(Hypertension. 1996;28:647-651.)
© 1996 American Heart Association, Inc.
Articles |
Beneficial Effects of Pravastatin on Fasting Hyperinsulinemia in Elderly Hypertensive Hypercholesterolemic Subjects
the Clinical Pharmacology and Therapeutics Unit, Department of Cardiology (P.C.); Taipei Municipal Chung-Hsiao Hospital and Institute of Clinical Medicine (P.C.) of the National Yang-Ming University and Division of Cardiology (C.-B.L., Y.-S.L.); Chang-Gung Medical Center at Linkou and Institute of Biomedical Sciences (W.-H.P.), Academia Sinica, Taipei, Taiwan; and Department of Clinical Pharmacology (B.T.), Chinese University of Hong Kong.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
We undertook this prospective double-blind, placebo-controlled study to evaluate the efficacy and safety of low-dose (15 mg) pravastatin in elderly hypercholesterolemic hypertensive subjects with concurrent antihypertensive treatment and to determine whether fasting hyperinsulinemia could also be improved. At three hypertension and lipid clinics of two medical centers, 96 elderly (49 women, 47 men) ambulatory subjects were randomized to active treatment or placebo for 12 months after a 3-month single-blind lead-in period. Hypertensive subjects with plasma total cholesterol levels of at least 6.47 mmol/L (250 mg/dL) and triglyceride levels less than 3.39 mmol/L (300 mg/dL) were treated with 15 mg pravastatin for 12 months after receiving 3 months of the American Heart Association step I diet. Lipid, glucose, and fasting insulin levels were measured; clinical laboratory tests included liver function and creatine kinase determinations. After 12 months of pravastatin therapy, plasma total cholesterol concentration decreased by 25.1% (from a mean of 7.29 to 5.47 mmol/L, P<.05), low-density lipoprotein cholesterol decreased by 30.2% (from 5.27 to 3.68 mmol/L, P<.05), and triglycerides decreased by 10.7% (from 1.68 to 1.50 mmol/L, P<.05). High-density lipoprotein cholesterol increased by 9.2% (from 1.20 to 1.31 mmol/L, P<.05). Fasting insulin levels decreased from 89.0 to 61.5 pmol/L (P<.05). All of these changes were greater (P<.05) than any tendency toward change in the placebo group. Adverse events and clinical laboratory abnormalities were generally mild and transient in both placebo and pravastatin groups. Study drugs were withdrawn from one subject in each group with asymptomatic creatine kinase elevations. We conclude that low-dose pravastatin was effective and safe in the treatment of hypercholesterolemic hypertensive subjects on concurrent antihypertensive therapy. It also improved fasting hyperinsulinemia despite the use of ß-blockers and diuretics in these hypertensive subjects.
Key Words: cholesterol • hydroxymethylglutaryl CoA reductases • hyperinsulinism • pravastatin
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Plasma or serum cholesterol concentration has been shown to correlate with CHD in both case-control and prospective studies.1 2 More recent data from a large prospective study suggest that the risk is continuous over the entire range of serum cholesterol,3 rising appreciably when serum cholesterol exceeds 6.5 mmol/L and even more steeply when it rises higher than 7.8 mmol/L. Lowest rates of CHD occurred in men with serum cholesterol less than 5.2 mmol/L.3 The association between total cholesterol and CHD became much weaker in both sexes after the age of 55 years in the Framingham Heart Study but remained a powerful predictor of CHD over 25 years of follow-up in Finnish men up to the age of 60 years.2
The primary prevention study of the Lipid Research Clinics Program was a landmark in developing the cholesterol hypothesis.4 This interventional trial showed a significant reduction in definite CHD death and nonfatal myocardial infarction.4 The recent Scandinavian Simvastatin Survival Study, a secondary prevention study, showed that lipid-lowering therapy had a beneficial effect in individuals with CHD.5 CHD mortality was reduced by 41% in the simvastatin treatment group and major coronary events by 32%. The risk was also significantly reduced in subgroups consisting of women and individuals of both sexes aged 60 years or more. Other benefits of treatment included a 37% reduction in myocardial revascularization procedures. The reduction of fatal and nonfatal cerebrovascular events was 29%.5
In recent years, different investigators have described the presence of insulin resistance and hyperinsulinemia in a substantial number of individuals with essential hypertension.6 7 8 The mechanism by which insulin resistance or hyperinsulinemia may increase the risk of hypertension has not been defined. Furthermore, hyperinsulinemia may be associated with a greater risk of atherosclerotic cardiovascular disease.9 10 11 12
Hypercholesterolemia, hyperinsulinemia, and hypertension frequently coexist, constituting the metabolic syndrome,6 7 and some antihypertensive therapies interfere with cholesterol metabolism. We undertook this study to evaluate whether lipid-lowering therapy with 15 mg pravastatin was effective in elderly subjects with hypercholesterolemia who had received antihypertensive treatment and to determine whether this hypolipidemic effect was accompanied by improvement of hyperinsulinemia.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Participant Selection
The study protocol conformed to the ethical guidelines of the 1989 Declaration of Helsinki and was approved by the investigational review board of the Academia Sinica at Taipei. All subjects gave written, informed consent.
