High risk strategies for atherosclerosis

Transcription

1 Clinica Chimica Acta 286 (1999) High risk strategies for atherosclerosis * Paul Cullen FRCPI, Gerd Assmann FRCP Institute of Clinical Chemistry and Laboratory Medicine and Institute of Arteriosclerosis Research, University of Munster, Munster, Germany Received 11 December 1998; accepted 19 January 1999 Abstract Calculating a person s chances of developing coronary heart disease (CHD) is not simple, as many risk factors interact in a complex fashion. Thus many markers, though significant in univariate comparisons, are no longer so when multivariate analysis is performed. Those factors contributing independently to risk can be identified only in prospective investigations such as the Munster Heart (PROCAM) or the Framingham studies. In the Munster Heart study, follow-up of middle-aged men for eight years identified the following nine independent risk variables: age, smoking history, personal history of angina pectoris, family history of myocardial infarction, systolic blood pressure, raised plasma low density lipoprotein cholesterol (LDL-C), low plasma high density lipoprotein cholesterol, raised fasting plasma triglyceride and presence of diabetes mellitus. These have been used to generate an algorithm for prediction of first coronary events 1 which is available in interactive fashion on the internet. Large trials have shown that lowering LDL-C reduces the risk of CHD, and diminishes CHD morbidity and mortality in persons without prior evidence of coronary atherosclerosis (primary prevention). This is even more the case in patients with such evidence (secondary prevention). It appears that lowering of LDL-C also reduces all-cause mortality in secondary prevention. reserved. Keywords: Coronary heart disease; Risk factors; Risk assessment 1999 Elsevier Science B.V. All rights *Corresponding author. Tel./ fax: address: cullen@uni-muenster.de (P. Cullen) 1 This algorithm is available in interactive fashion on the website of the International Task Force for Prevention of Coronary Heart Disease at / 99/ $ see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S (99)

2 32 P. Cullen, G. Assmann / Clinica Chimica Acta 286 (1999) Introduction In order to be efficient and effective, coronary heart disease (CHD) prevention requires a method to objectively estimate a person s risk of developing coronary atherosclerosis. This strategy, which allows preventive measures to be directed to those at highest risk, is not a simple matter, as many of the risk markers which have been identified in univariate analyses interact with one another and are no longer significant predictors in multivariate analyses when variables such as age, sex and smoking status are taken into account. Thus it is necessary to identify those factors which make an independent contribution to risk. Such information can be reliably derived only from prospective epidemiological studies such as the Munster Heart Study (formerly known as the Prospective Cardiovascular Munster Study, or PROCAM) [1,2] and the Framingham study [3]. Recently, the importance of the classical risk factors smoking, hypertension, plasma total cholesterol and high density lipoprotein (HDL) cholesterol were confirmed in an eight-year follow-up of the World Health Organization Monitoring Trends and Determinants in Cardiovascular Diseases (MONICA) study [4]. 2. Lessons from the Munster Heart Study In the Munster Heart Study, 10,856 men aged 36 to 65 years were followed up for 4 to 14 years during which time 313 deaths occurred, 118 of which were due to cardiovascular disease. Analysis of the data from the eight-year follow-up of the cohort of men aged 40 to 65 years in this study led to the identification of nine risk variables which independently contribute to CHD risk: age, smoking history, presence or absence of personal history of angina pectoris, presence or absence of a family history of myocardial infarction (MI), systolic blood pressure, plasma low density lipoprotein cholesterol (LDL-C), plasma high density lipoprotein cholesterol (HDL-C), triglyceride, and the presence or absence of diabetes mellitus. These factors have been used to generate an 2 algorithm for prediction of first coronary events. Since age, sex, and previous 2 The MLF function from PROCAM has the form: I 5 1/[11exp(2y)] where y (age in years ) 1 (systolic blood pressure in mmhg ) 1 (LDL-C inmg/dl ) 1 (HDL-C in mg/dl ) 1 (log e(triglyceride level in mg/dl) ) 1 (smoking behaviour, no 5 0, yes 5 1, ) 1 (diabetes mellitus, no 5 0, yes 5 1, ) 1 ( positive family history of myocardial infarction, no 5 0, yes 5 1, ) 1 (angina pectoris, no 5 0, yes 5 1, ). Conversion of cholesterol and triglyceride values From mg/dl to mmol/l: for cholesterol divide mg/ dl by 38.7 for triglyceride divide mg/ dl by 88.5 From mmol/l to mg/dl for cholesterol multiply mmol/ l by 38.7 for triglyceride multiply mmol/ l by 88.5

