Annals of Medicine
ISSN: 0785-3890 (Print) 1365-2060 (Online) Journal homepage: http://www.tandfonline.com/loi/iann20
The Helsinki Heart Study: Central Findings and Clinical Implications Jussi K. Huttunen, Vesa Manninen, Matti Mänttäri, Pekka Koskinen, Matti Romo, Leena Tenkanen, Olli P. Heinonen & M. Heikki Frick To cite this article: Jussi K. Huttunen, Vesa Manninen, Matti Mänttäri, Pekka Koskinen, Matti Romo, Leena Tenkanen, Olli P. Heinonen & M. Heikki Frick (1991) The Helsinki Heart Study: Central Findings and Clinical Implications, Annals of Medicine, 23:2, 155-159, DOI: 10.3109/07853899109148041 To link to this article: http://dx.doi.org/10.3109/07853899109148041
Published online: 08 Jul 2009.
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Date: 16 March 2016, At: 07:02
Special Section: Regulation of Cholesterol Metabolism
The Helsinki Heart Study: Central Findings and Clinical lmplications
Downloaded by [University of California, San Diego] at 07:02 16 March 2016
Jussi K. Huttunen, Vesa Manninen, Matti Manttari, Pekka Koskinen, Matti Romo, Leena Tenkanen. Olli P. Heinonen and M. Heikki Frick
This paper describes the central findings and discusses the clinical implications of the Helsinki Heart Study. This was a controlled primary prevention trial to test the hypothesis that using gemfibrozil to lower the concentrations of serum low density lipoprotein (LDL) and very low density lipoprotein (VLDL) and to raise that of high density lipoprotein (HDL) protects subjects against coronary heart disease. Key words: cholesterol; triglycerides; LDL; HDL; gemfibrozil. (Annals of Medicine 23: 155-9,
1991)
Introduction Epidemiological studies in various populations have provided evidence that plasma lipoprotein metabolism is closely linked to the development of atherosclerosis in man (1-4). Until recently it has not been clear whether correction of lipoprotein abnormalities by drugs, diet and other interventions is associated with a subsequent fall in the risk of cardiovascular disease. Several clinical trials have now shown, however, that treatment of dyslipidernia reduces coronary heart disease morbidity, at least in subjects of high-risk (5-9). The Helsinki Heart Study (10-13) was a controlled primary preventiontrial to test the hypothesisthat lowering the concentrationsof plasma low density lipoprotein (LDL) and very low density lipoprotein (VLDL) and raising that of high density lipoprotein (HDL) protects people against developing heart disease. This overwiew describes the central findings and discusses the clinical implications of the Helsinki Heart Study.
Study Design The study was a randomized, double-blind, placebocontrolled, primary-prevention trial covering 4081 men, aged 40 to 55 years, in a 5-year follow-up (10, 11). They were recruited from 23531 men employed by two state agencies and five private companies in various parts of Finland. The study assessed the efficacy of giving 600 From the First Department of Medicine, University of Helsinki, Department of Public Health, University of Helsinki, and the National Public Health Institute, Helsinki, Finland. Address and reprint requests: Jussi Huttunen, M.D., National Public Health Institute, Mannerheimintie 166, SF-00300 Helsinki, Finland.
mg of the drug gemfibrozil twice daily in reducing coronary events in subjects who were at increased risk for coronary heart disease. To qualify for the study, the participants had to have a concentration of non-HDL cholesterol namely, LDL cholesterol plus VLDL cholesterol greater than 5.2 mmol/l at two successive measurements. Subjectives with symptoms or signs of coronary heart disease or other major diseases were excluded. The follow-up examinations of the subjects at three monthly intervals included laboratory measurements and an interview on their main illnesses and any symptoms suggesting myocardial infarction. A routine electrocardiogram was taken at the annual medical examination. Definite fatal and non-fatal myocardial infarctions and cardiac deaths were the end-points. The end-point assessments were carried out before the breaking of the treatment code. Laboratory and statistical methods have been described elsewhere (10-1 4). The study represented a trial of both hygienic and drug measures for the control of coronary heart disease. Before randomizing the study group its members were given dietary advice and, as a result, their total cholesterol concentrations fell by about 7 % (11, 12). The effect of dietary couselling was restricted to the LDL fraction, as no change was observed in amounts of serum HDL cholesterol or triglycerides.
Risk Factors and CHD Incidence in the Placebo Group Clinical and laboratory examinationscarried out at baseline allowed us to study the effects of various risk factors on the incidence of coronary disease in the placebo group. The incidence of cardiac endpoints was negatively associated with baseline concentrations of HDL cholesterol
Ann Med 23
Huttunen Manninen Manttari, et al.
