis or Cholelithiasis in the Groups Given Placebo, 2.5 Mg of Estrogen (ESG1), 5.0 Mg of Estrogen (ESG2) and Dextrothyroxine (D-T4). summarize the incidence of cholecystitis or cholelithiasis in the Coronary Drug Project population.The patients receiving clofibrate and both estrogen-treated groups showed the highest incidence of newly recognized definite cholecystitis or cholelithiasis, each treatment group differing from the placebo control group by over twice the standard error of the difference. It is noteworthy that the experience of the group receiving 5 mg of estrogen continued to diverge from that of the placebo group for the full six years for which we have data from a large fraction of the population, even though the drug was given for an average of only 18 months. The group treated with nicotinic acid had more, and that treated with dextrothyroxine had less, gallbladder disease than the placebo group, but these differences were not statistically significant at the 5 per cent level. In Figures 1 and 2 the vertical symbols show twice the standard error of the difference between the placebo group and any one of the treated groups (not, as is more usual in single comparisons, twice the standard error of the mean for a single group). The z values for drug-placebo comparisons are 2.52 for 2.5 mg of estrogen, 2.55 for 5.0 mg of estrogen, 2.39 for clofibrate, -0.83 for dextrothyroxine and 1.65 for nicotinic acid.The comparisons for both estrogen groups and clofibrate are statistically significant at the 5 per cent level, even after adjustment for multiple drug-placebo comparisons using the Dunnett procedure for a one-sided test.12 (A one-sided test seems appropriate here, particularly for clofibrate, considering the reasons for initiating the collection of information on gallbladder disease in the Coronary Drug Project.) The horizontal bars in Figure 2 show the protocol changes described above. Note that in this life-table plot, which assigns a time value of zero to each patient's entry into the study, a simultaneous event like the discontinuation of a medication covers a range of 3 1/2 years — equal to the time-span of the recruitment period. Note also that there is no suggestion that the initiation of the CDPA has influenced the rate of ascertainment of gallbladder disease in the treatment groups from which recruitment occurred.
In the search for base-line characteristics that would be important risk factors either for base-line prevalence of known gallbladder disease or for subsequent incidence of new diagnosis, it was necessary to establish conservative criteria for significance because of the multiplicity of possible correlations (45 base-line variables, two possible outcomes and a population that had been randomized into six treatment groups that we had studied separately). Accordingly, we decided to report only correlations yielding a t value, adjusted for the other 44 variables, of 3.0 or more in absolute value (corresponding to a nominal P value of 0.003 or less) in the analysis of the entire population, and that we would question the true significance of any such correlation that did not appear consistently when separate treatment groups were studied. Table 2Table 2
Base-Line Characteristics Related to Prevalence of Known Gallbladder Disease before Entry into the Coronary Drug Project.* indicates the characteristics for which the analysis yielded a t 
3.0 or 
-3.0 with prevalence of gallbladder disease at entry as the outcome variable. The only base-line variable that seemed to correlate with incidence of new diagnosis of gallbladder disease during the Coronary Drug Project was serum triglyceride, for which values of r and t were 0.038 and 3.24, respectively. However, this last correlation was not consistent across treatment groups, with r values ranging from -0.014 to 0.063.Discussion
At the outset, it is important to consider whether or not these results, obtained in a study in which male sex and a history of myocardial infarction were prerequisites for entry, can be generalized. Friedman13 undertook a review of all the evidence of an association between coronary heart disease and gallbladder disease, and concluded that there was at most a weak positive association. More recently, Bateson and Bouchier,14 in an extensive autopsy study, found a trend toward a negative association that was not statistically significant. In the absence of any clear-cut indication that the presence of coronary disease is a noteworthy risk factor related to the development of gallstones, it is our belief that the present results should be generalizable to the larger population of all middle-aged men. The well known differences in incidence and prevalence of gallbladder disease between the sexes, however, limit the applicability of these findings to women. Some putative associations of gallbladder disease with other conditions have been reported only among women — for example, that with hypertension.15 Others are relevant only to women, such as that with parity.16 17 18 We believe that, with the exception of sex-specific relations of this sort, our results should qualitatively reflect correlations that might apply to women, but these correlations may not be quantitatively correct.