3 P. Cullen, G. Assmann / Clinica Chimica Acta 286 (1999) or family history are immutable, treatment should concentrate on those factors which can be changed, i.e. stopping smoking in smokers, lowering LDL-C and triglyceride concentrations if raised, normalization of raised blood pressure and optimal control of blood glucose in patients with diabetes mellitus. Taking regular exercise and stopping smoking also usually increase HDL-C. 3. Definition of risk: global risk and risk algorithms In order to define treatment goals, it is first necessary to identify the patient s category of risk. A pragmatic approach which combines a clinical approach with the use of the risk algorithm derived from the Munster Heart Study is outlined in Table 1. This algorithm is available in interactive fashion on the homepage of the International Task Force for Prevention of Coronary Artery Disease at Since the algorithm was derived from a population of German men aged 40 to 65 years, its applicability to women or men outside this age range and to other ethnic groups has yet to be established. The output of the Munster algorithm is expressed as the risk of a coronary event (definite fatal MI, definite non-fatal MI, sudden coronary death) in percent over eight years. In the German population of middle-aged men, the output of the algorithm may be divided into quintiles with the following cut-off points as shown in Fig. 1: first quintile # 0.91% in eight years ( # 0.11% per annum), second quintile 0.92% 1.40% in eight years (0.12% 0.18% per annum), third quintile 1.41% 3.65% in eight years (0.18% 0.46% per annum), fourth quintile 3.66% 7.60% in eight years (0.46% 0.95% per annum), fifth quintile. 7.60% in eight years (. 0.95% per annum). The target level to which LDL-C should be lowered depends on the patient s level of global risk, more stringent levels being required in those at highest risk. The levels shown in Table 2 are widely recommended in the United States [5] and Europe [6]. 4. Risk algorithms in secondary prevention of CHD The development of risk algorithms in secondary prevention is hampered by the smaller size of such populations. Nevertheless, valuable information could be gathered from the European Concerted Action on Thrombosis (ECAT) study which indicates that the risk factors in patients with a history of MI ( secondary risk factors ) may differ both quantitatively and qualitatively from those in primary prediction of CHD. Thus, in the ECAT study, HDL-C, apoa-i,

4 34 P. Cullen, G. Assmann / Clinica Chimica Acta 286 (1999) Table 1 Classification of coronary heart disease risk, from Ref. [31] Small increase in risk Moderate increase in risk High risk? presence of one risk? presence of one risk factor of? presence of atherosclerosis of ] ] factor of moderate severe degree, e.g. a middle- the coronary, carotid or degree, e.g. (in a aged man who smokes about peripheral arteries such as middle-aged man) e.g. 20 cigarettes per day history of myocardial infarction, plasma cholesterol 200 OR angina pectoris, history of 300 mg/ dl ( ? presence of two risk factors definite transient ischaemic ] mmol/ l) with no non- of moderate degree, e.g. a attack or of intermittent lipid risk factors middle-aged man with a claudication, carotid bruit, OR plasma cholesterol missing foot pulse, carotid? plasma cholesterol:hdl mg/ dl ( mmol/ l), HDL plaque in carotid artery on cholesterol ratio 4 to 5 cholesterol less than 40 mg/ dl ultrasound examination, OR (1 mmol/ l), obesity ischaemic changes in resting or? smokes about 10 OR exercise ECG cigarettes per day, but? quantitative risk estimate lies OR no other risk factors, in the fourth quintile of the? presence of three or more risk ] OR PROCAM algorithm factors, e.g. moderate? quantitative risk hypertension and plasma ] estimate lies in the third cholesterol mg/ dl (5.2 quintile of the 7.8 mmol/ l) and smokes about ] PROCAM algorithm 10 cigarettes per day which takes into account OR nine independent risk? presence of two risk factors of factors severe degree, e.g. plasma cholesterol.300 mg/ dl (7.8 mmol/l) and smoking 20 cigarettes per day OR? presence of a major genetic hyperlipidaemia, e.g. familial hypercholesterolaemia or type III (remnant) hyperlipidaemia OR? quantitative risk estimate lies in fifth quintile of the PROCAM algorithm fibrinogen, von Willebrand factor, plaminogen activator inhibitor-1 and triglycerides were predictive of MI after two years of follow-up in individuals with a history of angina pectoris, whereas factors such as LDL-C and apob, which are good predictors of an initial MI, were less good at predicting recurrent events (A. von Eckardstein, personal communication). In secondary prevention, LDL-C should be lowered to below 2.6 mmol/l (100 mg/dl).

