Gemfibrozil in the Treatment of Dyslipidemia an 18-Year Mortality Follow-Up of the Helsinki Heart Study

ORIGINAL INVESTIGATION Gemfibrozil in the Treatment of Dyslipidemia An 18-Year Mortality Follow-up of the Helsinki Heart Study

Leena Tenkanen, PhD; Matti Ma¨ntta¨ri, MD; Petri T. Kovanen, MD; Hanna Virkkunen, MSc; Vesa Manninen, MD

Background: The Helsinki Heart Study was a double- Cox proportional hazards models with and without blind, placebo-controlled primary prevention trial among covariates. 4081 dyslipidemic middle-aged men to test the efficacy of gemfibrozil in the prevention of coronary heart dis- Results: During the follow-up until 1995, subjects in the ease (CHD). After the 5-year trial, the participants were OG group had a 32% lower RR of CHD mortality (P=.03) notified of their treatment group and invited to con- compared with those in the OP group, and when followed tinue or start gemfibrozil therapy free of charge through up until 2000, the RR was 23% lower (P=.05). Overall, there 1995. Approximately two thirds of participants in both were no differences in all-cause or cancer mortality. How- groups chose gemfibrozil therapy. In this 18-year fol- ever, those in the OG group with both body mass index low-up through 2000, we compared the CHD, cancer, and triglyceride level in the highest tertiles had a 71% lower Ͻ and all-cause mortality among subjects in the original gem- RR of CHD mortality (P .001), a 33% lower RR of all- fibrozil (OG) group (n=2046) with those in the origi- cause mortality (P=.03), and a 36% lower RR of cancer mor- nal placebo (OP) group (n=2035). tality (P=.22) compared with those in the OP group. Conclusion: Long-term mortality follow-up showed that Methods: To provide an overview of the absolute risks patients with dyslipidemia benefited from beginning treat- in the 2 treatment groups as well as risk differences ment with gemfibrozil early, especially if their dyslipid- between them, we calculated crude mortality rates and emia entailed factors related to the metabolic syndrome. presented Kaplan-Meier plots of survival with log-rank tests. We also estimated the relative risks (RRs) using Arch Intern Med. 2006;166:743-748

HE HELSINKI HEART STUDY from the treatment was characterized by was a 5-year primary pre- a high baseline triglyceride (TG) level vention trial to test the hy- and an elevated ratio of LDL-C to pothesis that gemfibrozil HDL-C.5 Further analyses indicated that use reduces coronary heart gemfibrozil use reduced CHD risk espe- diseaseT (CHD) incidence by lowering low- cially in overweight subjects with addi- density lipoprotein cholesterol (LDL-C) tional risk factors known to contribute and increasing high-density lipoprotein or predispose to the metabolic syn- cholesterol (HDL-C) levels. During the drome.6 The effect of gemfibrozil therapy Author Affiliations: Helsinki original 5-year, double-blind phase of the in subjects with insulin resistance was Heart Study, Helsinki, Finland trial, a 34% reduction in cardiac end points, later confirmed in the Veterans Affairs (Drs Tenkanen, Mänttäri, and but no difference in all-cause mortal- High Density Lipoprotein Intervention Manninen and Ms Virkkunen); 1,2 7 School of Public Health, ity, was seen. When the 5-year trial Trial (VA-HIT). Tampere University, Tampere, ended, the participants in both treatment Finland (Dr Tenkanen and groups were offered gemfibrozil for the fol- Ms Virkkunen); Helsinki lowing 3.5 years. At the end of the 3.5- See also pages 715 and 737 University Jorvi Hospital, year open-label phase, the effect of long- Espoo, Finland (Dr Ma¨ntta¨ri); term vs short-term treatment with The present study is an 18-year fol- Helsinki University Central gemfibrozil was studied. No material dif- low-up of the original gemfibrozil (OG) and Hospital, Helsinki ferences in all-cause or coronary mortal- original placebo (OP) groups of the Hel- (Dr Manninen); and Wihuri ity were seen between the original treat- sinki Heart Study to examine the effects of Research Institute, Helsinki ment groups,3 whereas cancer mortality a 5-year earlier start of gemfibrozil treat- (Drs Ma¨ntta¨ri and Kovanen). was slightly (nonsignificantly) higher in ment on all-cause, CHD, and cancer mor- Group Information: 4 Drs Tenkanen, Mänttäri, and the original gemfibrozil group. tality. We also investigated whether the Manninen and Ms Virkkunen Subsequent subgroup analyses of the findings from the subgroup analyses of are members of the Helsinki double-blind trial data showed that the the double-blind trial phase would persist Heart Study Group. group that obtained the greatest benefit in the long-term analysis of mortality.

