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HDL Cholesterol, Very Low Levels of LDL Cholesterol, and Cardiovascular Events
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NEJM Sept 27, 2007
Philip Barter, M.D., Ph.D., Antonio M. Gotto, M.D., D.Phil., John C. LaRosa, M.D., Jaman Maroni, M.D., Michael Szarek, M.S., Scott M. Grundy, M.D., Ph.D., John J.P. Kastelein, M.D., Ph.D., Vera Bittner, M.D., M.S.P.H., Jean-Charles Fruchart, Pharm.D., Ph.D., for the Treating to New Targets Investigators
From the Heart Research Institute, Sydney (P.B.); the Joan and Sanford I. Weill Medical College of Cornell University, New York (A.M.G.); the State University of New York Downstate Medical Center, Brooklyn (J.C.L.); Pfizer, New York (J.M., M.S.); the Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas (S.M.G.); the Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); the Division of Cardiovascular Disease, University of Alabama, Birmingham (V.B.); and the Institut Pasteur, Lille, France (J.-C.F.).
ABSTRACT
Background High-density lipoprotein (HDL) cholesterol levels are a strong inverse predictor of cardiovascular events. However, it is not clear whether this association is maintained at very low levels of low-density lipoprotein (LDL) cholesterol.
Methods A post hoc analysis of the recently completed Treating to New Targets (TNT) study assessed the predictive value of HDL cholesterol levels in 9770 patients. The primary outcome measure was the time to a first major cardiovascular event, defined as death from coronary heart disease, nonfatal non-procedure-related myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke. The predictive relationship between HDL cholesterol levels at the third month of treatment with statins and the time to the first major cardiovascular event was assessed in univariate and multivariate analyses and was also assessed for specific LDL cholesterol strata, including subjects with LDL cholesterol levels below 70 mg per deciliter (1.8 mmol per liter).
Results The HDL cholesterol level in patients receiving statins was predictive of major cardiovascular events across the TNT study cohort, both when HDL cholesterol was considered as a continuous variable and when subjects were stratified according to quintiles of HDL cholesterol level. When the analysis was stratified according to LDL cholesterol level in patients receiving statins, the relationship between HDL cholesterol level and major cardiovascular events was of borderline significance (P=0.05). Even among study subjects with LDL cholesterol levels below 70 mg per deciliter, those in the highest quintile of HDL cholesterol level were at less risk for major cardiovascular events than those in the lowest quintile (P=0.03).
Conclusions In this post hoc analysis, HDL cholesterol levels were predictive of major cardiovascular events in patients treated with statins. This relationship was also observed among patients with LDL cholesterol levels below 70 mg per deciliter.
Population studies have consistently shown that high-density lipoprotein (HDL) cholesterol levels are a strong, independent inverse predictor of cardiovascular disease.1,2,3,4,5 In the Framingham Heart Study, HDL cholesterol level was more potent as a risk factor for coronary heart disease than was the level of low-density lipoprotein (LDL) cholesterol.4 An analysis of data from four large studies concluded that each increase of 1 mg per deciliter (0.03 mmol per liter) in HDL cholesterol is associated with a decrease of 2 to 3% in the risk of future coronary heart disease.6
Intervention trials using statins to lower LDL cholesterol have consistently shown substantial reductions in major cardiovascular events in the treated groups.7,8,9,10,11,12,13 Furthermore, the magnitude of the reduction in events is a function of the extent of LDL cholesterol lowering, with each decrease of 40 mg per deciliter (1.0 mmol per liter) in LDL cholesterol corresponding to a 24% reduction in major cardiovascular events.13 However, in all the statin trials, there remains a substantial residual risk in the treated groups.
One explanation for this may relate to the presence of a low baseline level of HDL cholesterol, which has been shown in several trials to remain predictive of major cardiovascular events, even during treatment with statins.14 In a recent pooled analysis of four trials of statins, the moderate increase in HDL cholesterol levels seen with these drugs correlated with regression of coronary atherosclerosis.15 These findings have added support to the proposition that HDL cholesterol levels should be considered as therapeutic targets independent of the lowering of LDL cholesterol levels. However, it could also be argued that if LDL cholesterol levels are reduced to very low levels, low HDL cholesterol levels may no longer be relevant. To date, this view has remained untested.
