Comprehensive evaluation of atherosclerotic cardiovascular disease (ASCVD) risk is the foundation of preventive cardiology. Accurate assessment of ASCVD risk facilitates shared decision-making regarding lifestyle interventions, medical therapy and goals of care. While many risk factors for ASCVD are well-established, emerging data have uncovered new opportunities for cardiovascular risk reduction.

Advances over recent decades have revolutionized ASCVD risk factor management. Antihypertensive therapy and more aggressive treatment goals have led to improved blood pressure control. Tobacco cessation campaigns and interventions have led to significant reductions in tobacco use. The statin story is well known, and these agents are largely considered the most effective foundation of ASCVD prevention. However, the statin mega-trials demonstrated a 30-40% reduction in ASCVD events, leaving most patients still at risk for recurrent events. The advent of additional therapies to lower LDL-C such as ezetimibe and, particularly, PCSK9 inhibitors have transformed lipid management and prevention of ASCVD.

Yet, the number of ASCVD events remain high.¹ This suggests residual risk factors are contributing significantly to the evolution and progression of ASCVD. Here is a survey of some of the key drivers of residual ASCVD risk.

Residual Inflammatory Risk

Systemic inflammation has a well-established relationship with development of atherosclerosis and subsequent ASCVD events. The relationship between measures of inflammation and ASCVD, high-sensitivity C-reactive protein (hsCRP) and interleukin (IL)-1β and IL-6, has been considered in multiple studies. Recent clinical trials have gone beyond association to demonstrate that targeting inflammation facilitates ASCVD risk reduction.

Canakinumab, a direct IL-1β inhibitor, reduced major adverse cardiovascular events in individuals with prior myocardial infarction (MI) and hsCRP >2 mg/L vs. placebo.² It may also reduce heart failure hospitalizations in patients with a previous MI.^3,4 This benefit comes at the cost of increased neutropenia and death secondary to sepsis.³ Low-dose colchicine, another anti-inflammatory drug, improved cardiovascular outcomes in several trials,^5-8 and may even prove to be practical, cost-effective preventive measure in the future.

Residual Thrombotic Risk

As ASCVD events are atherothrombotic, thrombotic risk has been an intense area of research. Antiplatelet therapy for secondary prevention following development of cardiovascular disease has become the standard of care. However, the role of routine anticoagulation use has been less studied.

The findings from two trials have made a case for low-dose anticoagulation for secondary prevention.^9,10 Both trials showed that adding low-dose rivaroxaban to aspirin for secondary prevention led to improvement in cardiovascular outcomes, but at the cost of increased bleeding risk. These data suggest a role for anticoagulation as an adjunct to aspirin secondary prevention in patients with low bleeding risk, particularly in those with polyvascular disease (where ASCVD risk is highest).

Residual Metabolic Risk

Statins and PCSK9 inhibitors have transformed lipid management. Beyond LDL-C, other atherogenic lipoproteins appear to be an important source of residual ASCVD risk. Additionally, two newer diabetes medications show promising ASCVD risk reduction.

Triglycerides

The association between plasma triglyceride concentrations and ASCVD are well known. Until recently, there was no evidence that targeting triglycerides with specific triglyceride-lowering drugs improved cardiovascular outcomes. Most recently, the use of high-dose, purified eicosapentaenoic acid (EPA) in patients with elevated triglycerides (135-500 mg/dL) on statin therapy and either ASCVD or diabetes reduced ASCVD events.¹¹ Interestingly the benefit of high-dose EPA was not related to baseline or attained triglyceride levels.

Lipoprotein(a)

Lipoprotein a (Lp[a]) is an LDL-like particle with an additional glycoprotein (apolipoprotein(a)) bound to its apolipoprotein B-100 moiety. Besides its lipid cargo, Lp(a) particles also serve as a repository for plasma oxidized phospholipids and share structural homology with plasminogen. As a result, Lp(a) exerts pro-atherosclerotic, anti-fibrinolytic and pro-inflammatory properties. The observational and genetic epidemiology demonstrate a close relationship between Lp(a) with ASCVD and calcific aortic stenosis. A novel antisense oligonucleotide targeting apolipoprotein(a) mRNA is safe and lowers plasma Lp(a) concentration by approximately 80%.¹² It is currently being investigated in a large cardiovascular outcomes trial.

Diabetes

Diabetes is a well-known risk factor for ASCVD. Until recently, medications used to treat diabetes improved hyperglycemia but did not specifically improve cardiovascular outcomes. There are now two distinct classes of diabetes medications, sodium-glucose transporter 2 inhibitors (SGLT2i) as well as glucagon-like peptide 1 agonists, that demonstrate impacts on a range of cardiovascular outcomes and mortality.^13–18 Moreover, the SGLT2i demonstrate benefit for management of heart failure with reduced ejection fraction independent of diabetes status.¹³ The recent developments in diabetes therapies have been remarkable and are poised to transform the prevention of cardiovascular disease.

Preventive cardiology is clearly in a renaissance. We now have a much greater understanding of residual risk factors and have the tools to target many of them. Diagnosis and management of key residual cardiovascular risk factors are crucial for optimizing prevention of ASCVD.

This article was authored by Trevor Caldarera, MD, internal medicine resident, and This article was authored by Trevor Caldarera, MD, internal medicine resident, and Michael D. Shapiro, DO, MCR, FACC, (@DrMichaelShapir), Fred M. Parrish Professor of Cardiology and Molecular Medicine, both at Wake Forest University, in North Carolina., (@DrMichaelShapir), Fred M. Parrish Professor of Cardiology and Molecular Medicine, both at Wake Forest University, in North Carolina.

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