156
LDL cholesterol
Tablel. Effect of gemfibrozil on serum lipids and lipoproteins. Data from a subgroup (n=30) of the Helsinki Heart Study (see Ref. 18) ~~
~
Lipid fraction
Before treatment
Six months after treatment with gemfibrozil
Total cholesterol Total triglycerides LDL cholesterol HDL cholesterol HDL, cholesterol HDL, cholesterol
6.2 f 0.9 2.3 f 1.1 4.39f 0.78 1.03 k 0.25 0.40 f 0.14 0.633 It 0.14
5.4 f 0.9" 1.1 0.7" 4.02 0.90" 1.23 f 0.31 *' 0.43 f 0.21 0.79 0.16"
+
*
*
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"Statistical significance of difference; k 0 . 0 1
1 2 3 HDL cholesterol tertile Figure 1. Crude incidence (per 1000 person years) of cardiac end-points in the placebo group of the Helsinki Heart Study by baseline high density lipoprotein (HDL) cholesterol tertile within each tertile of low density lipoprotein (LDL) cholesterol (see Ref. 13). Number of events in parentheses. Tertile limits were: LDL cholesterol < 4.49 mmol/l, 4.49 mmol/l to 5.2 mmolll and > 5.2 mmolil and HDL cholesterol < 1.08 mmolil, 1.08 mmol/l to 1.32 mmol/l and > 1.32 mmol/l, respectively.
and positively associated with baseline amounts of LDL cholesterol (13). Within each LDL tertile the risk of coronary heart disease increased with decreasing concentration of HDL (Fig. 1). The relative risk was also significantly raised in subjects with high concentrations of triglyceride. These risk patterns remained essentially similar after adjustment for age, smoking and systolic blood pressure (13, 14). As expected, smoking was a strong predictor of CHD risk in this group (15). A high concentration of lipoprotein (a) was not associated with risk in the Helsinki Heart Study cohort (16).
Effect of Gemfibrozil on Concentrations of Serum Lipid and Lipoprotein Cholesterol Rapid changes were observed in the serum concentrations of all lipids in subjects treated with gemfibrozil. The mean differences in concentrations of total cholesterol, LDL cholesterol, HDL cholesterol and triglyceride between the gemfibrozil and placebo groups over the intervention years were -1 0, -1 1, +11 and -35 %, respectively (11, 12). These changes represent only the mean alterations: the differences between gemfibrozil and placebo treated subjects with the best compliance (11001200 mg gemfibrozWday according to capsule count) during the 5-year study were -15, +14 and -45 Yo for LDL cholesterol, HDL cholesterol and triglycerides, respectively (17). The treatment response also differed among Fredrickson hyperlipoproteinemia types (12). A 13 Yo reduction in the amount of LDL cholesterol in the serum was seen in Type IIA subjects, and 8 Yo reduction in Type llB subjects and a 2 % increase in Type IV
Ann Med 23
subjects, compared to placebo group. The corresponding changes in HDL cholesterol were +11, + I 3 and +10 o/o for Types HA, IIB and IV hyperlipoproteinemia. Ultracentrifuge analysis of lipoprotein changes during the first six months in 60 participants (18) showed that increases in concentrations of HDL cholesterol were due to an increase in the HDL,subfraction (Table 1). Furthermore, gemfibrozil reduced the triglyceride content and raised the cholesterol/triglyceride ratio of LDL, HDL, and VLDL, especially in subjects with high initial concentrations of triglyceride. Such changes were not seen in HDL,. Lipid responses to gemfibrozil in relation to their respective baseline levels were analysed among subjects with good compliance (1900 mg gemfibrozil per day according to the capsule count) (17). A strong association was found between baseline levels and the response to treatment (expressed as the difference in mrnol/l between the gemfibrozil and placebo-treated groups) for LDL-cholesterol and triglycerides. In contrast, the corresponding change in the concentration of serum HDLcholesterol did not depend on the baseline level. The explanation for the different behaviour of individual lipoprotein fractions is unknown. No relationship was observed between the lipid response to gemfibrozil and apolipoprotein E, apolipoprotein B Xbal or apolipoprotein AI/CIII Sstl polymorphisms (19, 20). Gemfibrozil did not influence the serum concentration of lipoprotein (a) (16).
Treatment Compliance The excellent treatment compliance among the subjects receiving gemfibrozil was an important finding in itself. According to capsule count around 40 % of the participants took over 90 % and around 35 Yo took 75-90 o/o of the recommended dose during the 5-year trial (11). Poor compliance (< 50 % of the prescribed dose) was recorded in fewer than 5 Yoof the participants. Only a small difference in treatment compliance was observed between the groups taking gemfibrozil and placebo. Nor was there any significant fall in drug compliance as the study progressed - the percentage of prescribed capsules taken annually during the 5-year trial in the gemfibrozil group were 85, 85, 84, 84, and 82. These observations show that gemfibrozil is well tolerated, an essential property
The Helsinki Heart Study: Central Findings and Clinical Implications for a drug that has to be used for extended periods in the primary prevention of a chronic disease.