There is evidence from the Coronary Drug Project that two drugs (estrogen and clofibrate) that affect lipid metabolism also increase the risk of gallbladder disease. The fact that this was a prospective study, with drug and placebo groups having been randomized and tested for comparability in many base-line variables (even though none of the variables appear to predict risk of gallbladder problems), markedly strengthens the assumption that if the association is real, it is truly causal as well. Also, it should be borne in mind that the Coronary Drug Project was a study of a serious, life-threatening disease of the heart, and that the observations on gallbladder disorders were made only incidentally. We believe this fact minimizes the likelihood of bias due to preconceived notions on the part of either patients or observers.
The finding that clofibrate predisposes to the appearance of gallbladder disease is consistent with several other studies. Grundy et al.19 showed that clofibrate increases the secretion of cholesterol into bile. Pertsemlidis and his co-workers3 demonstrated an increased saturation of bile with cholesterol after clofibrate administration, and predicted that the drug would be lithogenic. More recently, Cooper et al.20 have indicated that findings in another prospective clinical trial of clofibrate point to more than a doubling of the rate of cholecystectomy among those receiving the drug. Finally, Bateson and Bouchier (personal communication) have found, in a cholecystographic survey among patients refered to a serum lipid clinic, that gallstones are significantly more common among those who had previously been given clofibrate. The risk of development of gallbladder disease should therefore be listed among the recognized untoward side effects of this agent.
The relation of estrogens to gallbladder disease is also not surprising. It is consistent with the known higher rates of gallbladder disease among women. Other evidence pointing in the same direction is to be found in the studies of Pertsemlidis3 and Bennion21 and their colleagues of the effects of estrogen-containing preparations on the lithogenicity of bile, and in the several epidemiologic studies showing a higher rate of gallbladder disease among women taking estrogens.22 23 24 Thus, we think that the development of gallstones must be accepted as an anticipated risk whenever estrogens are prescribed.
Throughout the present study there is an underlying uncertainty that might be eliminated in future investigations. Since the number of unsuspected cases of gallbladder disease in a population of this sort probably exceeds the number ever diagnosed,25 , 26 the possibility must be considered that an apparent aggravating factor, such as treatment with clofibrate, is not causing new gallstones to be formed, but only calling additional attention to those that already exist. This possibility could be tested rigorously if the true prevalence of gallbladder disease at entry had been determined by a cholecystographic survey of an adequate sample, and if all the cholecystograms obtained during the study, whether normal or abnormal, had been recorded. We recommend that consideration be given to collecting such data in future trials of therapy influencing cholesterol metabolism.
This study has failed to confirm some putative correlations for which there are claims in the literature — namely, those between gallbladder disease and hypertension15 , 16 or hyperglycemia.17 We found no t value as great as 1.5 for any of these correlations. It gives only weak and inconsistent evidence in favor of relative body weight16 , 17 as a determinant, and our apparent correlation of height with base-line prevalence of gallbladder disease is in a direction opposite to the trend reported by Friedman, Kannel and Dawber.16 The one consistent (but far from surprising) correlation was that between age and a previous diagnosis of cholecystitis or cholelithiasis. The finding that age correlated strongly with prevalence at entry, but not with subsequent incidence during the study, is consistent with the linear model proposed by Opit and Greenhill27 to fit autopsy data on prevalence of gallstones.