In the Treating to New Targets (TNT) trial (ClinicalTrials.gov number, NCT00327691 [ClinicalTrials.gov] ), 2661 subjects achieved an LDL cholesterol level below 70 mg per deciliter (1.8 mmol per liter) while receiving statin therapy.16 This target originally was proposed as an optional treatment goal in very-high-risk patients with coronary heart disease in an update to the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guidelines,17 and it has now been proposed by the American Heart Association and the American College of Cardiology guidelines as a reasonable target for therapy in patients with coronary heart disease or other forms of atherosclerotic disease.18
This post hoc analysis of the TNT trial examined the relationship between the frequency of major cardiovascular events and HDL cholesterol levels in a population of patients with clinically evident coronary heart disease who were being treated with statins. It also investigated whether any observed relationship was maintained when LDL cholesterol was reduced below 70 mg per deciliter.
From Medpage:
In an interview, Christopher Cannon, M.D., of Brigham and Women's Hospital and Harvard Medical School, agreed that the finding was "important," although he pointed out that it emerged from a post hoc analysis of a trial that was not designed to treat HDL. Nonetheless, when the data were analyzed "a lower risk was seen among this subset of patients with LDL less than 70 mg/dL whose HDL levels were in the highest quintile." Dr. Cannon was not involved in the trial.
The findings, both Drs. Barter and Cannon agreed, come at time when interventions targeting HDL have had mixed results.
Statin therapy in addition to lowering LDL can achieve modest increases in HDL, Dr. Cannon said.
"Losing weight and exercise are effective life style interventions," Dr. Barter said, "and if everybody was lean we wouldn't have the current epidemic of cardiovascular disease. But not every patient can run."
Niacin can increase HDL by 30% to 40%, but the chemical flush associated with its use makes it difficult for many patients to tolerate.
Results have been somewhat better with extended release niacin, as well as with an investigational compound that combines niacin with laropiprant, a potent, highly selective prostaglandin antagonist. (See: ESC: Investigative Niacin Combo Turns Down the Heat on Flushing)
And trials of the most promising HDL-boosting drug, torcetrapib, were halted late last year when researchers discovered excess cardiovascular mortality among patients taking the drug. (See: ACC: Torcetrapib Studies Offer More Questions About HDL Booster)
Dr. Barter said he will be reporting data at the American Heart Association meeting in November that will answer some of the remaining questions about torcetrapib, which boosts HDL by 50% to 100% by inhibiting cholesteryl ester transfer protein (CTEP).
The investigators said the current trial was limited by a number of factors including the fact that patients defined by HDL quintiles were "not similar with respect to other cardiovascular risk factors and there may have been other differences that were not evaluated but that could have influenced the analysis." Two such missing pieces of information were waist circumference and insulin levels.
But for now, Dr. Barter said, "I would recommend HDL modifying regimens such as niacin for any [dyslipidemia] patient who has achieved a low LDL but who has not increased their HDL [to 55 mg/dL or higher]."
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Results
Baseline Characteristics
The baseline characteristics and lipid levels of the subjects in each of the quintiles of HDL cholesterol level during statin treatment (month 3) are shown in Table 1. Subjects with higher HDL cholesterol levels were older, more likely to be female, and leaner than those with lower HDL cholesterol levels. Current smokers were less common in the higher quintiles of HDL cholesterol levels, and subjects with higher HDL cholesterol levels were more likely to have never smoked. The proportion of past smokers was similar in all quintiles.
As expected, subjects with higher HDL cholesterol levels during statin treatment (month 3) had higher concentrations of apolipoprotein A-I (a structural component of HDL) and lower plasma triglyceride levels. The concentration of apolipoprotein B (a structural component of the non-HDL lipoproteins) declined slightly with increasing HDL cholesterol levels (P<0.001). The prevalence of diabetes in the lowest quintile of HDL cholesterol levels was double that in the highest quintile. There were no significant differences in any of these baseline characteristics between the two atorvastatin treatment groups within each HDL cholesterol group.
Cardiovascular Events According to Quintile of HDL Cholesterol Level
The expected 5-year risk of major cardiovascular events was determined for each quintile of HDL cholesterol level in patients receiving statins across the entire TNT trial cohort. In the univariate model, the event rate was reduced by 40% in the highest quintile relative to the lowest. When the analysis included adjustments for covariates (Figure 1A), the quintile of HDL cholesterol level remained a significant predictor of major cardiovascular events, with a reduction in major cardiovascular events from 95% in the lowest quintile to 7.1% in the highest quintile, a 25% reduction in risk (hazard ratio, 0.75; 95% confidence interval [CI], 0.60 to 0.95). The risk of major cardiovascular events differed significantly across HDL cholesterol quintiles (P=0.04).
