Increased HDL-C Values and Mortality: Revolutionizing a Historical Paradigm?

Cardiovascular disease (CVD), encompassing acute myocardial infarction, ischemic stroke, and peripheral artery occlusive disease, is still the first cause of death and disability in Western countries. According to recent statistics from the American Heart Association and the U.S. National Institutes of Health, CVD accounts for around 31% of all deaths in the United States, thus preceding by far cancer (approximately 21%), chronic lower respiratory diseases (approximately 6%), and accidents (5%).[1] Therefore, focused prevention on atherosclerosis, which is the underlying cause of most CVD events, is still regarded as a primary target in health care all around the world.[2]

Most of the current guidelines on CVD risk assessment include specific recommendations that low values of high-density lipoprotein cholesterol (HDL-C) are associated with an increased likelihood of developing atherosclerosis-based ischemic events,[3] [4] in that this (“good”) cholesterol fraction is thought to reduce both the accumulation of cholesterol within the artery wall and lipoproteins oxidation. Interestingly, the American and European guidelines for the management of dyslipidemias indicate a low threshold value for HDL-C (typically between 40 and 50mg/dL, depending on sex and age), indicating as “normal” or “acceptable” serum levels of HDL-C equal or above (i.e., “≥”) such cut-offs,[5] [6] but also proposing some lifestyle interventions aimed at enhancing HDL-C levels (e.g., engaging in routine physical activity [PA], reducing body weight, avoiding dietary trans fats and so forth). Even the historical and still non-updated Adult Treatment Panel III of the National Cholesterol Education Program reports a desirable level of HDL-C “≥60mg/dL” and stated that “regular PA becomes a routine component in the management of high serum cholesterol because it raises HDL cholesterol.”[7]

These recommendations, especially the indication of engaging in regular PA, have become a paradigm of all primary and secondary prevention programs worldwide, with performance of (at least) 150 to 300minutes of moderate intensity or 75 to 150minutes of vigorous intensity PA per week now being universally recommended.[8] The benefits of aerobic exercise have been well-recognized for decades since PA is associated with a lower risk of developing osteoporosis, frailty, cancer, diabetes, obesity, and, last but not least, CVD.[9] The effect of PA on cardiovascular fitness is also mediated by a substantial impact on boosting HDL-C production by the liver.[10] [11] Nonetheless, the paradigm that boosting HDL-C would always be directly associated with health benefits is currently being challenged by a series of observations, which may ultimately revolutionize this straightforward historical concept.

In a meta-analysis of 37 prospective cohort studies, totaling over 3.5 million participants, published by Zhong et al in 2020,[12] HDL-C levels were associated with all-cause death and CVD and even cancer mortality through a paradigmatic J-shaped relationship. More specifically, compared with the reference HDL-C value (i.e., 56mg/dL), the pooled risk of all-cause death was 1.21 (95% confidence interval [95% CI], 1.09–1.36) higher for subjects in the highest HDL-C category, with a pooled hazard ratio of 1.03 (95% CI, 1.01–1.05) for each 10mg/dL increase of HDL-C concentration above the reference value. A similar trend was noted for cancer mortality, with a pooled hazard ratio of 1.02 (95% CI, 0.98–1.05) for each 10mg/dL increase above the reference HDL-C value and, even more surprisingly, for CVD mortality, with a pooled hazard ratio of 1.06 (95% CI, 1.01–1.10) for each 10mg/dL increase above the reference HDL-C value. This surprising analysis has been more recently confirmed by Liu et al,[13] who conducted a large prospective and multicenter cohort study in the United Kingdom and United States, including nearly 15,000 participants with coronary heart disease who were followed up between 7 and 9 years. Notably, the authors confirmed a U-shaped relationship with clinical outcomes, where higher risk was seen in both subjects with low and high HDL-C values compared with those displaying intermediate (“reference”) levels. More specifically, subjects with high values of HDL-C levels (i.e., >80mg/dL) had a nearly twofold higher risk of both all-cause (hazard ratio [HR], 1.96; 95% CI, 1.42–2.71) and CVD (HR, 1.71; 95% CI, 1.09–2.68) mortality compared to those with values in the range between 40 and 60mg/dL. Men with increased HDL-C values also had an over twofold risk of all-cause (HR, 2.63; 95% CI, 1.75–3.95) and CVD (HR, 2.50; 95% CI, 1.47–4.27) death compared with women.

These findings, somehow surprising, are perhaps not unexpected. Although the recent meta-analysis of Blond et al concluded that the future risk of death seems lower in people engaging in PA levels well over the recommended target,[14] one of the largest prospective studies that have been conducted so far for addressing the relationship between PA and mortality, the Copenhagen City Heart Study,[15] in which Schnohr et al followed up 1,098 healthy joggers and 3,950 healthy non-joggers for over 10 years, reported a U-shaped relationship between the dose of jogging and all-cause death. In particular, “strenuous” joggers (>4h/wk at >7 miles/h) displayed a trend toward substantially enhanced risk of all-cause mortality (HR, 9.08; 95% CI: 1.87–44.01) compared with “light” joggers. Notably, data on professional athletes are also contradictory, in that some studies reported a higher risk of premature death,[16] [17] while others did not.[18] [19] Indeed, other studies suggest a “sweet spot” for PA and subsequent clinical outcomes, with either loss of benefit or worse outcomes at very high doses.[20] [21]

Concerning HDL-C, it is now clear that the serum value of this lipoprotein fraction increases in parallel with the amount of PA,[10] with professional endurance athletes exhibiting “supranormal” (even exceptional) values at rest,[22] [23] often accompanied by concomitant enhancement of serum lipoprotein(a), a highly atherogenic lipoprotein which actively participates in the pathogenesis of atherosclerosis.[24] Two crucial questions would now hence emerge: (1) is the enhanced risk of death seen in certain categories of strenuous sportsmen somehow (also) linked to their magnified serum levels of HDL-C? (2) could the cholesterol fraction associated with HDL play an active role rather than acting as a simple bystander of PA in influencing the risk of death? Unfortunately, we have no definitive answers to these questions. Many clinical studies and the derived guidelines and recommendations have for long included exercise programs aimed at generating improvements in patient fitness and/or cardiovascular rehabilitation, with the underlying assumption that raising HDL-C would be always beneficial.[25] [26] [27] Nonetheless, it is now time to plan additional studies investigating the real interplay between HDL and PA in modulating the risk of death across a wide range of HDL-C concentrations. Moreover, taking the important evidence of a “J-” or even “U-”shaped association between HDL-C and mortality ([Figure 1]), doubts emerge as to whether the current guidelines that advocate boosting HDL-C values (mostly through PA) may need to be revised, for example by including a target range of desirable HDL-C values (e.g., between 60 and 80mg/dL) rather than a simple indication of “equal and/or above” (i.e., “≥”). Additionally, studies could better determine the potential harms of extremely high intakes of ethanol that may impact the association of HDL-C with all-cause and cancer mortality.

Fig. 1 The “J-shape” association between high-density lipoprotein cholesterol (HDL-C) and all-cause mortality.

Publication History

Article published online:
02 September 2022

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