Elderly hypertensive subjects older than 65 years with primary hypercholesterolemia (total plasma cholesterol of at least 6.47 mmol/L [250 mg/dL] or higher than the 90th percentile for age and sex) and triglyceride concentration less than 3.39 mmol/L (300 mg/dL) despite a 3-month period of dietary intervention with the American Heart Association (AHA) step I diet were enrolled from the outpatient clinics of two medical centers. These subjects were apparently healthy and ambulatory. Subjects with homozygous familial hypercholesterolemia or types I, III, IV, or V hyperlipoproteinemia were excluded, as were those with significant cardiovascular, renal, gastrointestinal, hepatic, or metabolic diseases such as diabetes mellitus, malignancies, or diseases expected to reduce life expectancy to less than 3 years. Also ineligible were individuals who were consuming corticosteroids or fish oil preparations. BP at entry was controlled to systolic less than 160 mm Hg and diastolic less than 95 mm Hg. Another group of 40 healthy elderly subjects without diabetes, hypertension, or dyslipidemia was selected as a control for measurement of fasting plasma insulin levels.
Study Design
This was a double-blind, randomized, placebo-controlled trial consisting of a dietary stabilization phase for 3 months with the AHA step I diet and a 3-month single-blind placebo lead-in period followed by randomization and a 12-month treatment period. The diet and previously given antihypertensive agents were continued unchanged throughout the study. Subjects were randomized to double-blind treatment with placebo or 15 mg pravastatin with the evening meal. They were examined at the hypertension or lipid clinics of two medical centers once monthly for 2 months and then bimonthly until the end of 12 months of treatment after randomization. Diet counseling was carried out by registered dietitians.
Clinical Evaluation and Blood Sampling
Demographic data, such as age, sex, and body mass index (kilograms per meter squared), were recorded at each follow-up visit. Venous blood was drawn between 8 and 10 AM after subjects had fasted overnight. The participants were asked to abstain from heavy meals for 48 hours before their visit. Blood was collected into suitable tubes for determination of insulin, glucose, lipids, renal function, electrolytes, and transaminase. Glucose, cholesterol, triglycerides, uric acid, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, and creatinine levels were measured with a Monarch Autoanalyzer System (Instrumentation Laboratories).
Total cholesterol and triglycerides were measured enzymatically with commercially available kits (Boehringer Mannheim). HDL-C level was obtained by precipitation,13 and LDL-C was calculated by the Friedewald approximation.14 EDTA-containing plasma was used for measurement of insulin level by the SERENO Insulin MAIA kit (ARES-Sereno Diagnostici SPA). Hyperinsulinemia was defined as a plasma insulin concentration more than 2 SD above the mean value from the control group.9 The coefficients of variation of the lipid assays were 2.6% for total cholesterol, 3.2% for HDL-C, 2.8% for LDL-C (calculated percentage), and 2.9% for triglycerides. A complete blood count and creatine phosphokinase were also measured. BP was determined with a noninvasive BP monitor (In Vivo Research Laboratory Inc). Subjects had been seated for 10 minutes before their BP was measured. Before randomization and at each visit, BP was measured consecutively three times with a 30-second pulse rate measurement in between.