The relationship between HDL cholesterol levels in patients receiving statins and the frequency of major cardiovascular events seen in the overall cohort was also apparent in each of the two atorvastatin treatment groups. The incidence of major cardiovascular events was substantially lower in the group receiving 80 mg of atorvastatin per day than in the group receiving 10 mg per day in all quintiles. However, in each treatment group, the frequency of major cardiovascular events increased with decreasing levels of HDL cholesterol (Figure 1B). After adjustment for covariates, among subjects assigned to 10 mg of atorvastatin, those in the highest quintile were significantly less likely to have a major cardiovascular event than those in the lowest quintile (hazard ratio, 0.71; 95% CI, 0.52 to 0.96). In subjects assigned to 80 mg of atorvastatin, the difference in cardiovascular risk between the highest and the lowest quintile did not reach significance (hazard ratio, 0.81; 95% CI, 0.58 to 1.14).
Effect of LDL Cholesterol Level
We performed a stratified regression analysis to determine the interaction between HDL and LDL cholesterol levels in patients receiving statins. In a multivariate model (Figure 2A), the quintile of HDL cholesterol level was of borderline significance as a predictor of major cardiovascular events (P=0.05), with no evidence of interaction with the quintile of LDL cholesterol level (P=0.67). The hazard ratios and 95% confidence intervals for quintiles 2 through 5 of HDL cholesterol level (with quintile 1 as a reference) were 1.00 (95% CI, 0.82 to 1.21), 0.80 (95% CI, 0.65 to 0.99), 0.92 (95% CI, 0.74 to 1.13) and 0.75 (95% CI, 0.60 to 0.95).
Figure 1. Multivariate Analysis of the Relationship between HDL Cholesterol Levels at Month 3 and the Risk of Major Cardiovascular Events.
Panel A shows the results for all patients. Quintile 1 is the reference group. The adjusted 5-year risk reflects the expected risk of a first major cardiovascular event for a cohort with the following characteristics: female sex, 19.0%; mean age, 61.0 years; past smoker, 63.2%; current smoker, 13.4%; mean body-mass index, 28.5; mean systolic blood pressure, 130.7 mm Hg; history of diabetes mellitus, 15.0%; history of myocardial infarction, 58.3%; history of cardiovascular disease, 5.2%; hypertension (systolic blood pressure, >140.0 mm Hg or patient receiving antihypertensive therapy), 54.1%; mean fasting glucose level, 107.7 mg per deciliter (6.0 mmol per liter); mean LDL cholesterol level at month 3, 85.8 mg per deciliter (2.2 mmol per liter); and mean triglyceride level at month 3, 140.1 mg per deciliter (1.6 mmol per liter). Panel B shows the results for the 10-mg and 80-mg atorvastatin groups. The lipid levels at month 3 in the 10-mg atorvastatin group were 98.9 mg of LDL cholesterol per deciliter (2.6 mmol per liter) and 151.8 mg of triglycerides per deciliter (1.7 mmol per liter). The lipid levels at month 3 in the 80-mg atorvastatin group were 72.6 mg of LDL cholesterol per deciliter (1.9 mmol per liter) and 128.2 mg of triglycerides per deciliter (1.4 mmol per liter). To convert values for HDL cholesterol to millimoles per liter, multiply by 0.02586.
A separate analysis was conducted to evaluate the influence of HDL cholesterol on outcome among subjects in the lowest LDL cholesterol stratum (<70 mg per deciliter). In this group, according to multivariate analysis (Figure 2B), the risk of a major cardiovascular event differed significantly among quintiles of HDL cholesterol levels (P=0.03). Subjects in the highest HDL cholesterol quintile had a lower risk of major cardiovascular events than subjects in the lowest quintile (hazard ratio, 0.61; 95% CI, 0.38 to 0.97).
