© 1997 American Heart Association, Inc.
Articles |
Relation of High TG–Low HDL Cholesterol and LDL Cholesterol to the Incidence of Ischemic Heart Disease
An 8-Year Follow-up in the Copenhagen Male Study
From the Copenhagen Male Study, Epidemiological Research Unit, Rigshopitalet, State University Hospital, Copenhagen (J.J., H.O.H., P.S., F.G.); and the Glostrup Population Studies, Department of Internal Medicine C, Glostrup Hospital, University of Copenhagen (H.O.H.), Denmark.
Correspondence to Jørgen Jeppesen, the Copenhagen Male Study, Epidemiological Research Unit, 7122 Rigshospitalet, DK-2200 Copenhagen, Denmark.
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Abstract |
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Abstract High triglyceride (TG) and low HDL cholesterol (HDL-C) is the characteristic dyslipidemia seen in insulin-resistant subjects. We examined the role of this dyslipidemia as a risk factor of ischemic heart disease (IHD) compared with that of high LDL cholesterol (LDL-C) in the Copenhagen Male Study. In total 2910 white men, aged 53 to 74 years, free of cardiovascular disease at baseline, were subdivided into four groups on the basis of fasting concentrations of serum TG, HDL-C, and LDL-C. "High TG–low HDL-C" was defined as belonging to both the highest third of TG and the lowest third of HDL-C; this group encompassed one fifth of the population. "High LDL-C" was defined as belonging to the highest fifth of LDL-C. A control group was defined as not belonging to either of these two groups. "Combined dyslipidemia" was defined as belonging to both dyslipidemic groups. Age-adjusted incidence of IHD during 8 years of follow-up was 11.4% in high TG–low HDL-C, 8.2% in high LDL-C, 6.6% in the control group, and 17.5% in combined dyslipidemia. Compared with the control group, relative risks of IHD (95% confidence interval), adjusted for potentially confounding factors or covariates (age, body mass index, alcohol consumption, physical activity, non–insulin-dependent diabetes, hypertension, smoking, and social class), were 1.5 (1.0-2.1), P<.05; 1.3 (0.9-2.0), P=.16; and 2.4 (1.5-4.0), P<.01, in the three dyslipidemic groups, respectively. In conclusion, the present results showed that high TG–low HDL-C, the characteristic dyslipidemia seen in insulin-resistant subjects, was at least as powerful a predictor of IHD as isolated high LDL-C. The results suggest that efforts to prevent IHD should include intervention against high TG–low HDL-C, and not just against hypercholesterolemia.
Key Words: dyslipidemia • high-density lipoprotein cholesterol • ischemic heart disease • triglycerides • low-density lipoprotein cholesterol
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Introduction |
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An increased plasma TG and decreased HDL-C concentration is the characteristic dyslipidemia seen in insulin-resistant subjects.1 It has been suggested that insulin resistance is a basic metabolic abnormality that plays an important role in the etiology of IHD.2 A high level of LDL-C is a well-established major risk factor of IHD.3 This lipid abnormality is not associated with insulin resistance per se.4 So far, it is not well defined which of these two metabolically different dyslipidemic syndromes is the more powerful predictor of IHD in a free-living, healthy population.
Using high TG–low HDL-C as a marker of insulin resistance, the aim of this prospective cardiovascular study was to examine the relative contribution to IHD risk of this dyslipidemic condition compared with that of high LDL-C in a cohort of middle-aged and elderly white men.
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Methods |
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The Copenhagen Male Study was started in 1970 as a prospective cardiovascular study of 5249 men from 14 randomly selected public or private companies.5 6 The participants had a mean age of 48 years (range 40 to 59). In 1985 and 1986, a new baseline was established, which was used for the present prospective study. All survivors from the 1970 study were traced by means of the Danish Central Population Register. Between June 1985 and June 1986, all survivors (except 34 emigrants) from the original cohort were invited to take part in this study. Seventy-five percent (3387 men) agreed and gave informed consent. Their mean age was 63 years (range 53 to 74). The study took place at Glostrup Hospital, University of Copenhagen. Each subject was interviewed by a physician (Dr Hein) about a previously completed questionnaire and was examined, with measurements of height, weight, and blood pressure. A venous blood sample was taken after the subjects had fasted for at least 12 hours for measurement of serum concentrations of lipids.