5 P. Cullen, G. Assmann / Clinica Chimica Acta 286 (1999) Fig. 1. Estimated risk of a coronary event among men aged 35 to 65 years in the Munster Heart Study, expressed as quintiles of the PROCAM multiple logistic function. 5. LDL-C and CHD risk Data from the PROCAM [1], the Framingham [3], and the MRFIT [7] studies indicate a log-linear relationship between the level of LDL-C and CHD risk (Fig. 2). Thus when relative risk of CHD is plotted against LDL-C, a straight line relationship is obtained. However the effect of lowering LDL-C depends on a person s global risk of CHD. Thus a person with a total cholesterol of 7.2 mmol/l (280 mg/dl) and no other risk factors ( average risk ) may have the same CHD risk as a person with a plasma total cholesterol of 5.2 mmol/l (200 mg/ dl) but with other risk factors ( high risk ). Data from large scale intervention trials indicate that this log-linear relationship between LDL-C and CHD risk also applies to levels achieved by treatment (diet, drugs), and that five years of cholesterol reduction produces a large part of the reduction in CHD risk predicted from epidemiological studies (Fig. 3). The nature of this relationship has implications for treatment decisions as explained in the figure legends. Table 2 LDL-C goals according to global CHD risk, from Ref. [6] Global risk Reduce LDL-C to (mg/ dl) (mmol/ l) Small increase in risk,160,4.0 Moderate increase in risk,135,3.5 High risk including secondary prevention,100,2.6

6 36 P. Cullen, G. Assmann / Clinica Chimica Acta 286 (1999) Fig. 2. PROCAM study, 8-year risk of a coronary event according to LDL-C in middle-aged men at high and moderate risk. Statins produce a similar proportional lowering of LDL-C (e.g. by 30% as shown beneath X axis) irrespective of the baseline LDL-C. Thus the absolute reduction in LDL-C is lower for a given baseline LDL-C. In addition, because of the log-linear relationship between LDL-C and CHD risk (when both axes have linear scales, as in this figure, the risk curve is exponential in shape; when one of the axes is logarithmic, as in Fig. 3, a straight-line plot is obtained), the absolute difference in CHD risk associated with the same absolute difference in LDL-cholesterol is greater at higher baseline levels of LDL-C. For these reasons, all other things (pre-existing CHD, other risk factors) being equal, a prolonged 30% difference in baseline LDL-C of 175 mg/dl (4.5 mmol/l) vs. 250 mg/dl (6.5 mmol/l) is associated with almost 4 times as much benefit as a prolonged 30% difference of 125 mg/dl (3.2 mmol/l) vs. 175 mg/dl (4.5 mmol/l). Note that high risk individuals may derive greater benefit from treatment than moderate risk individuals with the same LDL-C. Similar curves have been derived from the data of other large epidemiological investigations such as the Framingham study. 6. Trials of LDL-C lowering with clinical end-points One of the first large trials to be reported was the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), the results of which were published in 1984 [8]. In this trial, an 8% lowering of plasma total cholesterol for a mean of 7.4 years was associated with a 19% reduction in MI or CHD death. Since 1989, a series of large-scale prospective intervention trials have established that lowering LDL-C reduces the risk of CHD, and diminishes CHD morbidity and mortality both in patients without prior evidence of CHD (primary prevention) and even more so in patients with such evidence (secondary prevention). The features and results of these trials are summarized in Table 3. Moreover, it appears that lowering of LDL-C reduces all-cause