157
Number of end-points
34-
I
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Effect on Incidence of Coronary Heart Disease When averaged over the 5-year trial,, the gemfibrozil group showed a statistically significant ( P > 0.02, two tailed) reduction of 34 Yo in the incidence of definite coronary heart disease events (11). The major effect was confined to non-fatal Q-wave infarctions; a 4 5 % reduction ( P < 0.02, log-rank test) was observed in the cumulative incidence of Q-wave infarctions in the group taking gemfibrozil without a statistically significant effect on non-Q wave infarctions (21). The difference between the group on gemfibrozil and that on placebo began to emerge after a lag of 1,5-2 years (Fig. 2). Thereafter the two groups steadily diverged over the course of the study, and the difference amounted to 65 Yo during the fifth year. Fewer deaths occurred from ischaemic heart disease in the gemfibrozil than in the placebo group (14 vs. 19), but the difference was not statistically significant (1 1). No statistically significant differences in total mortality or in the incidence of cancer were observed between the two groups during the 5-year trial. Neither the Helsinki Heart Study nor any previous trial of coronary heart disease prevention has been designed to test the hypothesis that lipid modification influences coronary heart disease or total mortality; to achieve such a target, a much larger sample size or longer follow-up would have been needed. Statistical analyses carried out in connection with the Helsinki Heart Study strongly suggest that the risk reduction observed in subjects treated with gemfibrozil was a result of simultaneous changes in the amounts of LDL cholesterol and HDL cholesterol (12). Thus, when the relationship between the serum lipid changes during the gemfibrozil and placebo treatment and the incidence of cardiac end-points was studied using Cox proportional hazards models, the increase in the concentration of serum HDL cholesterol ( P 2.3 (rnrnol/l)
1.05 (0.56-2.00) 0.72 (0.35-1.47)
(mmolIl)
Tg > 2.3 (rnmolll)
1.19 (0.61-2.32) 1.24 (0.65-2.35)
3.82 (2.20-6.63) 1.08 (0.46-2.55)
LDL-C = low density lipoprotein cholesterol. HDL-C = high density lipoprotein cholesterol. Tg=triglycerides. The risks were estimated using Cox regression models with age, smoking status and systolic blood pressure as covariates. Those in the placebo group with serum LDL-C to HDL-C ratio 5 5.0 and triglycerides 5 2.3 rnmol/l were the reference group with unity risk. The 95 % confidence intervals are given in parentheses.
Huttunen
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158
.Manninen
lipoprotein amounts (1 1, 13). The incidence of definite cardiac end-points was lower in the group on gemfibrozil for all Fredrickson types, the greatest reduction being for Type I16 (P 5 and triglyceride levels of > 2.3 mmol/l as criteria it was possible to define a small subgroup with an over 70% reduction in CHD risk during treatment with gemfibrozil (Table 2 ) (14). In fact, most of the benefit associated with gemfibrozil treatment was confined to this subgroup, which comprised only 10 o/o of the trial population.
Manttari et al.
criteria are closely similar to the lipoprotein pattern described for the so called small dense LDL syndrome. This syndrome is common among subjects with myocardial infarction and is probably influenced by a common allele at a single gene locus (23). Whether gemfibrozil and possibly other fibrates specifically reduce the risk associated with this syndrome remains to be studied. In conclusion, the Helsinki Heart Study showed that gemfibrozil lowers the risk of coronary heart disease in middle-aged men with a raised concentration of nonHDL cholesterol. The risk reduction is most obvious among subjects with high LDL cholesteroVHDL cholesterol ratio and a raised concentration of triglyceride in their serum. Analysis of lipid and lipoprotein changes during the study further suggested that a reduction in risk resulted from changes in the amounts of both LDL cholesterol and HDL cholesterol.