It now appears that a medical alternative to cholecystectomy may soon be generally available, and that it will be most efficacious in the treatment of patients whose cholesterol gallstone disease is discovered early.28 For this reason, the identification of high-risk groups, among whom a search for early, easily curable gallstones will have a higher yield, will probably become important. Our inability to identify any base-line risk factors that were important determinants of the subsequent likelihood of the development of manifest gallbladder disease, in spite of a total of over 39,000 man-years of observation, is disappointing in this regard. It appears that a search for new, important risk factors in gallbladder disease, among men at least, will have to focus on characteristics not measured in the Coronary Drug Project.
Prepared for the Coronary Drug Project Research Group by Robert S. Gordon, Jr., M.D., Sandra Forman, M.A., Paul Canner, Ph.D., Kenneth Berge, M.D., and Dayton Miller, Ph.D. (address reprint requests to the Coronary Drug Project Coordinating Center, Division of Clinical Investigation, University of Maryland School of Medicine, 600 Wyndhurst Ave., Baltimore, MD 21210).
The Coronary Drug Project was carried out as a collaborative study supported by research grants and other funds from the National Heart, Lung, and Blood Institute (a more detailed version of this report is available on request).
The key bodies of the Coronary Drug Project and their senior staff members are as follows:
Policy Board: Robert W. Wilkins, M.D. (chairman); Jacob E. Bearman, Ph.D.; Edwin Boyle, M.D.; William M. Smith, M.D., M.P.H.; Christian R. Klimt, M.D., Dr. P.H. (ex officio); Jeremiah Stamler, M.D. (ex officio); Max Halperin, Ph.D. (ex officio); and William Zukel, M.D. (ex officio). Past member: Louis Lasagna, M.D.
Steering Committee: Jeremiah Stamler, M.D. (chairman); Kenneth Berge, M.D. (vice-chairman); William Bernstein, M.D.; Henry Blackburn, M.D.; Joseph H. Boutwell, M.D.; Jerome Cornfield; William Friedewald, M.D.; Lawrence Friedman, M.D.; Nicholas J. Galluzzi, M.D.; Max Halperin, Ph.D.; Christian R. Klimt, M.D., Dr. P.H.; Charles A. Laubach, Jr., M.D.; Jessie Marmorston, M.D.; and Nanette Wenger, M.D. Past members: David M. Berkson, M.D.; Gerald Cooper, M.D.; Kenneth Hyatt, M.D.; Bernard I. Lewis, M.D.; Milton Nichaman, M.D.; William Parsons, Jr., M.D.; Henry Schoch, M.D.; and William J. Zukel, M.D.
Coordinating Center: Paul L. Canner, Ph.D. (principal investigator); Christian R. Klimt, M.D., Dr. P.H. (co-investigator); Robert S. Gordon, Jr., M.D.; Frances Fazio; Sandra Forman, M.S.; Elizabeth C. Heinz; Yih-Min Bill Huang, Ph.D.; Genell L. Knatterud, Ph.D.; William F. Krol, Ph.D.; Curtis L. Meinert, Ph.D.; and Gerard Prud'homme, M.A. Past members: David R. Jacobs, Jr., Ph.D.; and Suketami Tominaga, M.D.
Central Laboratory: Joseph Boutwell, M.D. (medical director); Dayton Miller, Ph.D. (chief); John Donahue, M.S; James Gill, Jr., M.S.; Sara Gill. Past members: Gerald R. Cooper, M.D.; Eloise Eavenson, Ph.D.; Adrian Hainline, M.D.; Alan Mather, Ph.D.; and Margie Sailors.
ECG Center: Henry Blackburn, M.D. (director of the Laboratory of Physiological Hygiene); Ronald J. Prineas, M.D. (director of the ECG Center); and Gretchen Newman. Past member: Robin MacGregor.
National Heart, Lung, and Blood Institute Staff: William Friedewald, M.D.; Lawrence Friedman, M.D.; Max Halperin, Ph.D.; and William Zukel, M.D. Past members: Clifford Bachrach, M.D.; Jerome Cornfield; Eleanor Darby, Ph.D.; Michael Davidson, M.D.; Terrance Fisher, M.D.; Starr Ford, Jr., M.D.; William Goldwater, Ph.D.; Richard Havlik, M.D.; Thomas Landau, M.D.; Hubert Loncin, M.D.; Howard Marsh, M.D., Ph.D.; John Turner, M.D.; and William Vicic, M.D.