Men who at baseline had a history of AMI, angina pectoris, stroke, or intermittent claudication were excluded from the follow-up study. For all who reported admission to a hospital because of AMI before the start of the study, hospital records were checked. The diagnosis of AMI was accepted if at least two of the following symptoms or signs were recorded: retrosternal pain lasting more than 20 minutes; typical, serial electrocardiographic changes in more than two electrocardiograms; and acute increases in serum concentration of relevant enzymes (alanine aminotransferase, lactate dehydrogenase, or creatine phosphokinase MB). Information regarding angina pectoris, stroke, and intermittent claudication was established from the questionnaire. Three hundred forty-two men (10.1%) were excluded due to CVD and 135 men (4%) due to missing data. Thus, 2910 men were eligible for the prospective study.
Total weekly consumption of alcohol was calculated from questionnaire items about average alcohol consumption on weekdays and weekends. Intakes of beer, wine, and spirits were reported separately. Most of the alcohol consumption was in beer. One drink corresponded to 10 to 12 g ethanol. The men classified themselves as never smokers, previous smokers, or current smokers. Current tobacco consumption was calculated from information about number of cigarettes, cheroots, or cigars or the weight of pipe tobacco smoked daily. One cigarette was taken as equivalent to 1 g tobacco, one cheroot as 3 g tobacco, and one cigar as 4 g tobacco. As previously estimated by means of serum cotinine, the validity of tobacco reporting was high.7
With respect to leisure-time physical activity, the men classified themselves as either sedentary or slightly active (<4 h/wk) or physically more active. According to the system of Svalastoga,8 later modified, the men were divided into five social classes, on the basis of level of education and job profile.
Self-reported NIDDM was accepted, provided the diagnosis had previously been verified by a physician. It should be noted that none of the participants had insulin-dependent diabetes mellitus. Blood pressure was measured on the right arm with the subject seated, by means of the manometer developed by London School of Hygiene.9 The presence of hypertension was based on questionnaire information and blood pressure measurements; the criteria were self-reported use of antihypertensive treatment or systolic blood pressure of at least 150 mm Hg and diastolic blood pressure of at least 100 mm Hg. BMI (weight in kilograms divided by the square of the height in meters) was calculated.
Serum concentrations of total cholesterol, TG, and HDL-C were analyzed by standard methods.10 11 12 13 LDL-C was determined indirectly according to the formula of Friedewald et al.14 About 1.5% of the study population had a TG level >4.5 mmol/L, a level at which the indirect LDL-C calculation becomes unreliable. However, excluding subjects with TG >4.5 mmol/L from the study did not materially affect any of the results, so we simply continued to use the formula of Friedewald et al in subjects with TG >4.5 mmol/L and did not measure LDL-C directly.
The men were subdivided into four groups on the basis of serum concentrations of fasting TG, HDL-C, and LDL-C. "High TG–low HDL-C" was defined as belonging to both the highest third of TG (cut point: 1.59 mmol/L) and the lowest third of HDL-C (cut point: 1.18 mmol/L). This selection encompassed approximately one fifth of the study population, and accordingly we extracted a similar proportion of the population with respect to high LDL-C. Thus, "high LDL-C" was defined as belonging to the highest fifth of LDL-C (cut point: 5.25 mmol/L). A control group was defined as not belonging to either of the two groups. "Combined dyslipidemia" was defined as belonging to both high TG–low HDL-C and high LDL-C. Comparisons of risks and characteristics were made between those in high TG–low HDL-C (and who were without high LDL-C), high LDL-C (and who were without high TG–low HDL-C), and combined dyslipidemia, using the control group as a reference group.
In 1995, a register follow-up was carried out on morbidity and mortality between 1985/1986 and December 31, 1993. All men who had taken part in the 1985/1986 examination were traced from registers. Information on hospital admissions and death certificate diagnoses within the follow-up period were obtained. We used the diagnoses from registers. IHD diagnoses accepted were codes 410 through 414, International Classification of Diseases, eighth revision.