References Comments The reduction in the incidence of coronary heart disease during treatment with gemfibrozil observed in the Helsinki Heart Study is consistent with the results of primary and secondary prevention studies using various interventions to correct the atherogenic lipoprotein pattern (5-9). All these studies show that the progression of coronary atherosclerosis can be prevented by appropriate treatment of the dyslipidemia, both in asymptomatic subjects and in patients with existing disease. Despite the significant independent association seen between the concentrations of serum HDL-cholesterol and coronary disease in several cross-sectional and longitudinal studies (3, 4), direct evidence for the causal role of HDL in the development of coronary heart disease has been lacking. Our data from the Helsinki Heart Study strongly suggest that the rise in the concentration of serum HDL cholesterol during treatment with gemfibrozil contributed significantly to the observed reduction in coronary heart disease risk. Thus, a significant reduction in risk was seen among subjects belonging to the lowest tertile of baseline HDL cholesterol, whereas no reduction was seen in the subjects belonging to the highest tertile. Moreover, the increase in the amounts of HDL cholesterol and the fall in that of LDL cholesterol during treatment were both associated with a low risk of coronary events in the group on gemfibrozil. Our findings may also provide important information on the effects of HDL subfractions on coronary heart disease progression. On the basis of cross-sectional studies it has been assumed that the HDL,, not the HDL,, subfraction is associated with the risk of CHD (3). This belief has recently been questioned, however, as two prospective studies have found an inverse relationship between HDL, and the incidence of CHD (22). In support of the latter observations we found in a subgroup of the Helsinkki Heart Study cohort that gemfibrozil preferentially raises the amount of HDL, cholesterol. Using high baseline LDL cholesteroVHDL cholesterol ratio and hypertriglyceridemia as criteria it was possible to identify a small subgroup that experienced reduction in coronary risk of over 70 % (14). Interestingly, the
A n n Mad 31
1. Inter-Society Commmission for Heart Disease Resources. Atherosclerosis Studv Group: Optimal resources for primary prevention of atherosclerotic diseases. Circulaiion 1984: 70: 153A-205A. 2. Tyroler HA. Review of lipid-lowering trials in relation to observational epidemiologic studies. Circulation 1987; 76: 515-22. 3. Miller NE. Associations of high-densitylipoproteinsubclasses and apolipoproteins with ischemic heart disease and coronary atherosclerosis. Am Heart J 1987; 113: 589-97. 4. Gordon D, Probstfield JL, Garrison RJ, et al. High density lipoprotein cholesterol and cardiovascular disease: four prospective American studies. Circulation 1989; 79: 8-1 5. 5. Oliver MF, Heady JA, Morris JN, Cooper J. A co-operative trial in the primary prevention of ischemic heart disease using clofibrate. Report from the Committee of Principal Investigators. Br Heart J 1978; 40: 1069-1 18. 6. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Preventiontrial results. I: Reductionin incidence of coronary heart disease. JAMA 1984; 251 : 351-64. 7. Canner PL, Berge KG, Wenger NK, et el. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986; 8: 1245-55. 8. Buchwald H, Varco RL, Matts JP, et al. Effect of partial ileal by-pass on mortality and morbidity from coronary heart disease in patients with hvpercholesterolemia. ReDOrt of the Program on the Surgical’Control of the Hyperlipidemics (POSCH). N Ennl J Med 1990; 323: 946-55. 9. Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm lschaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand 1988; 223: 405-1 8. 10. ManttBri M,Elo 0, Frlck MH, et al. The Helsinki Heart Studv: basic design and randomization procedure. Eur Heart ‘J 1987; 8 : Suppl 1: 1-29. 11. Frlck MH, El0 0, Haapa K, et al. The Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987: 317: 1237-45. 12. Manninen V, Elo 0, Haapa K, et al. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA 1988; 260: 641-51. 13. Manninen V, Huttunen JK, Heinonen OP, Tenkanen L, Frick MH. Relation between baseline lipid and lipoprotein values and the incidence of coronary heart disease in the Helsinki Heart Study. Am J Cardiol 1989; 63: 42H-7H. 14. Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglyceride, LDL cholesterol and HDL cholesterol on coronary heart disease risk in the Helsinki Heart Study. Submitted for publication, 1991. 15. Manninen V, Tenkanen L, Koskinen P, et al. Smoking, dyslipidemia and the risk of coronary heart disease: how
The Helsinki Heart Study: Central Findings and Clinical Implications
16.
17. 18.
20.
21. 22.
23.
serum cholesterol response to dietary intervention. Metabolism 1991; 40: 217-21. Aalto-Setala K, Kontula K, Manttari M, et al. DNA polymorphisms of apolipoprotein B and AI/CIII genes and response to gemfibrozil treatment. Clin Pharmacol Ther 1991 (in press) Manttlri M, Romo M, Manninen V, et al. Reduction in Qwave myocardial infarctions with gemfibrozil in the Helsinki Heart Study. Am Heart J 1990; 119: 991-5. Sweetnarn P, Elwood P, Yarnell J, et al. HDL cholesterol and its subfractions in the Caerphilly and Speedwell Heart Disease Studies. In: Miller NE, ed. High-Density Lipoproteins and Atherosclerosis. Amsterdam: Elsevier, 1989: 43-50. Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation 1990; 82: 495-506.
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19.