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 Free Gemfibrozil A OG Group Group Double Blind Open Label Treatment 2.20 OP Group Placebo Gemfibrozil (n = 1320) OP 2.00 (n = 2035) No Drug (n = 608) 1.80 1.60 Gemfibrozil Gemfibrozil (n = 1301) OG 1.40 (n = 2046) No Drug (n = 660) 1.20 TG Level, mmol/L 8.5-y Follow-up 1.00

13-y Follow-up

18-y Follow-up B Clinical Follow-up 1.40 Register-Based Follow-up 1.35 1.30 1981-1982 1986-1987 1990 1995 2000 1.25 Calendar Year 1.20

HDL-C Level, mmol/L 1.15 Figure 1. Schematic presentation of the different phases of the 18-year follow-up of the Helsinki Heart Study. OG indicates original gemfibrozil; OP, original placebo. C

5.20 METHODS 5.00 4.80 DIFFERENT PHASES 4.60 OF THE HELSINKI HEART STUDY 4.40

LDL-C Level, mmol/L 4.20 Double-blind Trial Baseline 1 2 3 4 5 6 7 8 The Helsinki Heart Study was a 5-year, double-blind clinical trial Years to test the hypothesis that lowering serum LDL-C and triglyc- Double Blind Open Label eride levels and elevating serum HDL-C levels with gemfibrozil 1981-1982 1986-1987 1990 reduces CHD risk in middle-aged dyslipidemic men. The de- Calendar Year sign, conduct, and main results of the study have been de- 1,2 scribed in detail. Briefly, the volunteers for the trial were se- Figure 2. Development of annual mean values of triglyceride (TG) (A), lected in 1980 through 1982 by 2 successive screenings from men high-density lipoprotein cholesterol (HDL-C) (B), and low-density lipoprotein aged 40 to 55 years, employed by 2 government agencies and 5 cholesterol (LDL-C) (C) in the original placebo (OP) and original gemfibrozil industrial companies. To be eligible for the second screening or (OG) groups during the double-blind and open-label trials. To convert to for the trial, the subjects’ non–HDL-C level had to be 200 mg/dL milligrams per deciliter, divide by 0.0113 for TG and by 0.0259 for HDL-C and LDL-C. (5.2 mmol/L) or higher, and for the trial they also had to be without evidence of CHD or any other major illness. Of 18 936 men tality by linkage to population-based registers, especially the at the first screening, 4081 met these criteria and were willing Cause-of-Death Register kept by Statistics Finland, Helsinki. In to participate in the trial. Of these, 2035 were randomized to re- Finland, there is a centralized nationwide population registra- ceive placebo and 2046 to receive gemfibrozil, 1200 mg/d, 2 cap- tion system based on personal identification numbers, kept since sules twice daily. Compliance with medication was studied by 1966. This system ensures that the registration of deaths is vir- 8 several methods (eg, capsule counting). tually complete. The Cause-of-Death Register was found to be very reliable in terms of CHD deaths compared with the World Open-Label Phase Health Organization Monitoring of Trends and Determinants in Cardiovascular Disease (WHO MONICA) project data9 and the At the end of the 5-year trial, all subjects (including dropouts) were Helsinki Heart Study data.10 informed about their lipid values during the trial and invited to participate in an open 3.5-year trial extension with 2 annual visits and Present Mortality Follow-up a choice to take gemfibrozil (Figure 1). About the same proportion of subjects in the 2 original treatment groups chose to take This study extends the follow-up from the beginning of the double- gemfibrozil: 66.3% in the OG group and 68.5% in the OP group. blind trial in 1980-1982 through 2000 (18-year follow-up) and Compliance monitoring showed that in both groups the partici- is fully register based. The following CHD codes were moni- 3 pant took, on average, 3.5 capsules of gemfibrozil per day. tored: International Classification of Diseases, Eighth Revision codes 410 to 414 through 1986; International Classification of Diseases, Register-Based Follow-up Phase Ninth Revision codes 4100 to 4199 from 1987 through 1995; and International Statistical Classification of Diseases, 10th Revision codes At the end of the open-label phase in June 1990, subjects taking I20 to I25 from 1996 through 2000. These codes imply the pres- gemfibrozil were offered a free drug supply through a central phar- ence of 1 or several of the following conditions: angina, myocar- macy through 1995, but no regular follow-up visits. The trial co- dial infarction, myocardial infarction with complications, other hort was then followed up for all-cause, CHD, and cancer mor- ischemic heart diseases, and chronic ischemic heart disease.