Variables of interest were expressed as mean with SD or frequency in percent. Differences between groups were tested using Student's t test or 
2 analysis. The simultaneous contribution of several factors to the risk of IHD was analyzed using multiple logistic regression models and the maximum likelihood ratio method. In the multiple logistic regression analyses, lipids were entered either as dichotomized variables according to the dyslipidemic categories defined above, or more conventionally, lipid levels and lipid ratios were divided into equal fifths, and the results were presented as relative risk of IHD, defined as the proportionate change in risk for one-fifth change in the variable. All calculations were performed using the SPSSPC+ basic and advanced statistical software, version 3.1.15 16 A value of P
.05 was taken as significant unless otherwise stated.
The study was approved by the Ethics Committee for Medical Research in the County of Copenhagen.
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Results |
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Lipid characteristics of the four groups are summarized in Table 1
. By selection, TG concentrations were higher and HDL-C concentrations lower in high TG–low HDL-C and combined dyslipidemia than in high LDL-C and control groups, and LDL-C concentrations were higher in high LDL-C and combined dyslipidemia than in the other two groups. It is seen in Table 1 that high LDL-C and combined dyslipidemia corresponded to lipoprotein phenotypes IIA and IIB, respectively. The concentrations of total cholesterol and LDL-C were similar in the two low-cholesterol groups, high TG–low HDL-C and control group, as well as in the two high-cholesterol groups, high LDL-C and combined dyslipidemia, making it possible to examine the effects of high TG–low HDL-C independent of total cholesterol and LDL-C levels. Finally, the total cholesterol/HDL-C ratio was higher in high TG–low HDL-C than in both high LDL-C and the control group (P<.001), and the total cholesterol/HDL-C ratio was higher in combined dyslipidemia than in the other three groups (P<.001).
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Fig 1 shows the proportion of men with high TG–low HDL-C according to level of LDL-C. It is seen that the higher the LDL-C concentration, the higher the proportion of men with high TG–low HDL-C. Thus, the two lipid abnormalities of interest tended to coexist.
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Nonlipid CVD risk factor characteristics according to category of dyslipidemia are summarized in Table 2. It is seen that subjects with high TG–low HDL-C tended to have higher BMI, higher systolic and diastolic blood pressures, higher prevalence of NIDDM and hypertension, and tended to be less physically active. Therefore, important CVD risk factors, closely associated with insulin resistance,1 2 tended to cluster in the two groups with high TG–low HDL-C.
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Age-adjusted incidence of IHD and ACM during the 8-year follow-up period according to dyslipidemic category is summarized in Table 3. During the follow-up period, 234 men had a first IHD event, either nonfatal or fatal. In total, 426 men died from all causes. Table 3 shows that the incidence of IHD was higher in high TG–low HDL-C and combined dyslipidemia than in the control group. The incidence of IHD in high LDL-C was also higher than in the control group. It is also seen that ACM was similar in the four groups.
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The results of a stepwise logistic regression analysis are summarized in Table 4. The variables are ordered according to entry into a forward stepwise logistic regression model including dyslipidemic categories and the potentially confounding factors or covariates listed in Table 4. Combined dyslipidemia was entered into the model as the strongest risk factor of IHD. Also, high TG–low HDL-C was found to be a significant risk factor of IHD, whereas no significant association between high LDL-C and IHD could be demonstrated in this model. From the regression coefficients and standard errors derived from the multiple logistic regression model, adjusting for the variables listed in Table 4, the RRs of IHD with 95% CI were estimated; compared with control subjects, in men with combined dyslipidemia RR was 2.4 (95% CI, 1.5-4.0), P<.01; in men with high TG–low HDL-C, 1.5 (1.0-2.1), P<.05; and in men with isolated high LDL-C, 1.3 (0.9-2.0), P=.16. There was no significant difference in risk of IHD between high TG–low HDL-C and high LDL-C.