does gemfibrozil change the risk patterns? Cardiovasc Risk Factors 1991, (in press) Jauhiainen M, Koskinen P, Ehnholm C, et al. Lipoprotein (a) and coronary heart disease risk. A nested case-control study among the Helsinki Heart Study participants. Atherosclerosis 1991 (in press). Mlnttari M, Huttunen JK, Koskinen P, et al. Lipoproteins and coronary heart disease in the Helsinki Heart Study. Eur Heart J 1990; 11: Suppl H: 26-31 Manttari M, Koskinen P, Manninen V, Huttunen JK, Frick MH, Nikkila EA: Effect of gemfibrozil on the concentration and composition of serum lipoproteins. A controlled study with special reference to initial triglyceride levels. Atherosclerosis 1990; 81 : 11-1 7. Manttari M, Koskinen P, Enholrn C ; Huttunen JK; Manninen V. Apolipoprotein E polymorphism influences the
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Ann Med 23
ISSN: 0785-3890 (Print) 1365-2060 (Online) Journal homepage: http://www.tandfonline.com/loi/iann20
The Helsinki Heart Study: Central Findings and Clinical Implications Jussi K. Huttunen, Vesa Manninen, Matti Mänttäri, Pekka Koskinen, Matti Romo, Leena Tenkanen, Olli P. Heinonen & M. Heikki Frick To cite this article: Jussi K. Huttunen, Vesa Manninen, Matti Mänttäri, Pekka Koskinen, Matti Romo, Leena Tenkanen, Olli P. Heinonen & M. Heikki Frick (1991) The Helsinki Heart Study: Central Findings and Clinical Implications, Annals of Medicine, 23:2, 155-159, DOI: 10.3109/07853899109148041 To link to this article: http://dx.doi.org/10.3109/07853899109148041
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 23
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iann20 Download by: [University of California, San Diego]
Date: 16 March 2016, At: 07:02
Special Section: Regulation of Cholesterol Metabolism
The Helsinki Heart Study: Central Findings and Clinical lmplications
Downloaded by [University of California, San Diego] at 07:02 16 March 2016
Jussi K. Huttunen, Vesa Manninen, Matti Manttari, Pekka Koskinen, Matti Romo, Leena Tenkanen. Olli P. Heinonen and M. Heikki Frick
This paper describes the central findings and discusses the clinical implications of the Helsinki Heart Study. This was a controlled primary prevention trial to test the hypothesis that using gemfibrozil to lower the concentrations of serum low density lipoprotein (LDL) and very low density lipoprotein (VLDL) and to raise that of high density lipoprotein (HDL) protects subjects against coronary heart disease. Key words: cholesterol; triglycerides; LDL; HDL; gemfibrozil. (Annals of Medicine 23: 155-9,
1991)
Introduction Epidemiological studies in various populations have provided evidence that plasma lipoprotein metabolism is closely linked to the development of atherosclerosis in man (1-4). Until recently it has not been clear whether correction of lipoprotein abnormalities by drugs, diet and other interventions is associated with a subsequent fall in the risk of cardiovascular disease. Several clinical trials have now shown, however, that treatment of dyslipidernia reduces coronary heart disease morbidity, at least in subjects of high-risk (5-9). The Helsinki Heart Study (10-13) was a controlled primary preventiontrial to test the hypothesisthat lowering the concentrationsof plasma low density lipoprotein (LDL) and very low density lipoprotein (VLDL) and raising that of high density lipoprotein (HDL) protects people against developing heart disease. This overwiew describes the central findings and discusses the clinical implications of the Helsinki Heart Study.
Study Design The study was a randomized, double-blind, placebocontrolled, primary-prevention trial covering 4081 men, aged 40 to 55 years, in a 5-year follow-up (10, 11). They were recruited from 23531 men employed by two state agencies and five private companies in various parts of Finland. The study assessed the efficacy of giving 600 From the First Department of Medicine, University of Helsinki, Department of Public Health, University of Helsinki, and the National Public Health Institute, Helsinki, Finland. Address and reprint requests: Jussi Huttunen, M.D., National Public Health Institute, Mannerheimintie 166, SF-00300 Helsinki, Finland.
mg of the drug gemfibrozil twice daily in reducing coronary events in subjects who were at increased risk for coronary heart disease. To qualify for the study, the participants had to have a concentration of non-HDL cholesterol namely, LDL cholesterol plus VLDL cholesterol greater than 5.2 mmol/l at two successive measurements. Subjectives with symptoms or signs of coronary heart disease or other major diseases were excluded. The follow-up examinations of the subjects at three monthly intervals included laboratory measurements and an interview on their main illnesses and any symptoms suggesting myocardial infarction. A routine electrocardiogram was taken at the annual medical examination. Definite fatal and non-fatal myocardial infarctions and cardiac deaths were the end-points. The end-point assessments were carried out before the breaking of the treatment code. Laboratory and statistical methods have been described elsewhere (10-1 4). The study represented a trial of both hygienic and drug measures for the control of coronary heart disease. Before randomizing the study group its members were given dietary advice and, as a result, their total cholesterol concentrations fell by about 7 % (11, 12). The effect of dietary couselling was restricted to the LDL fraction, as no change was observed in amounts of serum HDL cholesterol or triglycerides.
Risk Factors and CHD Incidence in the Placebo Group Clinical and laboratory examinationscarried out at baseline allowed us to study the effects of various risk factors on the incidence of coronary disease in the placebo group. The incidence of cardiac endpoints was negatively associated with baseline concentrations of HDL cholesterol
Ann Med 23
Huttunen Manninen Manttari, et al.