7 P. Cullen, G. Assmann / Clinica Chimica Acta 286 (1999) Fig. 3. Similar proportional and absolute reductions in CHD risk are expected with the same absolute cholesterol reductions in individuals at the same absolute risk. Data from epidemiological studies including the PROCAM, the Framingham, and the MRFIT studies indicate a log-linear relationship between the level of LDL-C and CHD risk. Thus when relative risk of CHD is plotted against cholesterol, a straight line relationship is obtained. However the effect of lowering cholesterol on CHD risk depends on a person s global risk of CHD. Thus a person with an LDL-C of 240 mg/dl (6.2 mmol/l) and no other risk factors ( average risk ) may have the same CHD risk as a person with an LDL-C of 160 mg/dl (4.1 mmol/l) but with other risk factors ( high risk ). Data from large scale intervention trials indicate that this log-linear relationship between LDL-C and CHD risk also applies to levels achieved by treatment (diet, drugs), and that five years of cholesterol reduction produces a large part of the reduction in CHD risk predicted from epidemiological studies. Since a given dose of statins produces a given proportional and not absolute degree of cholesterol lowering, a higher dose of statin (or a statin with higher efficacy) is necessary to reduce LDL-C in the high risk individual from 160 mg/dl (4.1 mmol/l) to 120 mg/dl (3.1 mmol/l) than to reduce LDL-C in the average risk individual in the figure from 240 mg/dl (6.2 mmol/l) to 200 mg/dl (5.2 mmol/l). In both cases this would be expected to produce an approximate halving in the absolute coronary risk in the long term. Thus different doses of statin may be required to produce the same degree of risk reduction, depending on global risk (including LDL-C) at baseline. In both cases, prolonged lowering of cholesterol by 40 mg/dl (1 mmol/l) is associated with an approximate halving in CHD risk. mortality in secondary prevention. Evidence of reduced all-cause mortality in primary prevention trials is suggestive, but a study of sufficient statistical power to prove this finding has yet to be performed.

8 Table 3 Results of major recent randomized controlled clinical trials of cholesterol lowering. TG, triglycerides; HDL-C, HDL cholesterol Name Venue, design No. participants Inclusion criteria Treatment Follow-up Endpoints Changes in lipids Outcome (no. of cases in parentheses) Primary prevention trials Helsinki Heart Study [32] Employees of 4081 men? no history of CHD 600 mg 5 y? nonfatal MI? LDL-C by 9%? nonfatal MI: placebo 3.5% (71), Published Nov Finnish Telecom, aged y? no ECG abnormality gemfibrozil? fatal MI (from 189 to 173 mg/dl gemfibrozil 2.2% (45) RR 0.63, P,0.05 Finnish State Railways, (range y)? no congestive heart failure twice daily or? cardiac death (4.9 to 4.5 mmol/l))? fatal MI: placebo 0.3% (8), 15 companies in Finland? no other serious illness placebo? HDL-C by 11% gemifibrozil 0.4% (6), RR 0.67, NS (hypertension and type 2 (from 47.1 to 51.2 mg/dl? cardiac death: placebo 0.2% (4), diabetes mellitus were (1.2 to 1.3 mmol/l)) gemfibrozil 0.2% (5), RR 1.25, NS accepted)? TG by 43%? total mortality: placebo 2.1% (42)? LDL1VLDL-C$200 mg/dl (from to mg/dl gemfibrozil 2.2% (45), RR 1.07, NS (2.0 to 1.3 mmol/l)) West of Scotland highly centralized 6565 men? no history of MI 40 mg 4.9 y? death from CHD or? LDL-C by 26%? death from CHD or nonfatal Coronary Prevention primary care aged 5566 y? no serious ECG abnormality pravastatin (median) nonfatal MI (from 192 to 142 mg/dl MI: placebo 7.9% (248), Study (WOSCOPS) [13] service in (range: y)? no other serious illness each evening? total mortality (5.0 to 3.7 mmol/l)) pravastatin 5.5% (174), RR 0.69, Published Nov West of Scotland? BP#180 mmhg syst. and or placebo? HDL-C by 5% P,0.001 [26,33,34] #110 mmhg diast. (from 44 to 46 mg/dl? total mortality: placebo 4.1% (135),? LDL-C after diet (1.1 to 1.2 mmol/l)) pravastatin 3.2% (106), RR 0.78, mg/dl (4.5 6 mol/l)? TG by 12% P (from 162 to 143 mg/dl (1.8 to 1.6 mmol/l)) Air Force Texas San Antonio 5608 men and? absence of CHD 20 mg $5 y? first acute coronary event :? LDL-C by 25%? risk of first acute coronary event Coronary Atherosclerosis and Forth Worth, TX 997 women? average baseline LDL-C lovastatin/day, sudden death, MI, new (from 150 to 113 mg/dl reduced by 36% Prevention Study aged including 150 mg/dl (3.9 mmol/l) titrated to 40 mg/day onset of unstable angina (3.9 to 2.9 mmol/l)) (AFCAPS/Tex CAPS) [15] 1416 persons? average baseline HDL-C to target LDL-C of (18 endpoint)? HDL-C by 6% Published Nov aged $65, mg/dl (0.96 mmol/l) #110 mg/dl (from 37 to 39 mg/dl [35,36] Hispanic-Americans (2.8 mmol/l) or (0.96 to 1.0 mmol/l) and 206 placebo? TG by 15% African-Americans 38 P. Cullen, G. Assmann / Clinica Chimica Acta 286 (1999) 31 45

