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ARTICLE |

Lipid Alterations and Decline in the Incidence of Coronary Heart Disease in the Helsinki Heart Study FREE

Vesa Manninen, MD; M. Olli Elo, MD; M. Heikki Frick, MD; Kauko Haapa, MD; Olli P. Heinonen, MD, DSc; Pertti Heinsalmi, MD; Pekka Helo, MD; Jussi K. Huttunen, MD; Pertti Kaitaniemi, MD; Pekka Koskinen, MD; Hanna Mäenpää, MD; Marjatta Mälkönen, MSc; Matti Mänttäri, MD; Seppo Norola, MD; Amos Pasternack, MD; Jarmo Pikkarainen, MD; Matti Romo, MD; Tom Sjöblom, MD; Esko A. Nikkilä, MD
[+] Author Affiliations

°Dr Nikkilä died Sept 21,1986.

Reprint requests to First Department of Medicine, University of Helsinki, SF-00290 Helsinki, Finland (Dr Manninen).


JAMA. 1988;260(5):641-651. doi:10.1001/jama.1988.03410050061031
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In the Helsinki Heart Study, a randomized five-year, double-blind trial, a 34% reduction in the incidence of coronary heart disease (CHD) was observed in dyslipidemic men treated with gemfibrozil. Averaged over the five years of the trial, gemfibrozil therapy produced, compared with placebo, mean decreases of 10% in serum total cholesterol level, 14% in non-high-density lipoprotein (HDL) cholesterol level, 11% in low-density lipoprotein (LDL) cholesterol level, 35% in triglyceride level, and a mean increase of 11% in HDL cholesterol level from baseline levels measured prior to treatment. While changes in HDL cholesterol level were similar in all Fredrickson types, the effect on concentrations of total cholesterol and LDL cholesterol was largest in type IIA and on LDL minimal in type IV. The reduction of CHD incidence over placebo was largest in type IIB and smallest in type IIA. The lipid changes were dependent on lipid levels prior to treatment and on compliance with the medication regimen. When risk factors for CHD, including age, blood pressure, smoking and drinking habits, baseline lipid levels, and exercise and relative weight, were controlled by applying the Cox proportional hazards model, the changes in serum HDL and LDL cholesterol levels were both statistically significantly associated with the decline in CHD incidence within the gemfibrozil-treated group. The large decrease in serum triglyceride levels had relatively small effect on CHD incidence. Thus, the results of this study, together with earlier observations, suggest that both elevating HDL and lowering LDL cholesterol levels are effective in the primary prevention of CHD.

(JAMA 1988;260:641-651)