156
LDL cholesterol
Tablel. Effect of gemfibrozil on serum lipids and lipoproteins. Data from a subgroup (n=30) of the Helsinki Heart Study (see Ref. 18) ~~
~
Lipid fraction
Before treatment
Six months after treatment with gemfibrozil
Total cholesterol Total triglycerides LDL cholesterol HDL cholesterol HDL, cholesterol HDL, cholesterol
6.2 f 0.9 2.3 f 1.1 4.39f 0.78 1.03 k 0.25 0.40 f 0.14 0.633 It 0.14
5.4 f 0.9" 1.1 0.7" 4.02 0.90" 1.23 f 0.31 *' 0.43 f 0.21 0.79 0.16"
+
*
*
Downloaded by [University of California, San Diego] at 07:02 16 March 2016
"Statistical significance of difference; k 0 . 0 1
1 2 3 HDL cholesterol tertile Figure 1. Crude incidence (per 1000 person years) of cardiac end-points in the placebo group of the Helsinki Heart Study by baseline high density lipoprotein (HDL) cholesterol tertile within each tertile of low density lipoprotein (LDL) cholesterol (see Ref. 13). Number of events in parentheses. Tertile limits were: LDL cholesterol < 4.49 mmol/l, 4.49 mmol/l to 5.2 mmolll and > 5.2 mmolil and HDL cholesterol < 1.08 mmolil, 1.08 mmol/l to 1.32 mmol/l and > 1.32 mmol/l, respectively.
and positively associated with baseline amounts of LDL cholesterol (13). Within each LDL tertile the risk of coronary heart disease increased with decreasing concentration of HDL (Fig. 1). The relative risk was also significantly raised in subjects with high concentrations of triglyceride. These risk patterns remained essentially similar after adjustment for age, smoking and systolic blood pressure (13, 14). As expected, smoking was a strong predictor of CHD risk in this group (15). A high concentration of lipoprotein (a) was not associated with risk in the Helsinki Heart Study cohort (16).
Effect of Gemfibrozil on Concentrations of Serum Lipid and Lipoprotein Cholesterol Rapid changes were observed in the serum concentrations of all lipids in subjects treated with gemfibrozil. The mean differences in concentrations of total cholesterol, LDL cholesterol, HDL cholesterol and triglyceride between the gemfibrozil and placebo groups over the intervention years were -1 0, -1 1, +11 and -35 %, respectively (11, 12). These changes represent only the mean alterations: the differences between gemfibrozil and placebo treated subjects with the best compliance (11001200 mg gemfibrozWday according to capsule count) during the 5-year study were -15, +14 and -45 Yo for LDL cholesterol, HDL cholesterol and triglycerides, respectively (17). The treatment response also differed among Fredrickson hyperlipoproteinemia types (12). A 13 Yo reduction in the amount of LDL cholesterol in the serum was seen in Type IIA subjects, and 8 Yo reduction in Type llB subjects and a 2 % increase in Type IV
Ann Med 23
subjects, compared to placebo group. The corresponding changes in HDL cholesterol were +11, + I 3 and +10 o/o for Types HA, IIB and IV hyperlipoproteinemia. Ultracentrifuge analysis of lipoprotein changes during the first six months in 60 participants (18) showed that increases in concentrations of HDL cholesterol were due to an increase in the HDL,subfraction (Table 1). Furthermore, gemfibrozil reduced the triglyceride content and raised the cholesterol/triglyceride ratio of LDL, HDL, and VLDL, especially in subjects with high initial concentrations of triglyceride. Such changes were not seen in HDL,. Lipid responses to gemfibrozil in relation to their respective baseline levels were analysed among subjects with good compliance (1900 mg gemfibrozil per day according to the capsule count) (17). A strong association was found between baseline levels and the response to treatment (expressed as the difference in mrnol/l between the gemfibrozil and placebo-treated groups) for LDL-cholesterol and triglycerides. In contrast, the corresponding change in the concentration of serum HDLcholesterol did not depend on the baseline level. The explanation for the different behaviour of individual lipoprotein fractions is unknown. No relationship was observed between the lipid response to gemfibrozil and apolipoprotein E, apolipoprotein B Xbal or apolipoprotein AI/CIII Sstl polymorphisms (19, 20). Gemfibrozil did not influence the serum concentration of lipoprotein (a) (16).
Treatment Compliance The excellent treatment compliance among the subjects receiving gemfibrozil was an important finding in itself. According to capsule count around 40 % of the participants took over 90 % and around 35 Yo took 75-90 o/o of the recommended dose during the 5-year trial (11). Poor compliance (< 50 % of the prescribed dose) was recorded in fewer than 5 Yoof the participants. Only a small difference in treatment compliance was observed between the groups taking gemfibrozil and placebo. Nor was there any significant fall in drug compliance as the study progressed - the percentage of prescribed capsules taken annually during the 5-year trial in the gemfibrozil group were 85, 85, 84, 84, and 82. These observations show that gemfibrozil is well tolerated, an essential property
The Helsinki Heart Study: Central Findings and Clinical Implications for a drug that has to be used for extended periods in the primary prevention of a chronic disease.
