Evidence for LDL-C, Statins, and Nonstatins
Elevated low-density lipoprotein cholesterol (LDL-C) plays a causal role in atherosclerotic cardiovascular disease (ASCVD). Reducing lifetime exposure to LDL-C lowers risk for ASCVD.¹ Statins remain first-line lipid-lowering therapy for ASCVD risk reduction. Optimal responses to moderate- and high-intensity statins are LDL-C reductions of 30–49% and ≥50%, respectively. Although many patients achieve lipid-lowering goals with high-intensity statins, certain patients do not have an optimal response because of genetic issues, intolerance, nonadherence, or therapeutic inertia. Over the past decade, clinical trials have provided strong evidence demonstrating the effectiveness and safety of nonstatin medications added to statin therapy in high-risk patients. Current clinical guidelines still recommend using statin monotherapy titrated to the highest tolerated dose to reach the goals set for the specific level of risk before considering combination lipid-lowering therapy.²

Multiple clinical trials and meta-analyses have shown that the primary determinant in ASCVD risk reduction is the absolute reduction in LDL-C. Every 1.0-mmol/L (38.7-mg/dL) reduction in LDL-C is associated with a 23% relative risk reduction in major ASCVD events.³ In the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), ezetimibe added to moderate-intensity statin reduced LDL-C and ASCVD endpoints compared with statin monotherapy in patients with recent acute coronary syndromes (ACS).⁴ IMPROVE-IT was the first randomized controlled trial to demonstrate reduction in ASCVD outcomes when a nonstatin agent was combined with a statin in very-high-risk patients, with increasing benefit across increasing risk categories.⁵ The Further Cardiovascular Outcomes Research with proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibition in Patients with Elevated Risk (FOURIER) trial showed safety and efficacy of adding evolocumab to statin in ASCVD patients with LDL-C >70 mg/dL on optimized lipid-lowering therapy.⁶ ODYSSEY OUTCOMES showed that targeting an LDL-C level of 25–50 mg/dL with alirocumab reduced the number of ASCVD events by 15% in patients with recent ACS.⁷

New Guidelines with Thresholds and Targets
The results of these studies further validate the fact that lowering LDL-C is fundamental to preventing ASCVD events. Based on these findings, the 2019 European Society of Cardiology and European Atherosclerosis Society (ESC/EAS) guidelines defined new LDL-C targets according to patient risk; for very-high-risk patients, the LDL-C target is <55 mg/dL.⁸ The 2018 American Heart Association/American College of Cardiology guidelines recommend adding nonstatin agents to statin in very-high-risk ASCVD patients with LDL-C ≥70 mg/dL.²

Gaps — Failure to Use High-Intensity Statins and Combination Therapies
Despite proven pharmacologic options for lowering LDL-C and ASCVD risk, a large gap remains between guideline-recommended LDL-C targets and clinical practice. In the EU-Wide Cross-Sectional Observational Study of Lipid-Modifying Therapy Use in Secondary and Primary Care (DA VINCI), the majority of European patients with ASCVD were on either moderate-intensity statin or high-intensity statin; only 9% were on statin plus ezetimibe and only 1% were on combination therapy that included a PCSK9 inhibitor. In very-high-risk patients, 2019 ESC/EAS guideline–recommended LDL-C goal was achieved in 22% of patients on high-intensity statin monotherapy, 21% of patients on statin + ezetimibe, and 58% of patients on combination therapy including a PCSK9 inhibitor.⁹ Although these data reflect practices with specialized interest in ASCVD risk reduction, real world data on LDL-C reduction can be significantly worse. In a European retrospective study with >14,000 patients, approximately 80% of patients had LDL-C >70 mg/dL on moderate- to high-intensity statin. Despite inadequate LDL-C goal achievement, most patients did not have a change or titration in their regimen.¹⁰ In the United States, comparable data from the Getting to an Improved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management (GOULD) registry indicated that lipid-lowering therapy was intensified in only 14% of patients with ASCVD and LDL-C ≥70 mg/dL; statin was intensified in 6.3%, ezetimibe was added in 4%, and PCSK9 inhibitor was added in 2%.¹¹

Combination Therapy is More Effective than Monotherapy
Combining statins with ezetimibe, monoclonal antibody PCSK9 inhibitors, bempedoic acid, or inclisiran has additive effects on LDL-C reduction (Table 1),^12-15 whereas doubling statin dose provides only approximately 5–6% additional LDL-C reduction. Like data on antihypertensive treatments, fixed-dose combination tablets have been shown to lower LDL-C more effectively than two separate tablets.^16,17 Bempedoic acid combined with statin lowers LDL-C effectively¹⁸ and has the potential for improving cardiovascular outcomes. Fixed-dose combination tablets are available with atorvastatin plus ezetimibe, rosuvastatin plus ezetimibe, and bempedoic acid plus ezetimibe.

Table 1: Additional LDL-C % reduction for statin combined with nonstatin compared with statin monotherapy

Agent	LDL-C reduction vs statin
Ezetimibe	20–25%4
Bempedoic acid	45–55%18
Evolocumab, alirocumab	50–60%6,7
Inclisiran	50%15

Combination lipid-lowering therapy has several benefits. The incremental increase in LDL-C lowering likely results from the synergistic effect of targeting multiple pathways of lipid metabolism. While statins target hepatic cholesterol synthesis, ezetimibe inhibits cholesterol absorption in the small intestine and PCSK9 inhibitors increase LDL receptor bioavailability. These combined effects provide similar, and often improved, LDL-C–lowering efficacy with lower statin doses. Achieving the same clinical benefit with lower-intensity statin reduces the risk for side effects (muscle symptoms, insulin resistance) and therefore then leads to improved tolerability and adherence.¹⁹ Previously, cost-effectiveness limited the use of PCSK9 inhibitors in real world settings, but in 2018 and 2019, costs of PCSK9 inhibitors were reduced by 60%, reducing this barrier to adherence.

Conclusion
Given the advances in medical therapy for LDL-C reduction, initiating combination therapy early will help to reduce the risk for ASCVD. Fixed-dose combinations of statins plus ezetimibe, and combinations including PCSK9 inhibitors, have been shown to be safe and more effective than statin monotherapy in lowering LDL-C and reducing ASCVD events. With the exceptional amount of evidence demonstrating the causality of LDL-C in atherosclerosis and LDL-C lowering as the mechanism for ASCVD risk reduction in trials of lipid therapy, we believe that the current therapeutic model focused on the intensity of statin therapy should shift to a model focusing on the intensity of LDL-C reduction. Just as the guidelines for treatment of hypertension recommend early initiation of combination therapy for blood pressure control in high-risk individuals, we also recommend early initiation of combination therapy for LDL-C control in very-high-risk individuals and in patients with very high LDL-C such as in familial hypercholesterolemia.

References

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Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins, Prevention

Keywords: Antibodies, Monoclonal, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Antihypertensive Agents, Cholesterol, LDL, PCSK9 protein, human, Proprotein Convertase 9, Ezetimibe, Simvastatin Drug Combination, Retrospective Studies, Atorvastatin, Rosuvastatin Calcium, Cardiovascular Diseases, Acute Coronary Syndrome, American Heart Association, Biological Availability, Blood Pressure, Cost-Benefit Analysis, Cross-Sectional Studies, Insulin Resistance, Lipid Metabolism, Risk, Dyslipidemias, Atherosclerosis, Hyperlipoproteinemia Type II, Outcome Assessment, Health Care, Risk Reduction Behavior, Receptors, LDL, Primary Health Care, Subtilisins, Registries

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