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 1. All-Cause, Cancer, and CHD Mortality (per 10 000 Person-Years) During the 13- and 18-Year Follow-up Periods by the OP and OG Groups

Mortality Rate (No. of Deaths) RR* (95% CI)

Follow-up Period OP Group OG Group Not Adjusted Age Adjusted Adjusted† 13-y Follow-up through 1995‡ CHD 29.7 (83) 20.3 (57) 0.68 (0.49-0.96) 0.70 (0.50-0.98) 0.68 (0.48-0.95) Cancer 22.5 (63) 19.9 (56) 0.89 (0.62-1.27) 0.92 (0.65-1.33) 0.88 (0.62-1.27) All causes 71.2 (199) 65.9 (185) 0.93 (0.76-1.13) 0.95 (0.78-1.16) 0.93 (0.76-1.13) 18-y Follow-up through 2000 CHD 34.8 (128) 26.7 (99) 0.77 (0.59-1.00) 0.78 (0.60-1.01) 0.76 (0.59-0.99) Cancer 28.2 (104) 25.9 (96) 0.91 (0.69-1.21) 0.95 (0.72-1.25) 0.91 (0.69-1.20) All causes 90.2 (332) 83.3 (309) 0.92 (0.79-1.08) 0.94 (0.80-1.10) 0.92 (0.79-1.08)

Abbreviations: CHD, coronary heart disease; CI, confidence interval; OG, original gemfibrozil; OP, original placebo; RR, relative risk. *Relative risk of OG group compared with the OP group. †Adjusted for low- and high-density lipoprotein cholesterol level, systolic blood pressure, body mass index, and smoking. ‡Gemfibrozil was supplied free of charge through 1995.