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The age-adjusted incidence of IHD during the 8-year follow-up period, according to high TG–low HDL-C stratified on fifths of LDL-C levels, is shown in Fig 2. The figure shows that the presence of high TG–low HDL-C increased the risk of IHD approximately one and a half to two and a half times in each LDL-C fifth. It should be noted that the results were the same when high TG–low HDL-C was stratified on total cholesterol levels (data not shown). It is also apparent from Fig 2 that high TG–low HDL-C identified a group at very high risk of IHD, though they had LDL-C levels considered to be safe or borderline (<3.4 mmol/L).17 Thus, individuals with high TG–low HDL-C in the lowest fifth of LDL-C (3.6 mmol/L) had a risk of IHD similar to subjects without high TG–low HDL-C in the highest fifth of LDL-C (
5.3 mmol/L). Finally, it is seen that individuals with low LDL-C and without high TG–low HDL-C had a remarkably low risk of IHD compared with subjects with both high LDL-C and high TG–low HDL-C.
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The results of the conventional multilogistic analysis are presented in Table 5. In this model, the relation between risk of IHD, lipids, and lipid ratios was assessed by successive adjustment for potentially confounding factors or covariates. The TG/HDL-C ratio was derived from the continuous values of TG and HDL-C analogously to the total cholesterol/HDL-C ratio,18 with no a priori requirement of belonging to both the highest third of TG and lowest third of HDL-C. Of the subjects with the predefined high TG–low HDL-C profile, 84% were in the highest fifth of TG/HDL-C ratios and 16% were in the second highest fifth.
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Adjusted for age and nonlipid risk factors, the two lipid ratios (total cholesterol/HDL-C and TG/HDL-C) were the strongest predictors of risk of IHD, and these two lipid ratios were basically predicting risk of IHD with similar strength in this model. Further adjustment for TG did not affect the relation between risk of IHD and the total cholesterol/HDL-C ratio, whereas adjusting for total cholesterol reduced the strength of the relation between risk of IHD and the TG/HDL-C ratio, suggesting that part of the relation of the TG/HDL-C ratio to IHD was mediated through high total cholesterol levels. It should be noted that the result was exactly the same when the TG/HDL-C ratio was adjusted for LDL-C instead of total cholesterol (data not shown).
Adjusted for age and nonlipid risk factors, TG appeared to be a stronger predictor of risk of IHD than both HDL-C and LDL-C, and the relation between risk of IHD and TG remained significant after controlling for both HDL-C and LDL-C. It should be noted that restricting the analysis to men not taking ß-blockers or diuretics for high blood pressure did not materially affect the relation between TG and IHD (data not shown). In contrast, the significant relation between risk of IHD and HDL-C disappeared when adjustment was made for TG and LDL-C, whereas LDL-C was identified as an independent risk factor in the present analysis, though the relation between risk of IHD and LDL-C was weaker compared with that of TG and the TG/HDL-C ratio.
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Discussion |
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The major finding in the present study was that high TG–low HDL-C, the characteristic dyslipidemia seen in insulin-resistant subjects, was at least as powerful as isolated high LDL-C in predicting risk of IHD.
Our study design raises two important questions: (1) Is it reasonable to use high TG–low HDL-C as a marker of insulin resistance? and (2) Is it reasonable to focus on the combined lipid profile, high TG–low HDL-C, as a joint risk factor rather than on high TG and low HDL-C as individual risk factors?
In the medical literature, increased plasma TG and decreased HDL-C concentrations have consistently been associated with insulin resistance,19 20 21 22 23 and in well-matched group comparisons, insulin-resistant subjects have both higher TG and lower HDL-C concentrations than control subjects.22 23 Also, there is substantial evidence that insulin resistance is a basic metabolic abnormality predisposing individuals to develop high TG–low HDL-C. Physiologically, insulin resistance with compensatory hyperinsulinemia leads to enhanced hepatic VLDL TG secretion rates and hypertriglyceridemia,24 and once the plasma VLDL TG pool size increases, a variety of associated abnormalities in plasma lipoprotein metabolism are present, including a decrease in HDL-C concentrations.25 Besides high TG–low HDL-C, insulin resistance is closely associated with a variety of other well-established risk factors of IHD, such as NIDDM, hypertension, overweight, and a sedentary lifestyle.1 2 In the present cohort, all these risk factors tended to cluster in men with high TG–low HDL-C (see Table 2
), so by focusing on this dyslipidemia, all the characteristic features of the insulin-resistance syndrome or Reaven's syndrome X1 2 were easily identified in the same individuals.
