Moving toward combination lipid-lowering therapy for all patients with atherosclerotic cardiovascular disease

Evidence from hundreds of studies has established elevated low-density lipoprotein cholesterol (LDL-C) as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) [1]. It is evident that lowering LDL-C to far below 70 mg/dL reduces risk of future ASCVD events and remains safe. Statins and other lipid-lowering therapies (LLT) are therefore standard of care for patients with established ASCVD [2]. Despite the preponderance of evidence showing benefit of lowering LDL-C, utilization of lipid-lowering therapies and achievement of guideline-recommended LDL-C goals remain unacceptably inadequate. Among patients with ASCVD, 50% or less receive statins and one third or fewer achieve LDL-C goals below 70 mg/dL [3]. In conjunction with healthy lifestyle, lowering LDL-C remains one of the most effective ways to improve the health- and lifespans of populations with ASCVD and is therefore an urgent public health necessity.

There are many causes for poor utilization of LLT in clinical care, including clinical inertia, lack of knowledge, perceptions regarding side effects, and costs. Though work will be required on many fronts to address these issues and optimize ASCVD care, recommendations for combination LLT regardless of LDL-C could help address clinical inertia. The current treatment paradigm for ASCVD focuses on initiation of statin therapy, followed by rechecking labs with addition of supplemental LLT (e.g. ezetimibe and/or PCSK9 inhibitors) based on LDL-C and clinical risk factors. Though this framework should theoretically lead to optimal lipid-lowering in ASCVD patients, evidence suggests this course of action is the exception rather than the rule [4]. Furthermore, rates of adequate LLT and achievement of LDL-C goals are even lower in many patient groups such as women and those of non-white race [4,5].

Professional guidelines for other conditions such as hypertension, diabetes and heart failure with reduced ejection fraction have advocated for upfront combination therapy given clear efficacy of using multiple agents for these diseases. In contrast, current U.S. cholesterol guidelines recommend combination LLT only for patients with ASCVD deemed to be very high-risk. However, a relatively high percentage of patients with ASCVD are already very high-risk based on current guideline definitions (e.g. anyone ≥65 years old with hypertension and history of myocardial infarction would meet criteria for lower LDL-C goals in U.S. guidelines) [2]. Furthermore, it could be anticipated that most ASCVD patients are likely to move into the very high-risk category in the future, such as by simply getting older. Even in the more recently released American College of Cardiology expert consensus decision pathway for nonstatin therapies [6], use of combination LLT is only recommended if certain LDL-C thresholds are not met on statin monotherapy (<55 mg/dL for ASCVD patients at very high risk and <70 mg/dL for those not at very high risk). Recent European guidelines consider all patients with ASCVD as very high risk and endorse achieving an LDL-C goal of <55 mg/dL in this population [7,8]. Nevertheless, in practice this strategy often relies on reevaluating LDL-C only after statin monotherapy has been started. Given the real-world challenges with achieving LDL-C goals, it would be appropriate and certainly simpler to initiate combination therapy for lipid-lowering in all patients with ASCVD.

In order to adopt such an approach, the efficacy, safety, and cost of LLT agents needs to be considered. Statins are safe, effective and cheap medications which remain the mainstay of medical therapy for LDL-C lowering and secondary prevention of cardiovascular events; they should be administered to all patients with ASCVD based on Class I, Level of Evidence A recommendations [2]. Fortunately, there is a second effective, safe, and generic LLT option available - ezetimibe. Ezetimibe reduces LDL-C an average of 24% by inhibiting cholesterol absorption in the small intestine, thereby leading to upregulation of hepatic LDL-C receptors [9]. In the IMPROVE-IT trial, ezetimibe improved cardiovascular outcomes when added to statin therapy in patients with acute coronary syndrome within the preceding 10 days [9]. The Treat Stroke to Target Trial showed that using ezetimibe when needed to achieve LDL-C < 70 mg/dL reduced major cardiac events in patients with a recent ischemic stroke or transient ischemic attack [10]. More recently, the RACING trial showed that ASCVD patients treated with a combination of ezetimibe and moderate-intensity statin had similar outcomes compared with high intensity statin monotherapy; the combination LLT group also had a higher proportion of patients who achieved LDL-C < 70 mg/dL and lower rates of statin discontinuation and dose reduction [11].