STATISTICAL ANALYSES gemfibrozil treatment at the end of 1995 (mean, 13.7 The analyses were performed on an intention-to-treat prin- years) and the 18-year follow-up from the beginning of ciple (ie, by comparing mortality risks in the original treat- the study through 2000 (mean 18.1 years). Trends for ment groups). We thus estimated the mortality risk in approxi- all-cause and cancer mortality favored patients in the OG mately 18 years of follow-up among subjects belonging to the group but were significant only for CHD mortality: P=.03 OG group compared with those in the original OP group. To for the 13-year follow-up and P=.05 for the 18-year follow- provide an overview of the absolute risks in the 2 treatment up. In all these comparisons, the differences between the groups as well as risk differences between them, we calculated OP and the OG groups decreased when the follow-up was crude mortality rates and presented Kaplan-Meier plots of sur- extended beyond 1995. vival with log-rank tests. We also tested the statistical signifi- Adjustment for age slightly decreased the risk dif- cances of the differences using Cox proportional hazards mod- ferences between the OP and the OG groups. We els with and without covariates. The P values were based on the likelihood ratio test. To study whether age, baseline levels therefore also estimated the mortality when the study of lipids, or body mass index (BMI) would modify the treat- group was divided into 2 groups by median age (47 ment effect, we formed a new variable representing combina- years). The younger age group benefited slightly more tions of treatment group and levels of the other factor from an early start of treatment than did the older (eg, tertiles of TG: [OP, TGI], [OP, TGII], [OP, TGIII], group, particularly during the 13-year follow-up (data [OG, TGI], [OG, TGII], [OG, TGIII]). In this way, all data were not shown). included in the model, and spurious results originating in analy- Thus, among those aged 40 to 47 years at the begin- ses of separate subgroups were avoided. The analyses were per- ning of the study, the relative risk (RR) of CHD mortal- formed using the statistical package Egret for Windows (Cytel ity was 42% lower in the OG group compared with the Software Corp, Cambridge, Mass). OP group (P=.07), but it was only 24% lower among those who were 48 to 57 years old at that time. During the 18- RESULTS year follow-up, the corresponding figures were 31% (P=.08) and 17% (data not shown). LIPID LEVELS DURING THE DOUBLE-BLIND The Kaplan-Meier plots of Figure 3 give an over- AND OPEN-LABEL TRIALS view of the time-dependent trends in the mortality risks of the OP and OG groups. Coronary heart disease mor- As background information, Figure 2 shows the development of the annual mean values of TG, HDL-C, and tality was consistently lower in the OG group than in the LDL-C by treatment group during the 8.5-year follow- OP group, whereas no such trend was seen in all-cause up. Owing to successful randomization, the baseline val- or cancer mortality. ues were closely similar in the 2 treatment groups. Dur- ing the double-blind phase, the treatment soon led to CHD MORTALITY BY BASELINE LIPID substantial differences in the lipid levels. After the be- AND BMI LEVELS ginning of the open label phase, the lipid levels in both groups settled at a level that was between that in the OP To study if the observed difference in CHD risks and OG groups during the double-blind trial, mirroring between the OP and OG groups depended on factors the fact that approximately two thirds of subjects in both related to the metabolic syndrome, we calculated CHD groups were receiving gemfibrozil. mortality by tertiles of baseline lipid and BMI levels in the OP and OG groups during the 18-year follow-up. MORTALITY IN THE OP AND OG GROUPS The CHD mortality increased with increasing TG tertiles in the OP group but not in the OG group. Indeed, Table 1 presents mortality data for 2 periods: the 13- in the OG group the CHD mortality in the last tertile year follow-up from 1980-1982 until the end of the free was 50% lower (P=.001) than in the corresponding

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 CHD, ALL-CAUSE, AND CANCER MORTALITY BY A COMBINED LEVELS OF BASELINE TG AND BMI 1.00

0.98 P = .05 Table 2 gives the CHD and all-cause mortalities in com-

0.96 binations of tertiles of baseline levels of TG and BMI. In the OG group, the subjects with both high BMI and high 0.94 TG level at baseline had a 71% lower CHD mortality 0.92 (PϽ.001) and a 33% lower all-cause mortality (P=.03) 0.90 compared with those in the OP group. They also had 36%

Survival Function 0.88 lower risk of cancer mortality (P=.22) (data not shown). The baseline combinations of high BMI and low HDL-C 0.86 OG Group level or high TG and low HDL-C levels yielded similar 0.84 OP Group patterns of risk in terms of CHD or all-cause mortality 0.82 (data not shown).