9 P. Cullen, G. Assmann / Clinica Chimica Acta 286 (1999) Secondary prevention trials Scandinavian Simvastatin 94 clinical centres 3617 men? history of MI or angina pectoris 20 mg 5.4 y? total mortality? LDL-C by 35%? total mortality: placebo 11.5% (256), Survival Study (4S) [12] in Scandinavia aged 5867 y? total cholesterol after diet simvastatin/day (median,? major coronary event : (from 188 to 122 mg/dl simvastatin 8.2% (182), RR 0.7, Published Nov women mg/dl ( mmol/l) reduced to 10 mg/day range coronary death, definite or (4.9 to 3.2 mmol/l)) P [25,29] aged 6166 y? no secondary hypercholesterolemia, or increased to probable hospital-verified,? HDL-C by 8%? major coronary event : placebo (range: y) unstable angina, tendon xanthoma 40 mg/day so as to non-fatal acute MI, (from 46 to 49 mg/dl) 28.0% (622), simvastatin 19.4% (431), reduce total cholesterol resuscitated cardiac (1.2 to 1.3 mmol/l)) RR 0.58, P, to mg/dl arrest, definite silent? TG by 10% ( mmol/l) or MI on ECG (from 132 to 119 mg/dl placebo (1.5 to 1.3 mmol/l)) Cholesterol and 13 centres in 3583 men and? MI in 3 to 20 months before 40 mg 5 y? death from CHD or? LDL by 32%? death from CHD or nonfatal MI: Recurrent Events Study Canada and 576 postmenopausal recruitment pravastatin (median, nonfatal MI (from 139 to 95 mg/dl placebo 13.2% (274), (CARE) [11] 67 in USA women aged 5969 y? total cholesterol after diet once daily or range y) (primary end point) (3.6 to 2.5 mmol/l)) pravastatin 10.2% (212), RR 0.76 Published Oct [23] (range y),240 mg/dl (6.2 mmol/l) placebo? major coronary event :? HDL-C by 5% P50.003? LDL-C mg/dl primary end point (from 39 to 41 mg/dl? major coronary event : (3 4.5 mmol/l) 1CABG or PTCA (1.0 to 1.1 mmol/l)) placebo 26.4% 13.2% (274),? TG,350 mg/dl (4 mmol/l)? stroke? TG by 14% pravastatin 20.7% (430), RR 0.69? fasting blood glucose (from 155 to 133 mg/dl P50.03 #220 mg/dl (12.2 mmol/l) (1.8 to 1.5 mmol/l))? stroke: placebo 3.8% (78),? left ventricular ejection fraction pravastatin 2.6% (54), RR 0.68, $25% without symptomatic P50.03 congestive heart failure? total mortality: placebo 9.4% (196), pravastatin 8.6 (180), RR 0.91, NS Long-term Intervention 87 hospital 7503 men and? MI or unstable angina pectoris in 40 mg $5 y? death from CHD? Baseline values? death from CHD reduced by 24%, with Pravastatin in centres in 1511 women with previous 3 to 36 months pravastatin (18 endpoint)? LDL-C 150 mg/dl P Ischemic Disease Australia and average age 61 y? absence of congestive cardiac daily? total mortality (3.9 mmol/l)? total mortality reduced by 23%, (LIPID) [9,10] New Zealand (range y) failure, severe hepatic or renal? nonfatal MI1? HDL-C 37 mg/dl P disease, or poorly controlled death from CHD (1 mmol/l)? nonfatal MI1 death from CHD endocrine disorder? cardiovascular mortality? TG 157 mg/dl reduced by 23%, P ? Total cholesterol mg/dl? need for revascularization (1.8 mmol/l)? need for revascularization procedures (4-7 mmol/l) procedures? no information on reduced by 24%, P50.001? TG #445 mg/dl (5 mmol/l)? fatal1nonfatal MI lipid changes? fatal1nonfatal MI reduced by 29%,? stroke available at present P ? stroke reduced by 20%, P50.022