Drug Procurement and Distribution Center: Salvatore Gasdia (officer in charge).
Editorial Review Committee: Jeremiah Stamler, M.D. (chairman); Kenneth Berge, M.D.; Henry Blackburn, M.D.; Jerome Cornfield; William Friedewald, M.D.; Lawrence Friedman, M.D.; Max Halperin, Ph.D.; Christian R. Klimt, M.D., Dr. P.H.; Bernard Tabatznik, M.D.; Robert W. Wilkins, M.D.; and Nanette Wenger, M.D.
Principal Investigators, Clinical Research Centers: Kenneth G. Berge, M.D.; Nicholas Galluzzi, M.D.; Jessie Marmorston, M.D.; James A. Schoenberger, M.D.; Samuel Baer, M.D.; Henry K. Schoch, M.D.; J. Richard Warbasse, M.D.; Robert M. Kohn, M.D.; Bernard I. Lewis, M.D.; Richard J. Jones, M.D.; Kenneth Hyatt, M.D.; Dean A. Emanuel, M.D.; David Z. Morgan, M.D.; David Berkson, M.D.; William H. Bernstein, M.D.; Ernst Greif, M.D.; Richard R. Pyle, M.D.; Ephraim Donoso, M.D.; Jacob I. Haft, M.D.; Gordon L. Maurice, M.D.; Ralph Lazzara, M.D.; Irving M. Liebow, M.D.; Marvin S. Segal, M.D.; Charles B. Moore, M.D.; John H. Morledge, M.D.; Olga M. Haring, M.D.; Robert C. Schlant, M.D.; Joseph A. Wagner, M.D.; Ward Laramore, M.D.; Donald McCaughan, M.D.; Robert W. Oblath, M.D.; Peter C. Gazes, M.D.; Bernard Tabatznik, M.D.; R.G. Hutchinson, M.D.; Mario Garcia-Palmieri, M.D.; Nathaniel Berk, M.D.; Robert L. Grissom, M.D.; Ralph C. Scott, M.D.; Frank L. Canosa, M.D.; Charles A. Laubach, Jr., M.D.; Ralph E. Cole, M.D.; Thaddeus E. Prout, M.D.; Bernard A. Sachs, M.D.; Ernest O. Theilen, M.D.; C. Basil Williams, M.D.; Edward L. Michals, M.D.; Fred I. Gilbert, Jr., M.D.; Sidney A. Levine, M.D.; Louis B. Matthews, Jr., M.D.; Irving Ershler, M.D.; Elmer E. Cooper, M.D.; Allan H. Barker, M.D.; and Paul Samuel, M.D.
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Segundo Morán, Ma.Ximena Duque-López, Jorge Salmerón-Castro, Gustavo Rodrı́guez-Leal, Homero Martı́nez-Salgado, Misael Uribe. (2003) Association Between Serum Concentration of Apolipoproteins A-I and B with Gallbladder Disease. Archives of Medical Research 34:3, 194-199
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Chad R. Worz, Michael Bottorff. (2003) Treating Dyslipidemic Patients with Lipid-Modifying and Combination Therapies. Pharmacotherapy 23:5, 625-637
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Mark J. Messina. (2002) Soy Foods and Soybean Isoflavones and Menopausal Health. Nutrition in Clinical Care 5:6, 272-282
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Iris J.A.M. Jonkers, August H.M. Smelt, Arnoud van der Laarse. (2001) Hypertriglyceridemia. American Journal of Cardiovascular Drugs 1:6, 455-466
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Knopp , Robert H. . (1999) Drug Treatment of Lipid Disorders. New England Journal of Medicine 341:7, 498-511
Full Text15
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