B 1.00 COMMENT

0.98 P = NS In this long-term mortality follow-up study based on the 0.96 intention-to-treat principle, we compared mortalities in 0.94 the 2 original treatment groups of the Helsinki Heart Study 0.92 (ie, those randomized to receive placebo or gemfibro-

0.90 zil). The only manifest difference in treatment between the groups concerned the 5-year double-blind trial, af- Survival Function 0.88 ter which the same proportion of subjects in both groups 0.86 continued gemfibrozil therapy at least through 1995. The 0.84 major findings were a significant reduction in CHD mor-

0.82 tality in the OG group compared with the OP group and some statistically nonsignificant reductions in all-cause C and cancer mortalities. Subgroup analyses showed that 1.00 participants with high BMI, high TG level, or low HDL-C 0.98 P = NS level at baseline benefited most from an early start of treatment. For instance, participants with a combination of 0.96 high BMI and high TG level had a 71% lower risk of CHD 0.94 mortality in the OG group compared with those in the 0.92 OP group. 0.90 PARTICIPANTS WHO BENEFITED Survival Function 0.88 FROM THE TREATMENT 0.86 0.84 The finding that, at baseline, a combination of high BMI 0.82 and high TG level or high BMI and low HDL-C level pre- 0 3 6 9 12 15 18 21 Year dicts good treatment effect with gemfibrozil is consis- Double Open tent with our previous report from the double-blind trial Blind Label phase, in which we found that gemfibrozil use reduced 8.5 Years the risk of coronary events mainly in overweight sub- 13 Years jects with additional risk factors known to contribute to 18 Years 6 Follow-up the metabolic syndrome. In addition, a recent article from the VA-HIT trial reports that the reduction of events with gemfibrozil use was greater in subjects with insulin re- Figure 3. Kaplan-Meier survival functions describing mortality from coronary heart disease (A), cancer (B), and all causes (C) during the 18-year sistance than in those without, despite the finding that follow-up. NS indicates not significant; OG, original gemfibrozil; OP, original an increase in HDL-C level and a decrease in TG level placebo. with gemfibrozil use was less in subjects with insulin resistance than in those without.7 Actually, the authors of tertile in the OP group. A similar difference between this article conclude that “the benefit of fibrate therapy the 2 groups was noted for HDL-C but not for LDL-C. was much less dependent on levels of HDL-C or TG than For comparison, we also estimated the corresponding on the presence or absence of insulin resistance.”7 In the mortality data for BMI: there was no consistent pattern Helsinki Heart Study trial, insulin resistance was not mea- of risk across the 2 lowest tertiles, but the highest ter- sured, but BMI plays a central role in the metabolic tile yielded a risk peak in the OP group and a 52% syndrome.11 lower mortality in the OG group (PϽ.001) (data not Several trials have studied the putative effects of gem- shown). fibrozil on insulin resistance, insulin level, or factors

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 2. Coronary Heart Disease (CHD) and All-Cause Mortality (per 10 000 Person-Years) During the 18-Year Follow-up by Subgroups of the OP and OG Groups

Mortality Rate (No. of Deaths) RR* (95% CI)

BMI TG Level, mg/dL OP Group OG Group Unadjusted Age Adjusted CHD Յ27.5 Ͻ184 23.5 (43) 26.6 (48) 1.13 (0.75-1.71) 1.14 (0.76-1.72) Ն184† 34.0 (23) 29.0 (20) 0.86 (0.47-1.56) 0.85 (0.47-1.54) Ͼ27.5† Ͻ184 37.8 (24) 29.1 (20) 0.77 (0.42-1.39) 0.81 (0.45-1.46) Ն184† 70.5 (38) 20.7 (11) 0.29 (0.15-0.57) 0.30 (0.15-0.58) All causes Յ27.5 Ͻ184 75.9 (139) 77.1 (139) 1.01 (0.80-1.28) 1.02 (0.81-1.30) Ն184† 82.9 (56) 88.6 (61) 1.07 (0.75-1.54) 1.05 (0.73-1.52) Ͼ27.5† Ͻ184 102.3 (65) 88.7 (61) 0.86 (0.61-1.23) 0.93 (0.66-1.32) Ն184† 133.6 (72) 90.2 (48) 0.67 (0.47-0.97) 0.70 (0.48-1.00)