10 40 P. Cullen, G. Assmann / Clinica Chimica Acta 286 (1999) Those individuals with the highest pre-treatment LDL-C levels benefitted most from treatment. Subgroup analyses of these trials have shown that these beneficial effects were seen in all ethnic groups, in both sexes, at all age groups, and in diabetics. A further notable result was the reduction in the treatment group of the incidence of stroke, a predefined end point in the LIPID [9,10] and CARE [11] studies. Side-effects were not a serious problem in any of these trials and in no trial was cancer more common in the treatment group. No trial showed a significant increase in noncardiovascular mortality rates e.g. death by suicide or by violent or accidental means, in the treatment group. Fig. 4 summarizes the relation in the 4S [12], CARE [11] and WOSCOPS [13] trials between on-treatment cholesterol levels and CHD event rates. The reduction of risk observed in these trials may not be attributable purely to lowering of LDL-C; lowering of triglyceride, an increase in HDL-C, and non-lipid effects may also have contributed to the favourable outcome. Data from 28 intervention trials published before or during 1993 and comprising more than 500,000 men and 18,000 CHD events (MI, sudden cardiac Fig. 4. Event rates in the 4S [12], CARE [11], and WOSCOPS [13] studies as a function of plasma total cholesterol concentrations at baseline and on-treatment. WOSCOPS was a primary prevention trial. CARE was a trial of lipid lowering in individuals with a history of MI (i.e. also secondary prevention) and average lipid levels. As can be seen, CHD event rates in the CARE study were also greater than those in WOSCOPS at similar cholesterol levels.

11 P. Cullen, G. Assmann / Clinica Chimica Acta 286 (1999) death) was used by Law and colleagues to calculate the percent reduction in CHD events for each percentage point reduction in total serum cholesterol [14]. This meta-analysis concluded that a 10% reduction in total cholesterol resulted in a 7%, 22% and 25% reduction in CHD events after, 2, 2.1 5, and 5.1 to 12 years follow-up, repectively (Table 4) [14]. In the CARE [11] study, no benefit was seen in individuals with baseline LDL-C levels of # 3.2 mmol/l. This has raised an issue concerning the benefit of a further reduction in LDL-C in patients with relatively usual levels. However, in the LIPID [9,10] and AFCAPS/ TexCAPS [15] studies, the incidence of coronary events was lowered by statin treatment in patients with average baseline LDL-C levels. Moreover, the coronary artery bypass grafting study with lovastatin showed further improvement in angiographic findings and revascularization procedures when a baseline LDL-C of 4.0 mmol/ l was intensively reduced to 2.4 mmol/ l, in comparison to moderate reduction of LDL-C to 3.5 mmol/l [16]. 7. Triglycerides and CHD risk In the Munster Heart Study, triglyceride, as noted above, was an independent predictor of risk. In middle-aged men in this study, triglyceride levels above 5.2 mmol/ l were associated with a 1.6-fold increase in event risk in 8 years compared to the total cohort of middle-aged men. This was also true of middle-aged men with hypercholesterolemia (LDL-C. 4.0 mmol/ l [17]. A particularly atherogenic constellation is the lipid triad, consisting of low HDL-C (, 0.9 mmol/l), a high total cholesterol/hdl-c ratio (. 5) and high triglyceride level (. 2.3 mmol/l), a combination which is often found, together with obesity and hypertension, as part of the metabolic syndrome. Nearly 14% of middle-aged men with this constellation developed a coronary event within Table 4 Percent reduction in CHD events per 10% reduction in total cholesterol: meta-analysis of 28 trials in men (from Ref. [14]) Time from entry in years Trial group, Drug trials Dietary trials Men without CHD Men with CHD All trials % conf. interval

