INTRODUCTION

Over the last few decades, low-density lipoprotein (LDL) has been established as the main perpetrator of atherosclerotic cardiovascular disease (ASCVD), and statin has been established as the main therapy to reduce LDL.

However, LDL targets, as determined by various risk score models, are not always achievable by statins alone. Also, some patients have various forms of statin intolerance, where alternative therapies are required. Again, in certain situations, LDL may not be the primary lipid abnormality, but triglyceride (TG), high-density lipoprotein (HDL), lipoprotein(a) (Lpa), and very low-density lipoprotein (VLDL) may be the main culprit.

Many nonstatin drugs have been developed to treat these conditions. Some are backed by good evidence, and some others are still in the process of development.

NONSTATIN DRUGS

    Fibrates

Fibrates activate peroxisome proliferator-activated receptors, lower hepatic apolipoprotein C-III (apoC-III) production, increase lipoprotein lipase-mediated lipolysis, reduce synthesis and increase catabolism of fatty acids, and may reduce inflammation. All these lead to reduced TG and VLDL and increase of HDL. Fasting TG is reduced to the tune of 30–45%, and HDL may increase by 10–15%, along with a modest (10–15%) reduction of LDL. However, they raise plasma homocysteine and creatinine levels.

In the Helsinki Heart Study of primary prevention, gemfibrozil reduced myocardial infarction (MI) by 34%. However, FIELD trial, done in diabetic subjects, with fenofibrate was negative. In ACCORD trial of fenofibrate in diabetics on statin therapy, benefit was shown only when baseline TG was above 204 mg/dL and HDL was below 34 mg/dL. The stain fibrate combination increases the renal and hepatic side effects.

    Niacin

Niacin was tried before statin and initial result was negative. By the time, the Coronary Drug Project (CDP) long-term data showed its efficacy, statins have been firmly established as the first-line therapy to reduce LDL. The side effect profile of niacin never made it a popular drug.

    Bile Acid Sequestrants

Bile acid sequestrants (BASs), e.g., cholestyramine, colestipol, and colesevelam, reduce serum LDL by binding to bile acids in the gut, thereby interrupting enterohepatic circulation and depleting hepatic cholesterol. BASs also reduce blood glucose levels modestly.

They reduce LDL by up to 30% and may increase HDL by 10%. But, they may raise TG levels.

Though they showed clinical event reduction in the trials, BASs were never widely recommended due to their adverse effect profile and drug–drug interactions. They are still used during pregnancy where satins are contraindicated.

    Ezetimibe

Ezetimibe reduces absorption of cholesterol of diet and bile by the small intestine by inhibiting Niemann-Pick C1-Like 1 (NPC1L1) protein located at the enterocyte brush border membrane. Used alone they reduce LDL by 10%, but with statin, it reduces LDL by further 14–18%.

In the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), ezetimibe with statin reduced cardiovascular (CV) events by 2% absolute value compared to statin alone after an acute coronary syndrome (ACS) within 10 days of randomization (p = 0.016). In some trials, adding ezetimibe to atorvastatin achieved target LDL more frequently than doubling the dose of atorvastatin.

    Bempedoic Acid

Bempedoic acid (BA) inhibits adenosine triphosphate (ATP)-citrate lyase (ACL) and thus reduces levels of acetyl-CoA in liver which up regulates LDL-C receptors on hepatocyte surface to enhance LDL clearance from blood. Unlike statins, it does not cause myopathy. It also reduces high-sensitive C-reactive protein (hsCRP) level.

The CLEAR series of trials tested efficacy and safety of BA in statin intolerant patients or in patients with heterozygous familial hypercholesterolemia (HeFH). The pooled analysis of all these trials showed a “clear” evidence of LDL reduction by 17–25% with slightly higher incidence of hyperuricemia. ApoB and hsCRP reduction was also significant.

The cardiac event reduction was shown recently in the CLEAR OUTCOME trial, where, in statin naïve patients of high CV risk or having CV disease, BA significantly reduced three-point major adverse cardiovascular events (MACEs) by 13% (p = 0.004) compared to placebo. Tendon rupture is a known side effect of the drug.

