Over the course of the last three decades, age-adjusted coronary mortality rates have plummeted in Western societies due to more effective implementation of established preventive strategies. In many ways, this reflects the major success of randomized controlled trials demonstrating the benefits of lowering both blood pressure and cholesterol. Such triumphs have prompted leaders in the field to propose that the eradication of myocardial infarctions must lie just around the corner.
Yet, the sobering reality to clinicians, public health researchers and health systems in general reveals that atherosclerotic cardiovascular disease has not disappeared. Rather, the global burden of the disease has increased, spreading to the developing world. This is largely due to the impact of central adiposity and its associated metabolic complications. This reflects an evolution in the classical phenotype of the patient with cardiovascular disease from the thin, smoking executive to the sedentary, obese individual. As a reduction in physical activity and adoption of poor dietary habits has become increasingly prevalent, the presence of obesity has become more widespread, with a consequent increase in the burden of atherosclerotic disease.
In parallel with the rise in abdominal adiposity has been an increase in prevalence in both the clustering of risk factors included in the metabolic syndrome and Type 2 diabetes mellitus. Central to these processes appears to be the development of insulin resistance, inflammation and oxidative stress. To some degree, these states reflect points on a continuum of the worsening metabolic consequences of abdominal obesity. As obesity has become increasingly prevalent at a young age, these metabolic states appear early and will drive the impending epidemic of premature cardiovascular disease. This is demonstrated by reports from vascular imaging of macroscopic atherosclerosis in adolescence and an increase in cardiovascular events at younger ages, particularly in disadvantaged sectors of the community.
Unfortunately, many of these individuals do not come to our attention until they have either deranged metabolic states or clinically evident vascular disease. Our focus in these high risk situations is to aggressively target LDL-cholesterol and blood pressure, in accordance with the findings of clinical benefit from large-scale clinical trials. However, even with widespread use of these therapeutic strategies, there remains a large residual risk of clinical events. This is likely to reflect the presence of more aggressive forms of atherosclerotic disease and the importance of additional factors that underlie its natural history.
Increasing insights into the metabolic factors that drive the disease and the molecular pathways in the artery wall that underlie progression of atherosclerosis provide attractive targets for the development of novel anti-atherosclerotic strategies in addition to existing interventions. The presence of metabolic syndrome and diabetes is often accompanied by LDL-cholesterol levels that are considered to be in the ‘normal’ range. Increasing characterization of such patients has revealed the presence of a high burden of atherogenic lipoproteins. This includes the presence of large circulating levels of small, dense LDL particles, remnant lipoproteins and triglyceride-rich particles. Each of these factors has been demonstrated to be highly atherogenic, yet remains elusive to control by conventional lipid-lowering approaches. Despite the disappointing recent clinical trial failures, there remains considerable interest in the development of interventions that promote the protective biological activity of HDL. This is further supported by the demonstration that these metabolic states are associated not only with quantitative reductions in circulating HDL-cholesterol levels, but also the presence of functional impairment. As increasing interest has focused on the qualitative aspects of HDL, this may present novel approaches to the development of preventive therapies.
In parallel, there has been considerable interest in targeting inflammation, diabetes and obesity as the potential next step in cardioprotection. Yet to date, none of these approaches has been demonstrated to result in clinical benefit. Increasing elucidation of the specific molecular mediators of disease provide the potential to develop more precise approaches, yet it is difficult to know how to most effectively move such strategies through the pathway of clinical development to the point of the ultimate clinical outcome trial. While surrogate end points provide some opportunity, it is not always easy to know which of these markers are best for which agent. Given the large burden of disease and residual risk despite use of proven therapies, new agents are urgently needed.
The rise in atherosclerotic disease and its complications has important implications for the way we predict clinical risk. It is likely that the traditional approach, already less than optimal, will be less reliable in the setting of obesity. Whether we empirically treat all individuals or tailor the use of preventive therapies will require more effective methods to predict the risk of cardiovascular events. The development of novel blood-based and imaging biomarkers, potentially in combination, may provide a better strategy to tailor intensive treatment. Yet, no study has been performed that demonstrates how to effectively implement the use of these markers in practice.
While it is the individual that ultimately has the cardiovascular complication, the broader implication of the obesity pandemic is for the community as a whole. Increases in obesity, metabolic disease and atherosclerosis have a profound impact on society and will drive up healthcare expenditure. Healthcare systems urgently need to address the implications of obesity, many of which lie beyond the cardiovascular system. While for many the horse may have bolted, meaning use of high cost testing and pharmacologic therapies, the greatest societal benefit is still likely to be derived from interventions at an early stage to prevent obesity from the outset. Such systems talk a lot about the need for prevention of obesity and its consequences. The time to change from talk to action has arrived.
Financial & competing interests disclosure
SJ Nicholls has received research support from Amgen, AstraZeneca, Anthera, Eli Lilly, InfraReDx, LipoScience, Novartis, Resverlogix and Roche and is a consultant for AstraZeneca, Atheronova, Boehringer Ingelheim, CSL Behring, Eli Lilly, LipoScience, Merck, Resverlogix, Roche, Sanofi-Aventis and Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.