12 42 P. Cullen, G. Assmann / Clinica Chimica Acta 286 (1999) eight years. Although this subgroup comprised only 4.3% of middle-aged men in PROCAM, it contained no fewer than 21% of all observed CHD events [17]. It is noteworthy that individuals with the lipid triad frequently display postprandial hyperinsulinemia which may precede the onset of frank diabetes by many years (Fig. 5). Evidence from the Munster Heart Study also points to an association between the clotting system and triglycerides. Coagulation parameters were measured in 2780 men who were observed for eight years. In this group 130 coronary events occurred. The mean fibrinogen concentration in the event group was 0.32 g/l higher (P, 0.001) and the activity of factor VIIc 3.7% greater (P, 0.05) than in the non-event group. For fibrinogen and factor VIIc, between 1.5 and 3 times as Fig. 5. How insulin resistance leads to the metabolic syndrome: Normally, lipid metabolism is regulated in part by insulin, particularly in the postprandial period. Insulin, by its action on hormone sensitive lipase, inhibits the release of free fatty acids (FFA) from adipose tissue and the secretion of very low density lipoprotein (VLDL) by the liver. Insulin also accelerates the action of lipoprotein lipase (LPL), an enzyme localized in capillaries which hydrolyzes the triglycerides in VLDL and chylomicrons. In addition, during lypolysis of the lipid-rich lipoproteins, surface components including free cholesterol (Fc) are transferred into the HDL pool. All these effects lead to a reduction in circulating triglyceride-rich particles (VLDL and chylomicrons) and, secondarily, to a reduction in circulating LDL. But when peripheral insulin resistance is increased, the release of FFA from adipose tissue and of VLDL from the liver is accelerated and the breakdown of these particles by LPL is reduced. This increases circulating atherogenic triglyceride-rich remnant lipoprotein particles. Secondarily, there is a reduction in HDL cholesterol due to increased transfer of cholesteryl ester from HDL to VLDL and chylomicrons by the action of cholesteryl ester transfer protein. CE5cholesteryl ester (adapted from [30]).

13 P. Cullen, G. Assmann / Clinica Chimica Acta 286 (1999) many events occurred in the upper than in the lower tertile. However, the association between factor VIIc and CHD was no longer statistically significant when age and triglycerides were taken into account, whereas the association between fibrinogen and CHD was independent of triglyceride levels [18]. 8. Treatment of hypertriglyceridemia Uncertainty surrounds the issue of the extent to which elevated triglyceride levels should be lowered. However, the second report of the U.S. National Cholesterol Education Program has suggested that levels above 2.3 mmol/ l should be regarded as elevated [19] and some authorities have suggested a target level for triglyceride of 1.7 mmol/l. Up to now, treatment of hypertriglyceridemia and mixed hyperlipidemia has focused on the use of fibrates. However, evidence is emerging that statins are also effective under these circumstances. In the CURVES trial, triglycerides were reduced by fluvastatin, lovastatin, pravastatin, simvastatin and, particularly, by atorvastatin [20]. Stein and colleagues assessed the effectiveness of statins in lowering triglycerides by means of a ratio obtained by dividing the percentage change from baseline in triglyceride level by the percentage change from baseline in LDL-C [21]. In an analysis of seven separate studies with similar design [22 28], this TG/LDL-C ratio was found to be approximately one in patients with triglyceride above 2.8 mmol/ l and # 0.5 in patients with triglyceride levels, 1.7 mmol/ l [21]. Moreover, in subjects with baseline triglyceride. 2.8 mmol/ l, significant and dose-dependent reductions in triglyceride of 22 45% were seen with all statins. When baseline triglyceride was, 1.7 mmol/ l, no significant or dose-dependent effect on triglyceride occurred. This led the authors to conclude that all statins are effective in decreasing triglyceride levels, but only in hypertriglyceridemic patients. Further, their analysis indicates that the more effective the statin is in decreasing LDL-C, the more effective it will also be in decreasing triglyceride concentrations in patients with hypertriglyceridemia. This analysis by Stein et al. [21] is supported by data from the Scandinavian Simvastatin Survival Study (4S), in which increases in the baseline triglyceride in the placebo group, but not in the simvastatin-treated group were associated with increases in the coronary event rate [29]. 9. Conclusion There is now little doubt that treatment of CHD risk factors reduces the risk of coronary events. To be effective, this requires assessment of global risk in order to identify those patients at highest risk who will benefit most from

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