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); CI, confidence interval; OG, original gemfibrozil; OP, original placebo; RR, relative risk; TG, triglyceride. SI conversion factor: To convert TG to millimoles per liter, multiply by 0.0113. *Relative risk of the OG group compared with the OP group. †The highest tertile.

known to be related to the metabolic syndrome. In most only 24% for the older subjects (age, 48-57 years), lends studies, no effect of gemfibrozil has been found on in- some support to the hypothesis that not only an early start sulin resistance, serum insulin levels, or glucose metabo- of the treatment but also the age when treatment is started lism,12-14 whereas both insulin action and glucose me- may be of importance. How could we explain the ben- tabolism were improved by gemfibrozil use in a study by efit of an early start of gemfibrozil treatment on CHD mor- Avogaro et al.15 Gemfibrozil has been reported to im- tality? One reasonable mechanism is drug-related pre- prove the fibrinolytic system by decreasing plasmino- vention of the conversion of early, clinically innocent gen activator inhibitor type 1 activity,16,17 but contrast- coronary lesions (fatty streaks) into clinically signifi- ing findings have also been reported.13 It is interesting cant more complex lesions. This conversion already starts that in the VA-HIT secondary prevention trial in sub- in coronary arteries during the second decade of life, and jects with low HDL-C level, gemfibrozil was found to be by the end of the fourth decade, most male subjects have most effective in subjects with diabetes and in nondia- intermediate or advanced lesions in their coronary tree.21 betic subjects with high fasting plasma insulin levels.18 The studies on the actions of fibrates at the molecu- SAFETY OF TREATMENT lar level may provide a broader understanding for the observed multiple beneficial effects of gemfibrozil on CHD The earlier start of the treatment with gemfibrozil in the risk factors. The fibrates have been found to activate tran- OG group was not associated with increased risk of can- scription factors, the peroxisome proliferator-activated cer or all-cause mortality. Rather, the earlier start of gem- receptors (PPARs) (particularly the PPAR-␣ that con- fibrozil treatment significantly reduced all-cause mor- trols lipoprotein metabolism),19 and atherosclerotic plaque tality among subjects with high BMI and high TG level thrombogenicity.20 at baseline. In this subgroup, cancer mortality was also reduced, albeit not significantly. It is noteworthy that high LESSONS FROM THE LONG-TERM FOLLOW-UP BMI is a risk factor for several types of cancer, and there is much ongoing research on the association of insulin Because compliance was monitored in several ways dur- resistance and some cancers.22,23 ing the double-blind trial phase, we know that most subjects in the OG and OP groups were compliant.8 During LIMITATIONS OF THE STUDY the open-label phase, a similar proportion (approximately two thirds) of subjects in both groups chose to The design of the follow-up study inherently restricts the take gemfibrozil, which was offered free of charge through interpretation. Because there was no placebo group af- 1995. We do not know whether they continued using ter the double-blind phase, there was no opportunity to gemfibrozil after that date, but there is no reason to as- evaluate the effect of gemfibrozil therapy after the ini- sume that the 2 groups differed substantially in their tial trial phase. We could only compare the effect of a choice of therapy for dyslipidemia. Two differences thus 5-year earlier start of gemfibrozil treatment in 2 random- remain between the 2 groups: first, the subjects in the ized groups of dyslipidemic men (no women), and we OG group had a longer period of active treatment, and could only speculate on the possible reasons for a dif- second, they started active treatment at a younger age. ference in effect of this 5-year earlier start of treatment The finding that in the follow-up until 1995 the younger with gemfibrozil. subjects (age, 40-47 years) in the OG group had a 42% We had no clinical data on the participants after the lower CHD incidence compared with the correspond- 8.5-year trial, and especially after 1995 we have no in- ing subjects in the OP group, while the difference was formation on their choice of medication. However, it