REFERENCES

Mänttäri M, Elo O, Frick MH, et al:  The Helsinki Heart Study: Basic design and randomization procedure . Eur Heart J 1987;;8( (suppl 1) ):1-29.
Frick MH, Elo 0, Haapa K, et al:  Helsinki Heart Study: Primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia . N Engl J Med 1987;;317:1237-1245.
Mäenpää H, Javela K, Pikkarainen J, et al:  Minimal doses of digoxin: A new marker for compliance to medication . Eur Heart J 1987;;8( (suppl 1) ):31-37.
Mäenpää H, Manninen V, Heinonen OP:  Comparison of the digoxin marker with capsule counting and compliance questionnaire methods for measuring compliance to medication in a clinical trial . Eur Heart J 1987;;8( (suppl 1) ):39-43.
Kostner GM:  Enzymatic determination of cholesterol in high-density lipoprotein fractions prepared by polyanion precipitation . Clin Chem 1976;;22:695.
Friedewald WT, Levy RI, Fredrickson DS:  Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge . Clin Chem 1972;;18:499-502.
Fleiss JL: Statistical Methods for Rates and Proportions . New York, John Wiley & Sons Inc, 1973;, pp 112-118.
Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data . New York, John Wiley & Sons Inc, 1980;.
Torstila I, Kaukola S, Manninen V, et al:  Plasma prekallikrein, kallikrein inhibitors, kininogen and lipids during gemfibrozil treatment in type II dyslipidaemia . Acta Med Scand 1982;;( (suppl 668) ):123-129.
Dixon WJ: BMDP Statistical Software. Los Angeles , University of California Press, 1983;, pp 576-594.
Lipid Research Clinics Program:  The Lipid Research Clinics Coronary Primary Prevention Trial results: II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering . JAMA 1984;;251:365-374.
Oliver MF, Heady JA, Morris JN, et al:  A cooperative trial in the primary prevention of ischaemic heart disease using clofibrate: Report from the Committee of Principal Investigators . Br Heart J 1978;;40:1069-1118.
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.
Manninen V, Mälkönen M, Eisalo A, et al:  Gemfibrozil in the treatment of dyslipidaemia: A five-year follow-up study . Acta Med Scand 1982;;( (suppl 668) ):82-87.
Gemfibrozil:  A new lipid-lowering agent . Proc Roy Soc Med 1976;;69( (suppl 2) ):1-120.
Samuel P:  Effects of gemfibrozil on serum lipids . Am J Med 1983;;74:23-27.
Kesäniemi YA, Grundy SM:  Influence of gemfibrozil and clofibrate on metabolism of cholesterol and plasma triglycerides in man . JAMA 1984;;251:2241-2246.
Saku K, Gartside PS, Hynd BA, et al:  Mechanism of action of gemfibrozil on lipoprotein metabolism . J Clin Invest 1985;;75:1702-1712.
Newton RS, Krause BR:  Mechanisms of action of gemfibrozil: Comparison of studies in the rat to clinical efficacy , in Fears R (ed): International Telesymposium on Hyperlipidemia 1986: Pharmacological Control of Hyperlipidaemia . Barcelona, Spain, JR Prous Science Publishers, 1986;, pp 171-186.
Kovanen PT, Koskinen P, Manninen V:  A comparison of different formulations and dosage administrations of gemfibrozil . Am J Cardiol 1986;;57:31G-34G.
Pasternack A, Vänttinen T, Solakivi T, et al:  Normalization of lipoprotein lipase and hepatic lipase by gemfibrozil results in correction of lipoprotein abnormalities in chronic renal failure . Clin Nephrol 1987;;27:163-168.
Sorisky A, Ooi TC, Simo IE, et al:  Change in composition of high density lipoprotein during gemfibrozil therapy . Atherosclerosis 1987;;67:181-189.
Castelli WP, Garrison RJ, Wilson PWF, et al:  Incidence of coronary heart disease and lipoprotein cholesterol levels: The Framingham Study . JAMA 1986;;256:2835-2838.
Miller NE:  Associations of high-density lipoprotein subclasses and apolipoproteins with ischemic heart disease and coronary atherosclerosis . Am Heart J 1987;;113:589-597.
Pocock SJ, Shaper AG, Phillips AN, et al:  High density lipoprotein cholesterol is not a major risk factor for ischaemic heart disease in British men . Br Med J 1986;;292:515-519.
Carvalho ACA, Colman RW, Lees RS:  Clofibrate reversal of platelet hypersensitivity in hyperbetalipoproteinemia . Circulation 1974;;50:570-574.
Laustiola K, Lassila R, Koskinen P, et al:  Gemfibrozil decreases platelet reactivity in hypercholesterolemic patients during physical stress . Clin Pharm Ther 1988;;43:302-307.
Gordon DJ, Knoke J, Probstfield JL, et al:  High-density lipoprotein cholesterol and coronary heart disease in hypercholesterolemic men: The Lipid Research Clinics Coronary Primary Prevention Trial . Circulation 1986;;74:1217-1225.
Levy RI, Brensike JF, Epstein SE, et al:  The influence of changes in lipid values induced by cholestyramine and diet on progression of coronary artery disease: Results of the NHLBI Type II Coronary Intervention Study . Circulation 1984;;69:325-337.
Tatami R, Mabuchi H, Ueda K, et al:  Intermediate-density lipoprotein and cholesterol-rich very low density lipoprotein in angiographically determined coronary artery disease . Circulation 1981;;64:1174-1184.
Krauss RM:  Relationship of intermediate and low-density lipoprotein subspecies to risk of coronary artery disease . Am Heart J 1987;;113:578-582.
O'Brien JR, Etherington MD, Shuttleworth RD, et al:  A pilot study of the effect of gemfibrozil on some haematological parameters . Thromb Res 1982;;26:275-279.
Wilhelmsen L, Svärsudd K, Korsan-Bengtsen K, et al:  Fibrinogen as a risk factor for stroke and myocardial infarction . N Engl J Med 1984;;311:501-505.
Markowe HLJ, Marmot MG, Shipley MJ, et al:  Fibrinogen: A possible link between social class and coronary heart disease . Br Med J 1985;;291:1312-1314.
Kannel WB, Wolf PA, Castelli WP, et al:  Fibrinogen and risk of cardiovascular disease: The Framingham Study . JAMA 1987;;258:1183-1186.