157
Number of end-points
34-
I
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Effect on Incidence of Coronary Heart Disease When averaged over the 5-year trial,, the gemfibrozil group showed a statistically significant ( P > 0.02, two tailed) reduction of 34 Yo in the incidence of definite coronary heart disease events (11). The major effect was confined to non-fatal Q-wave infarctions; a 4 5 % reduction ( P < 0.02, log-rank test) was observed in the cumulative incidence of Q-wave infarctions in the group taking gemfibrozil without a statistically significant effect on non-Q wave infarctions (21). The difference between the group on gemfibrozil and that on placebo began to emerge after a lag of 1,5-2 years (Fig. 2). Thereafter the two groups steadily diverged over the course of the study, and the difference amounted to 65 Yo during the fifth year. Fewer deaths occurred from ischaemic heart disease in the gemfibrozil than in the placebo group (14 vs. 19), but the difference was not statistically significant (1 1). No statistically significant differences in total mortality or in the incidence of cancer were observed between the two groups during the 5-year trial. Neither the Helsinki Heart Study nor any previous trial of coronary heart disease prevention has been designed to test the hypothesis that lipid modification influences coronary heart disease or total mortality; to achieve such a target, a much larger sample size or longer follow-up would have been needed. Statistical analyses carried out in connection with the Helsinki Heart Study strongly suggest that the risk reduction observed in subjects treated with gemfibrozil was a result of simultaneous changes in the amounts of LDL cholesterol and HDL cholesterol (12). Thus, when the relationship between the serum lipid changes during the gemfibrozil and placebo treatment and the incidence of cardiac end-points was studied using Cox proportional hazards models, the increase in the concentration of serum HDL cholesterol ( P 2.3 (rnrnol/l)
1.05 (0.56-2.00) 0.72 (0.35-1.47)
(mmolIl)
Tg > 2.3 (rnmolll)
1.19 (0.61-2.32) 1.24 (0.65-2.35)
3.82 (2.20-6.63) 1.08 (0.46-2.55)
LDL-C = low density lipoprotein cholesterol. HDL-C = high density lipoprotein cholesterol. Tg=triglycerides. The risks were estimated using Cox regression models with age, smoking status and systolic blood pressure as covariates. Those in the placebo group with serum LDL-C to HDL-C ratio 5 5.0 and triglycerides 5 2.3 rnmol/l were the reference group with unity risk. The 95 % confidence intervals are given in parentheses.
Huttunen
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158
.Manninen
lipoprotein amounts (1 1, 13). The incidence of definite cardiac end-points was lower in the group on gemfibrozil for all Fredrickson types, the greatest reduction being for Type I16 (P 5 and triglyceride levels of > 2.3 mmol/l as criteria it was possible to define a small subgroup with an over 70% reduction in CHD risk during treatment with gemfibrozil (Table 2 ) (14). In fact, most of the benefit associated with gemfibrozil treatment was confined to this subgroup, which comprised only 10 o/o of the trial population.
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criteria are closely similar to the lipoprotein pattern described for the so called small dense LDL syndrome. This syndrome is common among subjects with myocardial infarction and is probably influenced by a common allele at a single gene locus (23). Whether gemfibrozil and possibly other fibrates specifically reduce the risk associated with this syndrome remains to be studied. In conclusion, the Helsinki Heart Study showed that gemfibrozil lowers the risk of coronary heart disease in middle-aged men with a raised concentration of nonHDL cholesterol. The risk reduction is most obvious among subjects with high LDL cholesteroVHDL cholesterol ratio and a raised concentration of triglyceride in their serum. Analysis of lipid and lipoprotein changes during the study further suggested that a reduction in risk resulted from changes in the amounts of both LDL cholesterol and HDL cholesterol.