Clinical Safety and Compliance
A complete physical examination, including a chest roentgenogram and 12-lead electrocardiogram, was done before administration of active medication and at the end of the study. Clinical laboratory tests, including complete blood counts with differential leukocyte counts and microscopic and dipstick urinalyses, were also done at each visit.
All clinical adverse events, either volunteered or elicited by questioning, at baseline and follow-up visits were recorded. Compliance was evaluated by tablet counting.
Statistics
Statistical analyses were carried out with the Statistical Analysis System, version 6.06 (SAS Institute Inc). Dispersion of data is given by mean±SD. When two groups were compared, the unpaired t test was used. Serial measurements in the two treatment groups were compared with the use of the average changes from baseline to each follow-up measurement.15 The incidence of adverse effects and laboratory abnormalities in the two treatment groups was determined with Fisher's exact test.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Baseline Characteristics of the Study Population
The 96 randomized subjects (49 women, 47 men) had a mean age of 76.5 years, with a mean body mass index of 23.2 kg/m2. Mean systolic BP was 140 mm Hg, and diastolic BP was 80 mm Hg. At the beginning of randomization, both placebo and active treatment groups were similar in demographic, clinical, and biochemical characteristics (Table 1
). All subjects had had a previous diagnosis of hypertension and were being treated with various combinations of antihypertensive drugs, including ß-blockers, diuretics, calcium channel blockers, and angiotensin-converting enzyme inhibitors (Table 2). During the study, systolic and diastolic BPs did not fall significantly in either group. Drug therapy to control hypertension was not altered in any subject during the study. Weight did not change significantly in either group. Fasting plasma insulin level of the 40 normotensive control subjects was 47.5±8.61 pmol/L.
|
|
Dietary Phase
During the run-in dietary phase, plasma cholesterol fell slightly. In the control group, plasma total cholesterol decreased from 7.28 to 7.24 mmol/L, and in the pravastatin treatment group, cholesterol fell from 7.32 to 7.29 mmol/L. These changes were not significant, nor did triglycerides, HDL-C, or the calculated level for LDL-C change significantly.
Placebo Control Group
In those subjects who completed the placebo part of the study, cholesterol fell slightly over the ensuing 12 months, the final cholesterol value being 6.87 mmol/L (266 mg/dL), which was not significantly different from baseline. Changes in triglycerides and fasting insulin and any rise in HDL-C levels were not significant. The calculated value for LDL-C did not change significantly. The placebo group also had a nonsignificant decrease of insulin levels from 86.1 to 73.9 pmol/L.
Pravastatin Group
After 12 months of active treatment, total cholesterol and LDL-C were significantly lower in the pravastatin group than in the placebo group (P<.05) (Table 3). Active treatment maintained the reduction of these plasma lipids during the entire 12-month treatment period (Table 3). In the pravastatin group, mean plasma concentration of total cholesterol decreased from 7.29 to 5.47 mmol/L (-25.1%), LDL-C was reduced from 5.27 to 3.67 mmol/L (-30.2%), and triglycerides were reduced from 1.68 to 1.50 mmol/L (-10.7%). Additionally, HDL-C increased from 1.20 to 1.31 mmol/L (+9.2%). Mean fasting plasma insulin level in the pravastatin group decreased from 89.0 to 61.5 pmol/L after 12 months of treatment, and this change was greater (P<.05) than the tendency toward a decrease in the placebo group, which was not significant. The decrease in fasting plasma insulin in the pravastatin group became significantly greater than the change in the placebo group by 2 months.
|
Tolerability and Compliance of Pravastatin
The drug was well tolerated. Both treatment groups experienced a similar incidence of minor side effects (Table 4). Only two subjects (one in each group) discontinued drug treatment prematurely because of adverse effects. One subject treated with placebo and one with pravastatin developed a threefold elevation of creatine kinase, requiring withdrawal of the drug. Another subject on placebo suffered from vague abdominal pain and diarrhea, and one experienced nausea and vomiting, but both of these subjects tolerated the side effects and continued the drug treatment.
