NON-STATIN TREATMENT FOR CHOLESTEROL

This article was written in collaboration with Dr. John J.P. Kastelein, M.D., Ph.D., FESC.
Professor of Medicine, University of Amsterdam.

NON-STATIN THERAPIES FOR LDL CHOLESTEROL LOWERING

The role of statin in the treatment of patients with atherosclerotic cardiovascular disease (ASCVD) has been well demonstrated to lower major cardiovascular events. It is the number one recommendation by all the Guidelines including the American Heart Association and the American College of Cardiology. In addition, statins have been shown to prevent coronary disease and stroke in adults who have significant risk factors and have never had any coronary disease (CAD) or symptoms of CAD. The statin clinical trials have shown that LDL cholesterol is strongly associated with increased CVD risk. While several statins are available, moderate-intensity statins such as rosuvastatin 10 mg can lower the LDL cholesterol by an average of 35% and coronary events by almost 30%. 

SO, WHY DO WE NEED NON-STATIN THERAPIES FOR LDL CHOLESTEROL LOWERING?

Despite the 30 years of advances in lipid management and more patients being treated with a statin, approximately 70% of our patients still remain at risk of developing an ASCVD event: In the FOURIER analysis of patients with cardiovascular disease treated with a statin only or with a statin and a PCSK9 antibody (evolocumab), patients on statin only had 20% more cardiovascular events that included: MI, stroke or death. The ODYSSEY clinical trial demonstrated the benefits of another PCSK9 inhibitor, Alirocumab on a background of statin treatment in patients who experienced an MI or unstable angina episode and lowered the incidence of adverse events by 15%.  IMPROVE-IT clinical trial demonstrated that the addition of ezetimibe to simvastatin was superior in preventing adverse cardiac outcomes compared to simvastatin alone with an absolute reduction of cardiac events by 2%.

WHO IS LIKELY TO BENEFIT FROM NON-STATIN THERAPIES FOR LDL LOWERING?

It is important to match the intensity of LDL lowering to the patient’s level of risk so that the patients that are most at risk of ASCVD will benefit the most from non-statin therapies. 

Patients are considered to be at very high risk if they have had multiple ASCVD events such as a recent episode of unstable angina or MI, previous MI or stroke, or PVD. Other very high-risk patients include patients who have had any of these events in addition to multiple high-risk conditions such as DM, HTN, current smoking, CKD, history of prior PCI or CABG, older age group (>65 yo), very high LDL cholesterol (>190 mg/dL) or persistently elevated LDL cholesterol (>70 mg/dL) despite tolerated statin and ezetimibe. 

In patients without ASCVD but with primary severe hypercholesterolemia (LDL>190 mg/dL) such as familial hypercholesterolemia, the addition of non-statin therapies is recommended to statin treatment.

In patients without ASCVD and without DM, who have an intermediate 10-year risk of 7.5 to 20% and a residual LDL >70 to 189 mg/dL despite statin therapy and who have an elevated Calcium score (>100) or have other risk-enhancing factors such as a family history of premature ASCVD, metabolic syndrome, CKD, high-risk race/ethnicities (South-Asian ancestry), chronic inflammation (rheumatoid arthritis, psoriasis, HIV and long-covid), other lipids/biomarkers such as high C-reactive protein, elevated Lp (a), elevated apoB (>130 mg/dL) or ABI <0.9.

Finally, truly statin-intolerant patients probably comprise 5-10% of the patient population. It is important to adhere to evidence-based statin treatment and the complete discontinuation of statin is discouraged. The most encountered side effect is muscle symptoms which tend to be symmetrical myalgias or weakness in large proximal muscle groups. Other causes such as hypothyroidism, Vitamin D deficiency, or recent strenuous exercise should be ruled out. Some patients, such as women, Asians, and the elderly, are more prone to develop statin-associated muscle symptoms. Interaction with other medications or food needs to be considered particularly amiodarone, diltiazem, or grapefruit which can alter the metabolism of statin.  Very often, after a period of discontinuation of statin, a low dose of rosuvastatin, 5 mg per week can be restarted and increased progressively either in dosage or frequency. When all fails, it is time to consider non-statin therapies

WHAT ARE THE NON-STATIN AGENTS TO BE CONSIDERED FOR LDL LOWERING?

Ezetimibe inhibits the absorption of cholesterol at the level of the small intestine cells and usually lowers the LDL cholesterol by 15-20%. When taken in combination with a low-dose statin (simvastatin 40 mg), it can lower the risk of MI or stroke as demonstrated in IMPROVE-IT (6% lower than simvastatin alone).

PCSK9 inhibitors given as antibodies include evolocumab and alirocumab. They bind to the PCSK9 receptor and increase the number of LDL receptors available to clear circulating LDL cholesterol. They are administered as an SC injection every 2 weeks or every month. In the FOURIER trial, evolocumab lowered the LDL cholesterol by an average of  59% to a median level of 30 mg/dL and reduced combined major cardiovascular events by 15% compared to statin alone, but it did not reduce cardiac mortality. In the ODYSSEY study, alirocumab dose was adjusted to lower the LDL to 25-50 mcg/dL and when given in addition to a maximally tolerated statin in patients recovering from an acute coronary syndrome, reduced the mortality and MI by 15% compared to statin alone.

Bempedoic acid (Nexletol) is a pro-drug for oral administration with activation inside the liver cell and not in the muscle cell. This could be considered an advantage in patients with statin-associated muscle symptoms, although tendon rupture has been reported and gout arthritis can be exacerbated. It is a small molecule that inhibits the synthesis of cholesterol, leading to the upregulation of the LDL receptor and increased LDL clearance. Bempedoic acid at 120 mg daily can lower the LDL cholesterol by 25%. It can be combined with ezetimibe and lower the LDL-C by 38%. The CLEAR outcomes trial of over 14,000 patients with or at high risk for ASCVD, statin-intolerant, and LDL >100 mg/dL was just completed in 2022 and results will be presented at the ACC this March.

Inclisiran, a long-acting, small interfering RNA (siRNA) molecule that reduced the production of PCSK9 through gene silencing, thereby up-regulating LDL receptor density on the liver cell and increasing LDL-C clearance. The recommended dosage in addition to maximally tolerated statin is 300 mg SC initially, again at 3 months, and then every 6 months thereafter. In the ORION clinical studies, the LDL-C was reduced by an average of 50%. ORION-4 and VICTORION-2P will enroll 15,000 patients each, with patients with ASCVD on a high-intensity statin and LDL-C >100 mg/dL for ORION and > 70 mg/dL for VICTORION-2P. These trials are still in the enrollment phase. 

Obicetrapib, a CETP inhibitor, is being evaluated for the treatment of patients with ASCVD and persistent elevation of LDL-C despite maximally tolerated statin. The TULIP study of 364 patients taking a statin and treated with a placebo, 5 and 10 mg daily of Obicetrapib. The average LDL-C was lowered by 45%, the HDL-C was raised by 157%, and apoA1 increased by 57% with a significant increase in HDL efflux capacity. Several outcomes studies are being conducted in patients with ASCVD who are not adequately controlled despite maximally tolerated lipid-lowering therapy (PREVAIL) or in patients with familial hypercholesterolemia (HeFH) as an adjunct to diet and maximally tolerated lipid-lowering therapies (BROOKLYN) and in patients with ASCVD (BROADWAY)

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