Cardiovascular disease is the number one cause of death in the United States, more than all cancers combined. In the United States, ten times as many women die of heart disease as die of breast cancer. What is equally concerning is that cardiovascular disease is largely preventable, whereas for many cancers, genetic etiology and effective therapy are still challenging. The article by Sakhuja et al. [1] in this issue of Cardiovascular Drugs and Therapy clearly demonstrates the problem facing physicians, i.e., compliance and adherence with prescribed anti-atherosclerotic therapy, primarily statins. As recently detailed, the exaggerated criticisms of statin’s side effects by social media have cost thousands of lives [2]. This statement is supported by the large number of individuals with proven cardiovascular disease who fail to achieve guideline-recommended low-density lipoprotein cholesterol (LDL-c) goals achievable with current statin therapy.

Sakhuja and coworkers [1] have examined two large databases (Medicare and Market Scan databases) to determine how many patients who have experienced a cardiovascular event are adhering to guideline-recommended anti-hyperlipidemic medications. They have also calculated the potential consequences of patients who are not adhering to recommended therapy. Inadequate compliance includes failure of appropriate discharge planning, patient fear of adverse medication effects, and inability to afford the medication. Whatever the reason(s), the consequences are the same—potentially avoidable recurrent cardiovascular events. The solution to this issue is challenging because of the multiplicity of underlying causes. The authors should be congratulated on a thorough assessment of both available databases and for estimating the large number of cardiovascular events that could be prevented. Combining both databases of approximately 230,000 patients with hospitalization for a myocardial infarction between 2018 and 2019, only 27% were receiving guideline-recommended cholesterol-lowering therapy. They estimate that if all patients were receiving this therapy, then a 22% relative risk reduction would occur in the 3-year period following the discharge from the initial cardiovascular event. Not only does this number indicate an unacceptable number of patient deaths, but the cost to society is staggering. In a separate analysis that included 2,294,244 patients who underwent PCI, the mean cost per patient was $23,541 (~ $10.8 billion/year) [3]. Another statistic reported by the authors is the number of recurrent cardiovascular events occurring even if adherence to medication was excellent and the therapeutic goal was obtained. The authors estimate that 19.8% of these 279,395 patients (55,320) would still have a recurrent atherosclerotic event occurring in the 3 years following the initial hospitalization, in spite of all patients reaching therapeutic guideline goals.

Even if all patients with clinical cardiovascular disease decide to comply with therapy, many patients will still have a second or third cardiovascular event. Therefore, LDL-c lowering therapy according to published guidelines would not be sufficient for thousands of individuals. This fact leads to another important question, i.e., is there an alternative approach to eradicate cardiovascular disease? One approach is to increase the removal of cholesterol arterial plaques by infusing apolipoprotein A (the principal protein in the high-density lipoprotein cholesterol particle). However, studies have not demonstrated that this approach reduces cardiovascular events. A second approach is to prescribe semaglutide. This approach is beneficial but expensive. Another approach is to prevent cardiovascular disease from progressing from subclinical to clinical cardiovascular disease [4]. For almost every disease, prevention is superior to treatment of established disease. This observation is true not only for improved patient health but also for society in savings of lost resources and productivity.

During the last decade, much has been learned about the pathogenesis of coronary disease. Atherosclerosis starts at birth, continues throughout life, and is greatly influenced by lifestyle and heredity. In addition, atherosclerosis is a progressive disease that causes years of minor vascular insults before manifesting itself as a clinical event. The principal atherosclerotic risk factors and how they promote progressive vascular disease are well-documented. Most importantly, numerous investigations have shown that atherosclerotic plaques (in the coronary arteries and elsewhere) are reversible when risk factors are significantly reduced (Fig. 1) [5]. This information provides a roadmap on how cardiovascular disease can be prevented before a clinical event occurs.

Fig. 1
figure 1

Reproduced with permission from reference [5]

Reversal of atherosclerosis with statin therapy as measured by intravascular ultrasound. The progressive removal of cholesterol from atherosclerotic plaques will increase the lumen and decrease the chance of plaque rupture (increased plaque stability).

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Prevention of cardiovascular disease requires an appreciation of the major contributors to atherosclerotic plaque formation. Previous randomized controlled studies have suggested that LDL-c was the prime instigator of cardiovascular disease. This may be true in individuals with very high LDL levels (i.e., homozygous, heterozygous, or combined hypercholesterolemia), but for a large number of individuals with cardiovascular disease events, other factors need to be measured and addressed. Both inflammation and lipoprotein a (Lp[a]) can be equally or more important than LDL-c. Furthermore, in contrast to current dogma, triglycerides per se are not atherogenic, but the remnant cholesterol that remains after triglyceride metabolism may also need to be addressed.