We decided to focus on high TG–low HDL-C as a joint risk factor, because we considered this combined lipid profile to provide a more appropriate representation of the physiology and pathogenic potential of the characteristic lipid abnormality seen in insulin-resistant subjects than either high TG or low HDL-C alone. In the medical literature, a low HDL-C concentration is a well-established major risk factor of IHD, whereas the independent relationship of TG to IHD is controversial.26 27 Most prospective cohort studies have reported a significant univariate association between increased TG and risk for IHD,26 but when these cohort studies are subjected to multivariate analysis controlling for other risk factors, particularly the level of HDL-C, the effect of TG is usually diminished or eliminated.26 27 28 The interpretation of multivariate models including TG as an independent variable is complex and associated with several problems, particularly when adjustment has been made for HDL-C. TG and HDL-C are closely associated both metabolically and statistically, and because of greater measurement variability in TG relative to HDL-C values, multivariate analysis may underestimate the association between TG and risk for IHD, because HDL-C is simply measured more precisely.26 In addition, unrelated to HDL-C, TG appears to be closely related to a series of potentially atherogenic and thrombogenic changes, such as small, dense LDL particles (pattern B),23 29 prolonged postprandial hypertriglyceridemia,30 accumulation of chylomicron remnants,30 higher concentrations of plasminogen activator inhibitor-1,31 32 and higher concentrations of coagulation factor VII.33 Thus, summarizing the clinical observations and statistical considerations listed above, it seemed more meaningful in this study to focus on the combined lipid profile, high TG–low HDL-C, as a risk factor of IHD than on high TG and low HDL-C as individual risk factors. Indeed, the usefulness of the combined lipid profile, high TG–low HDL-C, is suggested by our conventional multilogistic analysis. In this model the TG/HDL-C ratio, in which the highest fifth of ratios of TG to HDL-C basically corresponded to the predefined high TG–low HDL-C profile, was a stronger predictor of risk of IHD than TG and HDL-C.
In contrast to most studies26 but in accordance with others,28 34 35 TG was here identified as an independent risk factor of IHD after controlling for HDL-C, whereas HDL-C was not identified as an independent risk factor in the present study. We have no obvious explanation for this discrepancy, but this interesting point will be subjected to future investigation, and we would like to point out that compared with the other conventional lipid risk factors, ie, total cholesterol, LDL-C, and HDL-C, TG was a very strong risk factor of IHD in this Danish cohort.
In the present cohort, subjects with high TG–low HDL-C had a higher total cholesterol/HDL-C ratio (see Table 1), a lipid combination suggested to be a superior measure of risk of IHD than other lipid risk factors,18 and this factor may explain the higher risk of IHD associated with the high TG–low HDL-C profile. It is interesting to note that adjusted for age, the risk associated with the TG/HDL-C ratio was quite similar to that associated with the total cholesterol/HDL-C ratio.
High TG–low HDL-C may be the result of metabolic abnormalities other than insulin resistance. This fact should not obscure another important and clinically relevant point made by our results. At both low and high levels of total cholesterol and LDL-C, the presence of high TG–low HDL-C approximately doubled the risk of IHD, and individuals with high TG–low HDL-C in the lowest fifth of LDL-C (3.6 mmol/L) had a similar risk of IHD to subjects without high TG–low HDL-C in the highest fifth of LDL-C (5.3 mmol/L). High TG–low HDL-C thus clearly identified a group at high risk of IHD, though they had LDL-C levels considered to be safe or borderline (<3.4 mmol/L).17
The present study was performed in middle-aged and elderly males. Could our results be due to a selection bias, and is the risk of IHD associated with high TG–low HDL-C confined to this age group alone? This does not appear to be the case. At baseline, the age-adjusted prevalence of CVD was 7.2% in the control group, 14.9% in high TG–low HDL-C, 12.2% in high LDL-C, and 23.5% in combined dyslipidemia, following the subdivision criteria described in "Methods," and even though high TG–low HDL-C encompassed only 20% of the study population, this dyslipidemia included more than 35% of the cases excluded at baseline due to preexisting CVD. The significance of high TG–low HDL-C as a risk factor of IHD in all age groups is underscored by the observation that in men with a first AMI before the age of 45, approximately half of the cases had a lipid disorder matching the high TG–low HDL-C profile.36 In this context, it is interesting to point out that these young survivors of AMI were also insulin resistant.36