As for safety, data from IMPROVE-IT, RACING, and 48 other smaller randomized clinical trials have not shown an increased risk of adverse events with ezetimibe compared to placebo [9,11,12]. This includes no increased risk of myalgias, neurocognitive events, or diabetes when taken with statin therapy. Based on this evidence, ezetimibe has a better safety profile than most medications used in combination therapy for hypertension, diabetes, and heart failure. Regarding cost, ezetimibe became widely generic in 2017 and can now be purchased in the U.S. for a total cost of under $5 per month [13]. Despite its efficacy, safety, low cost, and recommended use for many patients, ezetimibe is prescribed with statins in less than 5% patients with ASCVD [3].

Therefore, with a few exceptions such as in advanced age, there is more than enough evidence to support upfront combination LLT with statin and at least ezetimibe in all ASCVD patients. Notably, IMPROVE-IT is the largest clinical trial of ezetimibe and only enrolled patients at the time of acute coronary syndrome [9]. Compared to statin therapy alone statin therapy alone, combination therapy with ezetimibe and statin is therefore most likely to benefit ASCVD patients at highest risk of future events, particularly in the short term. Even so, increased use of ezetimibe would decrease LDL-C across larger and younger ASCVD patient populations. Given the preponderance of data demonstrating the positive impact LDL-C lowering has on clinical outcomes, this regimen would likely decrease risk of future cardiovascular events over longer time horizons. In light of the recent results from RACING, the addition of ezetimibe would also help maintain lower LDL-C levels amidst perceived concerns about statin side effects and subsequent dose reductions that occur all too frequently in real-world practice. Where generically available or otherwise low in cost, ezetimibe combined with a high-intensity statin in a single pill could help improve adherence to this regimen.

The PCSK9 inhibitors evolocumab and alirocumab are the other combination LLT options shown to reduce adverse cardiovascular outcomes in randomized trials of ASCVD patients. Though total and out-of-pocket costs as well as the need for subcutaneous injections may be limiting widespread uptake [14], these medications can reduce LDL-C by more than 50% when added to statins. They should be carefully considered as part of combination LLT in appropriately selected patients with ASCVD, such as those with extremely elevated LDL-C levels, multiple major ASCVD events, or very high-risk patients who do not achieve low LDL-C on maximally tolerated statin and ezetimibe [2]. Notably, initiation of PCSK9 inhibitors in patients hospitalized with acute coronary syndrome is safe and results in the vast majority of patients achieving LDL-C goals within weeks [15,16]. Other potential novel options for combination LLT, such as inclisiran and bempedoic acid, also significantly lower LDL-C though broad recommendations for use will need to be based on clinical outcomes in randomized controlled trials currently underway. Consideration of these newer nonstatin agents is addressed in the recent expert consensus decision pathway by the American College of Cardiology [6].

In summary, appropriate use of LLT and achievement of low LDL-C in patients with ASCVD remains poor, putting millions at increased risk of future cardiovascular events. In order to address gaps in care, minimize health disparities and simplify treatment decisions, combination LLT should be prescribed to nearly all patients with ASCVD (Fig. 1). In absence of true contraindications, statins should always be prescribed, ideally at high-intensity dosing. Generic ezetimibe is cheap, safe, and effective, and evidence strongly supports adding this agent to statins for patients with ASCVD regardless of age or other risk factors. Use of PCSK9 inhibitors should also be considered in selected patients based on risk assessment and cost considerations. Universal adoption of combination LLT for ASCVD is consistent with management of other chronic diseases, and should be a focal point of public health strategies for widespread prevention of morbidity and mortality.

Fig. 1.

Recommendations for Combination Lipid Lowering Therapy in Atherosclerotic Cardiovascular Disease.

Author contributions

All authors have reviewed and approved the manuscript being submitted. Specific contributions are detailed below.

KF Faridi: Dr. Faridi contributed to the conception and design of this commentary, manuscript drafting, and the critical revision of the manuscript. NR Desai: Dr. Desai contributed to the conception and design of this commentary, manuscript drafting, and the critical revision of the manuscript.

Funding

There was no funding for this manuscript.

Statement of disclosures

KF Faridi: Dr. Faridi receives research funding from the NIH/NHLBI (K23HL161424), outside the scope of this commentary.

NR Desai: Dr. Desai reports working under contract with the Centers for Medicare and Medicaid Services to develop and maintain performance measures used for public reporting and pay for performance programs. He reports research grants and/or consulting for Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, MyoKardia, Novartis, scPharmaceuticals, and Vifor Pharma.