There are four steps the physician should take to prevent clinical cardiovascular disease (Fig. 2). First, a thorough history and physical exam plus measurement of proven cardiovascular disease risk factors will provide a guideline to the next step. Utilization of the American College of Cardiology Risk Estimator Plus may also be helpful. Second, an assessment of the current anatomical state of the patient’s coronary arteries by non-invasive techniques is warranted. Both computerized tomography (CT) angiography and coronary artery calcium scoring may be used depending on the resources available [6]. Calcium scoring has the advantage of minimal radiation, low cost, minimally required resources, and excellent patient acceptability. However, CT angiography is better at defining specific arterial lesions if invasive procedures are anticipated. Exercise treadmill testing is too insensitive to accurately describe the quantity of atherosclerosis present. The third step in preventing atherosclerosis is to significantly reduce atherosclerotic risk factors to allow for atherosclerotic plaque reversal. This usually requires a change in lifestyle and aggressive treatment of hyperlipidemia, hypertension, diabetes, and smoking cessation. Referral to the appropriate support groups and/or specialists for treatment of these conditions is often warranted. The role of the cardiologist is to alert the patient to the potential future danger of a cardiovascular disease event and to convince the patient that his/her atherosclerotic disease is reversible. When the patient is aware of the presence of atherosclerotic plaques in his/her heart arteries, compliance with risk factor medication is increased [7]. The fourth step is periodic monitoring of the patient’s response and ongoing risk factors. As a person ages and encounters new obstacles and stresses (e.g., menopause, medical comorbidities, mental aging), metabolic indices change. In addition, good compliance requires reminding the patient of his/her subclinical cardiovascular disease and the consequences of not adhering to treatment. For individuals with zero calcium scores, aggressive therapy may not be urgently necessary, but retesting should be done every 4 to 5 years depending on the severity of risk factors. Sequential yearly calcium scoring studies have demonstrated that at 4 years, 15% of zero calcium scores will turn positive, and at 5 years, 25% will be positive [8]. Repeating a calcium score in individuals who are already positive is unnecessary. Calcium scores do not decline, and some medications (i.e., statins), increase the score but reduce the cardiovascular risk. Calcium in an atherosclerotic plaque is not harmful and may stabilize the plaque.

Fig. 2
figure 2

The four steps necessary to reverse subclinical atherosclerotic plaques. Lp(a), lipoprotein (a); hsCRP, high-sensitivity C-reactive protein; CT, computed tomography; Chol, cholesterol; Rx, treatment

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Understanding known metabolic risk factors and the approved therapies is a challenge when new therapies are available each year. Published guidelines can be helpful, although one of their limitations is the several years’ duration between updates. In addition, with at least 20 different professional organizations publishing guidelines, disagreement among organizations can be confusing [9]. Measuring and addressing proven metabolic risk factors of LDL, Apo (a), and inflammation (as C-reactive protein) is the initial starting place.

The largest database of clinical trials for the benefit of reducing a risk factor is for LDL-c. Underappreciated is the role of diet in achieving an LDL goal [10]. This low-cholesterol diet does not involve weight loss, making it very acceptable to patients. It focuses on reducing the quantity of cholesterol in the diet. Since plants cannot produce cholesterol, individuals primarily consuming a plant-based diet have both lower LDL levels and lower cardiovascular events. The addition of statins plus a low-cholesterol diet almost always achieves a guideline goal. In addition, the optimal use of statins to lower LDL-c has recently been reviewed [11].

The importance of inflammation as measured by high-sensitivity C-reactive protein (hsCRP) has been emphasized by Ridker [12]. In the Women’s Health Initiative study, this risk factor was more important than LDL-c in predicting future cardiovascular disease events. Both statins and ezetimibe lower hsCRP, and this may be the principal mechanism by which they reduce cardiovascular disease.

The third metabolic risk factor to monitor is Lp(a) [13]. This risk factor is primarily determined by heredity, so measuring it more than once is not required. Lp(a) is an LDL particle that also contains a variable number of amino acid side chains (kringles) that result in increased thrombogenesis. This particle has been identified in atherosclerotic plaques. Because it contains an LDL particle, it is variably measured in LDL-c assays. It is one reason that some patients do not respond to statin-induced LDL-c lowering, since statins may increase its concentration. However, medications that block or inhibit PCSK9 protein (inclisiran or antibodies against PCSK9) lower Lp(a) by approximately 30%, at least acutely. Studies are currently underway to demonstrate whether lowering Lp(a) will reduce cardiovascular disease events.

If the patient has a strong family history of cardiovascular disease and an LDL-c greater than 180 mg/dl, genetic testing may be warranted for four reasons. First, it explains to the patient why his/her LDL-c is elevated. Second, the result may indicate that family members should also be tested with a lipid profile and other metabolic risk factors. Third, if a genetic abnormality is identified, insurance coverage for anti-hyperlipidemic medications is usually much more readily obtained. Fourth, the result may indicate which hypolipemic therapy would be optimal for the patient.

What LDL-c should be the goal of therapy? This depends on which guideline(s) the physician chooses to follow. Patients respond better when they agree to a specific goal. From a preventive standpoint, the lower the LDL-c, the better the outcome. Potential hazards of very low LDL-c have not been confirmed. Published guidelines do not specifically state the extent to which risk factors must be decreased in order to reverse atherosclerosis (i.e., reverse cholesterol plaques). Studies utilizing intravenous ultrasound monitoring of atherosclerotic plaques have shown that when the LDL-c is reduced by statins to a level between 70 and 80 mg/dl, approximately 50% of plaques regress and 50% increase [14]. Assuming that the response to statins follows a bell-shaped curve, then an LDL-c goal of below 55 mg/dl is reasonable. Several recent guidelines have chosen this level for high-risk individuals. This is the level of LDL-c that most individuals have at birth. Taking this approach in the outpatient clinic population is not only feasible but it has also been shown to be effective in preventing cardiovascular events [15].

Reducing the incidence of cardiovascular disease should be the goal of every physician. The American Heart Association estimates that current expenditures for the treatment of cardiovascular disease approximate $350 billion per year, and this figure will triple by 2030. With the current knowledge of the pathogenesis of this disease and the availability of effective medications to prevent atherosclerotic plaques, reversing preclinical atherosclerosis should be a very high priority. The famous statement by Benjamin Franklin in 1736 that “an ounce of prevention is worth a pound of cure” can readily be applied to cardiovascular disease.