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Mänttäri M, Elo O, Frick MH, et al:  The Helsinki Heart Study: Basic design and randomization procedure . Eur Heart J 1987;;8( (suppl 1) ):1-29.
Frick MH, Elo 0, Haapa K, et al:  Helsinki Heart Study: Primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia . N Engl J Med 1987;;317:1237-1245.
Mäenpää H, Javela K, Pikkarainen J, et al:  Minimal doses of digoxin: A new marker for compliance to medication . Eur Heart J 1987;;8( (suppl 1) ):31-37.
Mäenpää H, Manninen V, Heinonen OP:  Comparison of the digoxin marker with capsule counting and compliance questionnaire methods for measuring compliance to medication in a clinical trial . Eur Heart J 1987;;8( (suppl 1) ):39-43.
Kostner GM:  Enzymatic determination of cholesterol in high-density lipoprotein fractions prepared by polyanion precipitation . Clin Chem 1976;;22:695.
Friedewald WT, Levy RI, Fredrickson DS:  Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge . Clin Chem 1972;;18:499-502.
Fleiss JL: Statistical Methods for Rates and Proportions . New York, John Wiley & Sons Inc, 1973;, pp 112-118.
Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data . New York, John Wiley & Sons Inc, 1980;.
Torstila I, Kaukola S, Manninen V, et al:  Plasma prekallikrein, kallikrein inhibitors, kininogen and lipids during gemfibrozil treatment in type II dyslipidaemia . Acta Med Scand 1982;;( (suppl 668) ):123-129.
Dixon WJ: BMDP Statistical Software. Los Angeles , University of California Press, 1983;, pp 576-594.
Lipid Research Clinics Program:  The Lipid Research Clinics Coronary Primary Prevention Trial results: II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering . JAMA 1984;;251:365-374.
Oliver MF, Heady JA, Morris JN, et al:  A cooperative trial in the primary prevention of ischaemic heart disease using clofibrate: Report from the Committee of Principal Investigators . Br Heart J 1978;;40:1069-1118.
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.
Manninen V, Mälkönen M, Eisalo A, et al:  Gemfibrozil in the treatment of dyslipidaemia: A five-year follow-up study . Acta Med Scand 1982;;( (suppl 668) ):82-87.
Gemfibrozil:  A new lipid-lowering agent . Proc Roy Soc Med 1976;;69( (suppl 2) ):1-120.
Samuel P:  Effects of gemfibrozil on serum lipids . Am J Med 1983;;74:23-27.
Kesäniemi YA, Grundy SM:  Influence of gemfibrozil and clofibrate on metabolism of cholesterol and plasma triglycerides in man . JAMA 1984;;251:2241-2246.
Saku K, Gartside PS, Hynd BA, et al:  Mechanism of action of gemfibrozil on lipoprotein metabolism . J Clin Invest 1985;;75:1702-1712.
Newton RS, Krause BR:  Mechanisms of action of gemfibrozil: Comparison of studies in the rat to clinical efficacy , in Fears R (ed): International Telesymposium on Hyperlipidemia 1986: Pharmacological Control of Hyperlipidaemia . Barcelona, Spain, JR Prous Science Publishers, 1986;, pp 171-186.
Kovanen PT, Koskinen P, Manninen V:  A comparison of different formulations and dosage administrations of gemfibrozil . Am J Cardiol 1986;;57:31G-34G.
Pasternack A, Vänttinen T, Solakivi T, et al:  Normalization of lipoprotein lipase and hepatic lipase by gemfibrozil results in correction of lipoprotein abnormalities in chronic renal failure . Clin Nephrol 1987;;27:163-168.
Sorisky A, Ooi TC, Simo IE, et al:  Change in composition of high density lipoprotein during gemfibrozil therapy . Atherosclerosis 1987;;67:181-189.
Castelli WP, Garrison RJ, Wilson PWF, et al:  Incidence of coronary heart disease and lipoprotein cholesterol levels: The Framingham Study . JAMA 1986;;256:2835-2838.
Miller NE:  Associations of high-density lipoprotein subclasses and apolipoproteins with ischemic heart disease and coronary atherosclerosis . Am Heart J 1987;;113:589-597.
Pocock SJ, Shaper AG, Phillips AN, et al:  High density lipoprotein cholesterol is not a major risk factor for ischaemic heart disease in British men . Br Med J 1986;;292:515-519.
Carvalho ACA, Colman RW, Lees RS:  Clofibrate reversal of platelet hypersensitivity in hyperbetalipoproteinemia . Circulation 1974;;50:570-574.
Laustiola K, Lassila R, Koskinen P, et al:  Gemfibrozil decreases platelet reactivity in hypercholesterolemic patients during physical stress . Clin Pharm Ther 1988;;43:302-307.
Gordon DJ, Knoke J, Probstfield JL, et al:  High-density lipoprotein cholesterol and coronary heart disease in hypercholesterolemic men: The Lipid Research Clinics Coronary Primary Prevention Trial . Circulation 1986;;74:1217-1225.
Levy RI, Brensike JF, Epstein SE, et al:  The influence of changes in lipid values induced by cholestyramine and diet on progression of coronary artery disease: Results of the NHLBI Type II Coronary Intervention Study . Circulation 1984;;69:325-337.
Tatami R, Mabuchi H, Ueda K, et al:  Intermediate-density lipoprotein and cholesterol-rich very low density lipoprotein in angiographically determined coronary artery disease . Circulation 1981;;64:1174-1184.
Krauss RM:  Relationship of intermediate and low-density lipoprotein subspecies to risk of coronary artery disease . Am Heart J 1987;;113:578-582.
O'Brien JR, Etherington MD, Shuttleworth RD, et al:  A pilot study of the effect of gemfibrozil on some haematological parameters . Thromb Res 1982;;26:275-279.
Wilhelmsen L, Svärsudd K, Korsan-Bengtsen K, et al:  Fibrinogen as a risk factor for stroke and myocardial infarction . N Engl J Med 1984;;311:501-505.
Markowe HLJ, Marmot MG, Shipley MJ, et al:  Fibrinogen: A possible link between social class and coronary heart disease . Br Med J 1985;;291:1312-1314.
Kannel WB, Wolf PA, Castelli WP, et al:  Fibrinogen and risk of cardiovascular disease: The Framingham Study . JAMA 1987;;258:1183-1186.
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