|
In the pravastatin group, one subject suffered from muscle pain, and he discontinued the study. Creatine kinase was about two times above the normal limit. Another two subjects experienced headache and dizziness, which were not considered to be drug related. Laboratory tests, either at baseline or during double-blind treatment, showed no significant difference between the two groups. All the remaining subjects followed the prescribed treatment schedule during the entire 12-month treatment period. Subjects' compliance was evaluated by tablet counting, which showed a similar degree of compliance in the two treatment groups throughout the entire course of randomized treatment. Tablet intake averaged 94±4% of the planned number of tablets at randomization and 92±3% during double-blind treatment in the placebo group. The pravastatin group intake averaged 95±4% at randomization and 92±2% during double-blind treatment.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In the group of 48 subjects who received pravastatin, total cholesterol, triglycerides, and LDL-C decreased significantly and HDL-C increased significantly compared with the control period and the placebo group. The lipoprotein profile improved and the risk factors for CHD were reduced to near the atherosclerosis-free range.16
The 96 subjects in this study spent 3 months or more on a standard lipid-lowering diet before starting treatment with pravastatin or placebo. During this period, cholesterol fell slightly, but none of the other parameters measured changed. However, many subjects had previously been given dietary advice in a hypertension or lipid clinic to reduce sodium and increase potassium intake and may already have been on a cholesterol-reducing diet. In the placebo group, total cholesterol fell slightly during the ensuing 12 months. Triglycerides and HDL-C did not change significantly. Despite the fact that a well-maintained diet over a prolonged period did affect some risk factors for atherosclerosis, the effects were relatively small compared with effects achieved by pravastatin administration.
In this group of elderly hypertensive, hypercholesterolemic subjects, pravastatin was well tolerated, and 15 mg was sufficient to cause a fall in total cholesterol to the desirable range. Previous studies have shown a dose-response relationship between LDL-C reduction and pravastatin doses up to 40 mg,17 but a recent study found a low dose (10 mg) to have a maximal effect.18 Our previous work in elderly hypertensive hypercholesterolemic individuals showed that a low dose (10 mg) reduced LDL-C by 26%.19 We used a 15-mg dose in the present study to try to obtain a slightly greater hypocholesterolemic effect with a relatively low dose as a compromise between safety and efficacy in elderly subjects. Previous reports concerning other statins have shown that the elevation of liver transaminases or creatine kinase was more common with higher doses.20 21 However, the present data show that side effects with 15 mg pravastatin were infrequent. The few subjects who developed nausea, abdominal pain, dizziness, or headache came from both the placebo and pravastatin group. Pravastatin in a dose that does not cause significant clinical or biochemical adverse effects can therefore be used successfully in elderly individuals with hypertension to lower cholesterol.
Some antihypertensive agents, especially diuretics and ß-blockers, may cause an untoward increase of plasma cholesterol and/or triglyceride levels or reduction of HDL-C; however, calcium antagonists or converting enzyme inhibitors have no unfavorable effects on lipid profile.22 23 In the present study, decreases of total cholesterol and LDL-C were still highly significant and comparable to reports in mixed populations (normotensive as well as treated and untreated hypertensive subjects) of hypercholesterolemic individuals.24 25 The reduction of approximately 25.1% in total cholesterol and a greater fall in LDL-C make pravastatin a useful drug for determination of whether the prognosis for CHD can be improved by reducing cholesterol in elderly hypertensive individuals. Previous reports concerning fasting plasma hyperinsulinemia have shown that this phenomenon is linked to CHD.9 10 11 12 Theoretically, amelioration of hyperinsulinemia could reduce the risk of coronary events. The present data show that treatment of these hypertensive, hypercholesterolemic subjects with pravastatin leads to an accompanying reduction of hyperinsulinemia, which probably implies an additional beneficial effect attained by pravastatin besides lowering lipids. Whether this improvement in hyperinsulinemia was primary (caused by a direct effect of pravastatin) or secondary (caused by lipid lowering) needs further study.