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 seems plausible that whether they continued using any with low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT). medication or chose another drug, the study groups did Diabetes Care. 2003;26:1513-1517. 8. Ma¨enpa¨a¨ H, Manninen V, Heinonen OP. Compliance with medication in the Hel- not differ essentially in their choice of treatment. sinki Heart Study. Eur J Clin Pharmacol. 1992;42:15-19. In conclusion, the long-term follow-up of mortality 9. Ma¨ho¨nen M, Salomaa V, Torppa J, et al. The validity of the routine mortality sta- in Helsinki Heart Study treatment groups revealed sig- tistics on coronary heart disease in Finland: comparison with the FINMONICA nificantly reduced CHD mortality among subjects who MI register data for the years 1983-1992: Finnish multinational MONItoring of started gemfibrozil therapy at age 40 to 47 years than trends and determinants in CArdiovascular disease. J Clin Epidemiol. 1999; 52:157-166. among those who started the treatment 5 years later at 10. Pietila¨ K, Tenkanen L, Ma¨ntta¨ri M, Manninen V. How to define coronary heart age 48 to 57 years. Subgroup analyses showed that those disease in register-based follow-up studies: experience from the Helsinki Heart with dyslipidemia related to the metabolic syndrome es- Study. Ann Med. 1997;29:253-259. pecially benefited from an earlier start of treatment, with 11. Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C. Definition of meta- significantly reduced CHD and all-cause mortality. bolic syndrome: Report of the National Heart, Lung, and Blood Institute/ American Heart Association conference on scientific issues related to definition. Circulation. 2004;109:433-438. Accepted for Publication: November 29, 2005. 12. Sane T, Knudsen P, Vuorinen-Markkola H, Yki-Ja¨rvinen H, Taskinen MR. De- Correspondence: Leena Tenkanen, PhD, Helsinki Heart creasing triglycerides by gemfibrozil therapy does not affect the glucoregula- Study, Kalliolinnantie 4, 00140 Helsinki, Finland (leena tory or antilipolytic effect of insulin in nondiabetic subjects with mild [email protected]). hypertriglyceridemia. Metabolism. 1995;44:589-596. 13. Asplund-Carlson A. Effects of gemfibrozil therapy on glucose tolerance, insulin sen- Financial Disclosure: None. sitivity and plasma plasminogen activator inhibitor activity in hypertriglyceridaemia. Funding/Support: This study was supported in part by J Cardiovasc Risk. 1996;3:385-390. grants from the Aarne Koskelo Foundation and the Paavo 14. Jeng CY, Sheu WH, Fuh MM, Shich SM, Chen YD, Reaven GM. Gemfibrozil treat- Nurmi Foundation, Helsinki, Finland, and EVO re- ment of endogenous hypertriglyceridemia: effect on insulin-mediated glucose disposal and plasma insulin concentrations. J Clin Endocrinol Metab. 1996; search funds of the Helsinki University Central Hospi- 81:2550-2553. tal, Helsinki. The Wihuri Research Institute is main- 15. Avogaro A, Beltramello P, Marin R, et al. Insulin action and glucose metabolism tained by the Jenny and Antti Wihuri Foundation, are improved by gemfibrozil treatment in hypertriglyceridemic patients. Helsinki. Atherosclerosis. 1995;113:117-124. 16. Jeng JR, Jeng CY, Sheu WH, Lee MM, Huang SH, Shich SM. Gemfibrozil treatment of hypertriglyceridemia: improvement on fibrinolysis without change of in- REFERENCES sulin resistance. Am Heart J. 1997;134:565-571. 17. Nordt TK, Lutzi S, Ruef J, et al. Attenuation by fibrates of plasminogen activator 1. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary prevention trial inhibitor type-1 expression in human arterial smooth muscle cells. 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