The findings presented here are supported by other investigations, though this study appears to be the first to have thoroughly compared the contribution to IHD risk of high TG–low HDL-C to that of high LDL-C in a population-based study of middle-aged and elderly males. Analysis from the Framingham Heart Study showed that men who were in the lowest tertile of HDL-C and also in the highest TG tertile were a very important high-risk group, and because the high TG–low HDL-C trait appeared to be a common lipid abnormality in the Framingham population, it apparently produced more cases of IHD than isolated high LDL-C.35 Also, in the Prospective Cardiovascular Münster (PROCAM) study, approximately half of the IHD cases had a lipid disorder matching the high TG–low HDL-C profile.37
In conclusion, the present results showed that high TG–low HDL-C, the characteristic dyslipidemia seen in insulin-resistant subjects, was at least as powerful a predictor of IHD as isolated high LDL-C. The results suggest that efforts to prevent IHD should include intervention against high TG–low HDL-C, and not just against hypercholesterolemia.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study received grants from King Christian X Foundation, the Danish Medical Research Council, the Danish Heart Foundation, and Else and Mogens Wedell-Wedellsborg Foundation.
Received January 3, 1996; accepted August 15, 1996.
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References |
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R. M. Krauss Lipids and Lipoproteins in Patients With Type 2 Diabetes Diabetes Care, June 1, 2004; 27(6): 1496 - 1504. [Abstract] [Full Text] [PDF]
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 I. Lemieux, B. Lamarche, C. Couillard, A. Pascot, B. Cantin, J. Bergeron, G. R. Dagenais, and J.-P. Despres Total Cholesterol/HDL Cholesterol Ratio vs LDL Cholesterol/HDL Cholesterol Ratio as Indices of Ischemic Heart Disease Risk in Men: The Quebec Cardiovascular Study Arch Intern Med, December 10, 2001; 161(22): 2685 - 2692. [Abstract] [Full Text] [PDF]
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A. Pascot, I. Lemieux, D. Prud'homme, A. Tremblay, A. Nadeau, C. Couillard, J. Bergeron, B. Lamarche, and J.-P. Despres Reduced HDL particle size as an additional feature of the atherogenic dyslipidemia of abdominal obesity J. Lipid Res., December 1, 2001; 42(12): 2007 - 2014. [Abstract] [Full Text] [PDF]
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 V. Mohan, R. Deepa, S. Shanthi Rani, and G. Premalatha Prevalence of coronary artery disease and its relationship to lipids in a selected population in South India: The Chennai Urban Population Study (CUPS No. 5) J. Am. Coll. Cardiol., September 1, 2001; 38(3): 682 - 687. [Abstract] [Full Text] [PDF]
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 J.W.G. Yarnell, C. C. Patterson, P. M. Sweetnam, H. F. Thomas, D. Bainton, P. C. Elwood, C. H. Bolton, and N. E. Miller Do Total and High Density Lipoprotein Cholesterol and Triglycerides Act Independently in the Prediction of Ischemic Heart Disease?: Ten-Year Follow-Up of Caerphilly and Speedwell Cohorts Arterioscler Thromb Vasc Biol, August 1, 2001; 21(8): 1340 - 1345. [Abstract] [Full Text] [PDF]
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C. Couillard, J.-P. Despres, B. Lamarche, J. Bergeron, J. Gagnon, A. S. Leon, D. C. Rao, J. S. Skinner, J. H. Wilmore, and C. Bouchard Effects of Endurance Exercise Training on Plasma HDL Cholesterol Levels Depend on Levels of Triglycerides : Evidence From Men of the Health, Risk Factors, Exercise Training and Genetics (HERITAGE) Family Study Arterioscler Thromb Vasc Biol, July 1, 2001; 21(7): 1226 - 1232. [Abstract] [Full Text] [PDF]
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 A. H. Slyper Childhood Obesity, Adipose Tissue Distribution, and the Pediatric Practitioner Pediatrics, July 1, 1998; 102(1): 4e - 4. [Abstract] [Full Text]
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