Lipid Luminations: New Evidence For Non-Statin Lipid-Lowering Medications

The American College of Cardiology/American Heart Association (ACC/AHA) Blood Cholesterol Guideline recommends high-intensity statin therapy for high-risk patients to reduce the risk of major adverse cardiovascular events (MACE).¹ Despite treatment with high-intensity statins, patients continue to experience MACE. Additionally, some patients have a less-than-anticipated response to, or are unable to, tolerate high-intensity statins. Whether additional non-statin lipid-lowering therapies further reduce the risk of MACE in these patients has not been extensively studied. Several trials investigating the benefit of non-statin lipid-lowering medications in addition to statins have been published since publication of the ACC/AHA guideline and provide new information for managing high-risk patients.^2-4

The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) compared simvastatin 40 mg/placebo to simvastatin/ezetimibe in patients with low-density lipoprotein cholesterol (LDL-C) of 50-100 mg/dL and recent acute coronary syndrome.² The simvastatin/ezetimibe group had a 6 percent reduction in the primary outcome of MACE vs. the simvastatin/ placebo group (hazard ratio (HR): 0.936; 95 percent confidence interval (CI), 0.89-0.99; p=0.016). The mean LDL-C level attained at one year was significantly lower in the simvastatin/ezetimibe vs. simvastatin/placebo group (53.2 vs. 69.9 mg/dL; p<0.001) with similar rates of adverse effects in both groups. Although IMPROVE-IT used moderate-intensity statin in a population recommended to receive high-intensity treatment, the results of IMPROVE-IT may apply to high-risk patients unable to tolerate high- intensity statins and those at increased risk of statin intolerance. IMPROVE-IT also supports the hypothesis that attaining lower LDL-C with additional non-statin lipid-lowering medication results in lower MACE.

Clinical trials with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are underway to further test the LDL-C lowering hypothesis. Two of the first clinical trials evaluating PCSK9 inhibitors, Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events (ODYSSEY LONG TERM)³  and Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER)⁴  reported significant reductions in LDL-C in patients treated with PCSK9 inhibitor vs. placebo. Although not a primary outcome, both studies reported significant reductions in MACE in patients receiving PCSK9 inhibitors compared to placebo.

In ODYSSESY LONG TERM, patients at high-risk of MACE receiving maximally- tolerated statin and an LDL-C >70 mg/dL were randomized to receive alirocumab or placebo. At 24 weeks, the LDL-C reduction from baseline was 62 percent with alirocumab (mean LDL-C: 48 mg/dL) vs. 0.8 percent with placebo (mean LDL-C: 118 mg/dL). Post-hoc analysis demonstrated a significantly lower rate of MACE with alirocumab compared to placebo at 78 weeks (HR: 0.52; 95 percent CI, 0.31-0.90; p=0.02).

Similar reductions in LDL-C and MACE were reported in the OSLER trial.⁴ Patients with or without current statin treatment and a median LDL-C of 120 mg/dL were randomized to evolocumab or placebo. At 12 weeks, the evolocumab group attained a 61 percent reduction in LDL-C from baseline (median attained LDL-C: 48 mg/ dL) compared to placebo. Prespecified exploratory analysis of MACE at 1 year favored treatment with PCSK9 inhibitor vs. placebo (HR: 0.47; 95 percent CI, 0.28-0.78; p=0.003).

While previous trials failed to show clinical benefit from adding non-statin lipid-lowering therapies (niacin and fibrates, specifically) to statins vs. statins alone, the medications used in these studies primarily improved high-density lipoprotein cholesterol and triglycerides as opposed to LDL-C.^5-7 The differences in LDL-C between groups at study end were at the most 10 mg/dL.⁷ Alternatively, LDL-C reductions between groups were significant in IMPROVE-IT, ODYSSEY LONG TERM and OSLER suggesting  that further LDL-C reduction reduces risk of MACE in high-risk patients. Updates to the current ACC/AHA guidelines should recommend adding non-statin lipid- lowering medications (ezetimibe and/or PCSK9 inhibitors) to maximally-tolerated statin in order to further lower LDL-C in high-risk patients unable to tolerate high-intensity statin or for those who demonstrate a less-than-expected LDL-C reduction despite maximally-tolerated statin.

Disclosure statement: Dr. Kelly has no disclosures to report. Dr. Olson has no disclosures to report.

References are listed on page 35.