Ratios of LDL Cholesterol and Total Cholesterol to HDL Cholesterol
The ratio of LDL cholesterol to HDL cholesterol at month 3 of the trial was also highly predictive of major cardiovascular events. There were major differences at the extremes: the event rate of 5.8% in subjects with the lowest ratio was less than half that in subjects with the highest ratio (13.5%). The ratio of LDL cholesterol to HDL cholesterol among patients receiving statins (month 3) remained highly predictive (P=0.006) of major cardiovascular events, even after adjustment (Figure 3A). Subjects in the quintile with the highest ratio of LDL cholesterol to HDL cholesterol had a significantly greater risk of major cardiovascular events than did subjects in the lowest quintile (hazard ratio, 1.82; 95% CI, 1.32 to 2.51).
Figure 3. Relationship between Major Cardiovascular Events and Ratio of LDL Cholesterol to HDL Cholesterol at Month 3 (Panel A) and Ratio of Total Cholesterol to HDL Cholesterol at Month 3 (Panel B).
The adjusted 5-year risk reflects the expected risk of a first major cardiovascular event for a cohort with the following characteristics: female sex, 19.0%; mean age, 61.0 years; past smoker, 63.2%; current smoker, 13.4%; body-mass index, 28.5; mean systolic blood pressure, 130.7 mm Hg; history of diabetes mellitus, 15.0%; history of myocardial infarction, 58.3%; history of cardiovascular disease, 5.2%; hypertension, 54.1%; and mean fasting glucose level, 107.7 mg per deciliter. The lipid levels at month 3 were 85.8 mg of LDL cholesterol per deciliter and 140.1 mg of triglycerides per deciliter for all subjects, 98.9 mg of LDL cholesterol per deciliter and 151.8 mg of triglycerides per deciliter for those receiving 10 mg of atorvastatin, and 72.6 mg of LDL cholesterol per deciliter and 128.2 mg of triglycerides per deciliter for those receiving 80 mg of atorvastatin.
The ratio of total cholesterol to HDL cholesterol at month 3 was also predictive of major cardiovascular events (Figure 3B). After adjustment, subjects in the quintile with the highest ratio were at significantly greater risk of major cardiovascular events than were those in the quintile with the lowest ratio, with a hazard ratio after adjustment for potential confounders of 1.72 (95% CI, 1.26 to 2.35).
Continuous HDL Cholesterol Levels
The risk of a major cardiovascular event was also determined for each increment of 1 mg per deciliter (0.03 mmol per liter) in HDL cholesterol level at baseline and during statin treatment (Table 2). In a model adjusted for covariates, an increase of 1 mg per deciliter in the HDL cholesterol level at month 3 could be expected to reduce the risk of major cardiovascular events by 1.1% (P=0.003) (Table 2).
In the multivariate analysis, the relationship between baseline HDL cholesterol level and the risk of major cardiovascular events was almost identical to that observed between HDL cholesterol level and the risk of major cardiovascular events during statin treatment. However, inclusion of the baseline ratio of apolipoprotein B to apolipoprotein A-I in the analysis model reduced the predictive relationship to nonsignificance (P=0.46).
Interaction tests indicated that relationships between HDL cholesterol levels at baseline or during statin treatment and the risk of major cardiovascular events did not depend on sex (P=0.11 for baseline levels, P=0.34 for levels during statin treatment), age (P=0.75 for baseline levels, P=0.31 for levels during statin treatment), smoking status (P=0.55 for baseline levels, P=0.64 for levels during statin treatment), body-mass index (P=0.13 for baseline levels, P=0.09 for levels during statin treatment), or any of the other covariates considered in the analysis (all P>0.10 for levels at baseline and during statin treatment).
Discussion
It has long been known that a low level of HDL cholesterol is a powerful predictor of increased cardiovascular risk,1,2,3,4,5,6 but it has not been clear whether a low HDL cholesterol level would remain a significant risk factor in people whose LDL cholesterol was reduced to very low levels. Indeed, it has been argued hypothetically that if the LDL cholesterol level were reduced sufficiently, the level of HDL cholesterol might become irrelevant.
In this post hoc analysis from the TNT trial, HDL cholesterol level was a significant predictor of major cardiovascular events across the entire study cohort, even after all other baseline risk factors, including baseline LDL cholesterol level, had been taken into account. This effect was more pronounced in the analyses using HDL cholesterol level as a continuous variable than in those using quintiles of HDL cholesterol levels at month 3 of the trial, a result suggesting that outlier HDL cholesterol levels may have had an important role in the relationship we observed.