Although the treatment of hypertension or diabetes in the elderly is standard medical practice, treatment of dyslipidemia in this age group remains controversial, and many elderly people with hyperlipidemia remain untreated.26 Recently, the data from a prospective study suggested that treatment of hypercholesterolemic elderly who have CHD could reduce mortality,5 and based on the findings in younger people and on evidence from regression trials, efforts aimed at the management of dyslipidemia may be important in the elderly, particularly for those with CHD.27
If the changes achieved in plasma cholesterol had effects on mortality and CHD similar to those achieved with a supervised diet and other drugs, an approximately one-third reduction in deaths from myocardial infarction could be predicted.4 28 29 This attained level of benefit would justify the use of pravastatin in elderly individuals with essential hypertension and associated elevated cholesterol.
In conclusion, when using lipid-lowering drugs in elderly people, clinicians should pay attention to potential side effects and be especially cautious, perhaps emphasizing lower-dose regimens. Besides this safety issue, low-dose pravastatin therapy would help reduce the financial burden of rising medical costs in both developing and developed countries. The improvement in hyperinsulinemia with cholesterol lowering could account in part for the reduced incidence of adverse coronary events that is known to result from cholesterol-lowering therapy. It thus can be concluded that for elderly hypertensive individuals with hypercholesterolemia, low-dose (15 mg) pravastatin is a safe and effective lipid-lowering therapy and also may improve fasting hyperinsulinemia.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Footnotes |
|---|
Reprint requests to Paul Chan, MD, PhD, Department of Cardiology, Taipei Municipal Chung-Hsiao Hospital, No. 87, Tung-Teh Rd, Nan Kang, Taipei, Taiwan 115.
Received August 16, 1995; first decision September 5, 1995; accepted May 28, 1996.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. LaRosa JC, Hunninghake D, Bush D, Criqui MH, Getz GS, Gotto AM Jr, Grundy SM, Rakita L, Robertson RM, Weisfeldt ML, Cleeman JI. The cholesterol facts: a summary of the evidence relating dietary fats, serum cholesterol, and coronary heart disease. Circulation.. 1990;81:1721-1733.
2. Pekkanen J, Nissinen A, Puska P, Punsar S, Karvonen MJ. Risk factors and 25 year risk of coronary heart disease in male population with a high incidence of the disease: the Finnish cohorts of the Seven Countries Study. Br Med J.. 1989;299:81-85.
3. Martin MJ, Hulley SB, Browner WS, Kuller LH, Wenworth D. Serum cholesterol, blood pressure and mortality: implications from a cohort of 361,662 men. Lancet.. 1986;1:933-936.
4.
Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results, I: reduction in incidence of coronary heart disease. JAMA.. 1984;251:351-364.
5. Pederson TR. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet.. 1994;344:1383-1389.[Medline] [Order article via Infotrieve]
6. Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, Pedrinelli R, Brandi L, Bevilacqua S. Insulin resistance in essential hypertension. N Engl J Med.. 1987;317:350-357.[Abstract]
7. Swislocki AL, Hoffman BB, Reaven GM. Insulin resistance, glucose intolerance and hyperinsulinemia in patients with hypertension. Am J Hypertens.. 1989;2:419-423.[Medline] [Order article via Infotrieve]
8. Berglund G, Larsson B, Andersson O, Larsson O, Svardsudd K, Bjorntorp P, Wilhelmsen L. Body composition and glucose metabolism in hypertensive middle-aged men. Acta Med Scand.. 1976;200:163-169.[Medline] [Order article via Infotrieve]
9. Zavaroni I, Bonora E, Pagliara M, Dall'Aglio E, Luchetti L, Buonanno G, Bonati PA, Bergonzani M, Gnudi L, Passeri M, Reaven G. Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med.. 1989;320:702-706.[Abstract]
10. Welbon TA, Wearne K. Coronary heart disease incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentration. Diabetes Care.. 1979;2:154-160.[Abstract]
11. Ducimetiere P, Eschwege R, Papoz L, Richard JL, Claude JR, Rosselin G. Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia.. 1980;19:205-210.[Medline] [Order article via Infotrieve]
12. Pyorala K, Uusitupa M, Laakso M, Siitonen O, Niskanen L, Ronnemaa T. Macrovascular complications in relation to hyperinsulinemia in non-insulin dependent diabetes mellitus. Diabete Metab.. 1987;13:345-349.[Medline] [Order article via Infotrieve]
13. Gidez LI, Miller GJ, Burstein M. Separation and quantification of subclasses of human high-density lipoproteins by a simple precipitation procedure. J Lipid Res.. 1982;23:1206-1223.[Abstract]
14. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of preparative ultracentrifuge. Clin Chem.. 1972;18:499-502.[Abstract]
15. Matthews JNS, Altman DG, Campbell MJ, Royston P. Analysis of serial measurements in medical research. Br Med J.. 1990;300:230-235.