References Comments The reduction in the incidence of coronary heart disease during treatment with gemfibrozil observed in the Helsinki Heart Study is consistent with the results of primary and secondary prevention studies using various interventions to correct the atherogenic lipoprotein pattern (5-9). All these studies show that the progression of coronary atherosclerosis can be prevented by appropriate treatment of the dyslipidemia, both in asymptomatic subjects and in patients with existing disease. Despite the significant independent association seen between the concentrations of serum HDL-cholesterol and coronary disease in several cross-sectional and longitudinal studies (3, 4), direct evidence for the causal role of HDL in the development of coronary heart disease has been lacking. Our data from the Helsinki Heart Study strongly suggest that the rise in the concentration of serum HDL cholesterol during treatment with gemfibrozil contributed significantly to the observed reduction in coronary heart disease risk. Thus, a significant reduction in risk was seen among subjects belonging to the lowest tertile of baseline HDL cholesterol, whereas no reduction was seen in the subjects belonging to the highest tertile. Moreover, the increase in the amounts of HDL cholesterol and the fall in that of LDL cholesterol during treatment were both associated with a low risk of coronary events in the group on gemfibrozil. Our findings may also provide important information on the effects of HDL subfractions on coronary heart disease progression. On the basis of cross-sectional studies it has been assumed that the HDL,, not the HDL,, subfraction is associated with the risk of CHD (3). This belief has recently been questioned, however, as two prospective studies have found an inverse relationship between HDL, and the incidence of CHD (22). In support of the latter observations we found in a subgroup of the Helsinkki Heart Study cohort that gemfibrozil preferentially raises the amount of HDL, cholesterol. Using high baseline LDL cholesteroVHDL cholesterol ratio and hypertriglyceridemia as criteria it was possible to identify a small subgroup that experienced reduction in coronary risk of over 70 % (14). Interestingly, the
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1. Inter-Society Commmission for Heart Disease Resources. Atherosclerosis Studv Group: Optimal resources for primary prevention of atherosclerotic diseases. Circulaiion 1984: 70: 153A-205A. 2. Tyroler HA. Review of lipid-lowering trials in relation to observational epidemiologic studies. Circulation 1987; 76: 515-22. 3. Miller NE. Associations of high-densitylipoproteinsubclasses and apolipoproteins with ischemic heart disease and coronary atherosclerosis. Am Heart J 1987; 113: 589-97. 4. Gordon D, Probstfield JL, Garrison RJ, et al. High density lipoprotein cholesterol and cardiovascular disease: four prospective American studies. Circulation 1989; 79: 8-1 5. 5. Oliver MF, Heady JA, Morris JN, Cooper J. A co-operative trial in the primary prevention of ischemic heart disease using clofibrate. Report from the Committee of Principal Investigators. Br Heart J 1978; 40: 1069-1 18. 6. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Preventiontrial results. I: Reductionin incidence of coronary heart disease. JAMA 1984; 251 : 351-64. 7. Canner PL, Berge KG, Wenger NK, et el. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986; 8: 1245-55. 8. Buchwald H, Varco RL, Matts JP, et al. Effect of partial ileal by-pass on mortality and morbidity from coronary heart disease in patients with hvpercholesterolemia. ReDOrt of the Program on the Surgical’Control of the Hyperlipidemics (POSCH). N Ennl J Med 1990; 323: 946-55. 9. Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm lschaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand 1988; 223: 405-1 8. 10. ManttBri M,Elo 0, Frlck MH, et al. The Helsinki Heart Studv: basic design and randomization procedure. Eur Heart ‘J 1987; 8 : Suppl 1: 1-29. 11. Frlck MH, El0 0, Haapa K, et al. The Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987: 317: 1237-45. 12. Manninen V, Elo 0, Haapa K, et al. Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA 1988; 260: 641-51. 13. Manninen V, Huttunen JK, Heinonen OP, Tenkanen L, Frick MH. Relation between baseline lipid and lipoprotein values and the incidence of coronary heart disease in the Helsinki Heart Study. Am J Cardiol 1989; 63: 42H-7H. 14. Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglyceride, LDL cholesterol and HDL cholesterol on coronary heart disease risk in the Helsinki Heart Study. Submitted for publication, 1991. 15. Manninen V, Tenkanen L, Koskinen P, et al. Smoking, dyslipidemia and the risk of coronary heart disease: how
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16.
17. 18.
20.
21. 22.
23.
serum cholesterol response to dietary intervention. Metabolism 1991; 40: 217-21. Aalto-Setala K, Kontula K, Manttari M, et al. DNA polymorphisms of apolipoprotein B and AI/CIII genes and response to gemfibrozil treatment. Clin Pharmacol Ther 1991 (in press) Manttlri M, Romo M, Manninen V, et al. Reduction in Qwave myocardial infarctions with gemfibrozil in the Helsinki Heart Study. Am Heart J 1990; 119: 991-5. Sweetnarn P, Elwood P, Yarnell J, et al. HDL cholesterol and its subfractions in the Caerphilly and Speedwell Heart Disease Studies. In: Miller NE, ed. High-Density Lipoproteins and Atherosclerosis. Amsterdam: Elsevier, 1989: 43-50. Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation 1990; 82: 495-506.
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19.
does gemfibrozil change the risk patterns? Cardiovasc Risk Factors 1991, (in press) Jauhiainen M, Koskinen P, Ehnholm C, et al. Lipoprotein (a) and coronary heart disease risk. A nested case-control study among the Helsinki Heart Study participants. Atherosclerosis 1991 (in press). Mlnttari M, Huttunen JK, Koskinen P, et al. Lipoproteins and coronary heart disease in the Helsinki Heart Study. Eur Heart J 1990; 11: Suppl H: 26-31 Manttari M, Koskinen P, Manninen V, Huttunen JK, Frick MH, Nikkila EA: Effect of gemfibrozil on the concentration and composition of serum lipoproteins. A controlled study with special reference to initial triglyceride levels. Atherosclerosis 1990; 81 : 11-1 7. Manttari M, Koskinen P, Enholrn C ; Huttunen JK; Manninen V. Apolipoprotein E polymorphism influences the
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