The effect of LDL cholesterol levels during statin treatment on the predictive value of HDL cholesterol was examined. After adjustment for covariates, the predictive value of HDL cholesterol levels was of borderline significance, a result consistent with a suggestion that in patients with coronary heart disease, higher HDL cholesterol levels may offset the increased risk associated with higher LDL cholesterol levels.
In a further analysis, we examined the relationship between the quintile of HDL cholesterol level during statin treatment with risk in those patients in the lowest stratum of LDL cholesterol level (<70 mg per liter). This analysis demonstrated that even among patients in this very low LDL cholesterol stratum, the risk of major cardiovascular events was reduced in those with higher rather than lower HDL cholesterol levels.
Given that HDL and LDL cholesterol levels during statin treatment were both independently predictive of major cardiovascular events across the whole range of HDL and LDL cholesterol levels in this analysis, it was not surprising to find that the ratio of LDL to HDL cholesterol was also highly predictive of the risk of major cardiovascular events. A similar result was observed for the ratio of total cholesterol to HDL cholesterol. These results are consistent with previous studies.20,21,22,23
There are several limitations of this study that should be considered when evaluating our findings. The groups of patients defined by quintile of HDL cholesterol level were not similar with respect to other cardiovascular risk factors (Table 1), and there may have been other differences that were not evaluated but that could have influenced the results of the analysis. We did not measure waist circumference or insulin levels in our study population, and thus we cannot determine to what degree the observed effect of HDL cholesterol level may be due to the coincidence of a low HDL cholesterol level with the metabolic syndrome. This relationship is suggested in our data by the fact that most of our study subjects who had low HDL cholesterol levels were also obese and had elevated plasma triglyceride levels.
In summary, this analysis from the TNT trial evaluated the effect of HDL cholesterol levels in patients with clinically evident coronary heart disease who were receiving statin therapy to reduce LDL cholesterol levels. Across the entire study cohort in multivariate analysis, HDL cholesterol levels were a significant inverse predictor of subsequent major cardiovascular events. When the effect of the LDL cholesterol level achieved in patients receiving therapy was taken into account, the role of HDL cholesterol was less marked, though still of borderline significance. The relationship remained significant even in patients whose LDL cholesterol level was less than 70 mg per deciliter.
Supported by Pfizer.
Dr. Barter reports receiving consulting fees from Pfizer and AstraZeneca, lecture fees from Pfizer, AstraZeneca, and Merck, and grant support from Pfizer. Dr. Gotto reports receiving consulting fees from Aegerion Pharmaceuticals, Arisaph Pharmaceuticals, DuPont, Johnson & Johnson, Merck, Kowa, Schering-Plough, Novartis, and Reliant Pharmaceuticals, receiving lecture fees from Pfizer, Merck, Schering-Plough, Reliant Pharmaceuticals, and Sanofi-Aventis, and testifying before the Food and Drug Administration on behalf of Johnson & Johnson-Merck. Dr. LaRosa reports receiving consulting fees from Pfizer, Bayer, and Merck and lecture fees from Pfizer. Dr. Maroni and Mr. Szarek report being employees of Pfizer and owning equity in Pfizer. Dr. Grundy reports receiving consulting fees from Pfizer, Merck, Kos Pharmaceuticals, Abbott, Schering-Plough, Fournier Pharma, Bristol-Myers Squibb, Daiichi Sankyo, Sanofi-Aventis, GlaxoSmithKline, Eli Lilly, and AstraZeneca and grant support from Kos Pharmaceuticals, Abbott, and Merck. Dr. Kastelein reports receiving consulting fees and lecture fees from Pfizer, Merck, Schering-Plough, AstraZeneca, Bristol-Myers Squibb, and Daiichi Sankyo. Dr. Bittner reports receiving consulting fees from Pfizer, Reliant Pharmaceuticals, CV Therapeutics, and Novartis and grant support from Pfizer, AtheroGenics, Kos Pharmaceuticals, and Merck. Dr. Fruchart reports receiving consulting fees from Pfizer, Sanofi-Aventis, and Fournier Pharma and lecture fees from Pfizer, Merck, Schering-Plough, Reliant Pharmaceuticals, and Sanofi-Aventis. No other potential conflict of interest relevant to this article was reported.
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