16. Brown MS, Goldstein JL. How LDL receptors influence cholesterol and atherosclerosis. Sci Am.. 1984;251:58-66.[Medline] [Order article via Infotrieve]
17. Blum CB. Comparison of properties of four inhibitors of 3-hydroxyl-3 methylglutaryl-coenzyme A reductase. Am J Cardiol.. 1994;73:3D-11D.[Medline] [Order article via Infotrieve]
18. Celis H, Lijnen P, Fagard R, Staessen J, Thijs L, Amery A. Efficacy and safety of pravastatin in hypertensive hypercholesterolemic patients on antihypertensive drug therapy. J Hum Hypertens.. 1994;8:525-530.[Medline] [Order article via Infotrieve]
19. Chan P, Lee CB, Lin TH, Ko JT, Pan WH, Lee YH. The effectiveness and safety of low dose pravastatin in elderly hypertensive hypercholesterolemic subjects on antihypertensive therapy. Am J Hypertens.. 1995;8:1099-1104.[Medline] [Order article via Infotrieve]
20. Dujovne CA, Chremos AN, Pool JL, Schnaper H, Bradford RH, Shear CL, Higgins J, Downton M, Franklin FA, Nash DT, Gould AL, Langendorfer A. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results, IV: additional perspectives on the tolerability of lovastatin. Am J Med. 1991;91(suppl 1B):25S-30S.
21. Morgan T, Anderson A, McDonald P, Hopper J, Macaskill G. Simvastatin in the treatment of hypercholesterolemia in patients with essential hypertension. J Hypertens. 1990;8(suppl 1):25S-32S.
22. Lardinois CK, Neuman SL. The effects of antihypertensive agents on serum lipids and lipoproteins. Am Heart J.. 1991;121:696-701.[Medline] [Order article via Infotrieve]
23. Pollare T, Lithell H, Bern C. A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med.. 1989;321:868-873.[Abstract]
24. McTavish D, Sorkin EM. Pravastatin: a review of its pharmacological properties and therapeutic potential in hypercholesterolemia. Drugs.. 1991;42:65-89.[Medline] [Order article via Infotrieve]
25. Jungnickel PW, Cantral KA, Maloley PA. Pravastatin: a new drug for the treatment of hypercholesterolemia. Clin Pharmacy.. 1992;11:677-689.
26. Kashyap ML. Cardiovascular disease in the elderly: current considerations. Am J Cardiol.. 1989;63:3H-4H.[Medline] [Order article via Infotrieve]
27. Denke MA, Grundy SM. Hypercholesterolemia in elderly persons: resolving the treatment dilemma. Ann Intern Med.. 1990;112:780-792.
28.
Turpeinen O, Karvonen MJ, Pekkarinen M, Miettenen M, Elsusou R, Paavilainen E. Dietary prevention of coronary heart disease: the Finnish Mental Hospital Study. Int J Epidemiol.. 1979;8:99-118.
29.
Multiple Risk Factor Intervention Trial: risk factor changes and mortality results. JAMA.. 1982;248:1465-1477.
This article has been cited by other articles:
 |
|
 |
|
  C. G. P. Roberts, E. Guallar, and A. Rodriguez Efficacy and Safety of Statin Monotherapy in Older Adults: A Meta-Analysis J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2007; 62(8): 879 - 887. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. D. Ross, I. E. Allen, J. E. Connelly, B. M. Korenblat, M. E. Smith, D. Bishop, and D. Luo Clinical Outcomes in Statin Treatment Trials: A Meta-analysis Arch Intern Med, August 9, 1999; 159(15): 1793 - 1802. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||