    Omega-3 Fatty Acids

Omega-3 fatty acids (O3FAs) [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] reduce TG levels by 25%. They are naturally found in fatty fish. In the REDUCE-IT study with CV disease patients or high risk diabetic patients on statin (with or without ezetimibe), the primary endpoint of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, and hospitalization for heart failure was reduced by 25% [hazard ratio (HR) 0.75; p < 0.00000001], after 5 years of mean follow-up. But the VITAL study, using a lower dose of O3FA, could not show any clinical benefit. DHA reduces TG more than EPA, but also tends to raise LDL.

    Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor

As proprotein convertase subtilisin/kexin type 9 (PCSK9) competitively blocks LDL receptors on hepatocytes, PCSK9 inhibitors promote clearance of LDL by liver from blood stream. It can reduce LDL by 40–50%.

In the FOURIER trial with stable CV disease patients, evolocumab reduced LDL by 59% compared to placebo, and the effect was evident with first month of therapy. It translated into clinical benefit of 15% reduction of three-point MACE (p < 0.0001). In the ODYSSEY OUTCOMES trial after ACS, alirocumab reduced five-point MACE by 15% (p < 0.0003), and all-cause death was reduced by 15% (p = 0.026). In the EVOPACS trial, high-dose statin was given with and without evolocumab in ST-elevation myocardial infarction (STEMI) patients within 24 hours and in other ACS patients within 72 hours. Within 8 weeks, many more patients in the combination arm attained the LDL target. In the OCT trial in ACS patients, evolocumab increased the fibrous cap thickness of the coronary plaques, thereby reducing their chance of rupture.

    INCLISIRAN

Inclisiran is a long-acting double-stranded small interfering RNA (siRNA). It inhibits the transcription of PCSK9 in liver and increases LDL receptors on the liver cell membrane.

The ORION trials were conducted in familial hypercholesterolemia (FH) patients and patients with LDL not controlled with statins. It produced an impressive 70% reduction of LDL on statins. In the ORION-10 trial, inclisiran reduced ApoB, non-HDL-C, TG, and Lp(a) by 43.1%, 47.4%, 12.6%, and 25.6%, respectively, while increasing HDL-C by 5.1%. In ORION-9 trial, inclisiran further reduced LDL by 50% on maximally tolerated dose of statin. ORION-4 trial is designed to find CV clinical benefit with inclisiran, but already a meta-analysis showed a 24% lower MACE rate with inclisiran compared to placebo.

In July, 2023, Food and Drug Administration (FDA) approved inclisiran for primary prevention of ASCVD in high-risk individuals like diabetics, in addition to its previous indications for secondary prevention in patients with established ASCVD.

    Saroglitazar

Saroglitazar is a peroxisome proliferator-activated receptor α (PPAR-α) and γ agonist, and has antidiabetic and TG lowering effects. It has a good safety profile and can be safely combined with statin, but lacks clinical data for CV event reduction. Rather it has proven effect in fatty liver disease. In clinical trials, it reduced TG by 45–62%, non-HDL by 21–36%, small dense LDL by 20%, and glycated hemoglobin (HbA1c) by 0.7–1.6%.

USE OF NONSTATIN THERAPY TO ATTAIN LDL GOAL

The European Society of Cardiology (ESC) published the guideline for management of dyslipidemia in 2019. As per that, the average LDL-C reduction by different drug regimen was as follows:

• Moderate intensity statin—by 30%
• High intensity statin—by 50%
• High intensity statin + ezetimibe—by 65%
• PCSK9 inhibitor—by 60%
• High intensity statin + PCSK9 inhibitor—by 75%
• High intensity statin + ezetimibe + PCSK9 inhibitor—by 85%

The next job for the clinician is to determine the target of LDL for an individual patient. Four different targets have been set depending on the clinical profile of the patient. The highest risk patients need an LDL below 55 mg/dL, the high risk ones below 70 mg/dL, the moderate risk people below 100 mg/dL and for the low-risk population, below 114 mg/dL. The recommended strategy is to begin with the appropriate dose of statin, and to attain highest tolerated dose if the LDL is not in target. If still not, then ezetimibe is added, and if still not the target is achieved, PCSK9 inhibitor is added. The advent of BA may change this algorithm, and may be used in an earlier stage. Another area of recent argument is whether to treat LDL aggressively with combination therapy of two or three drugs to begin with, especially in ACS setting, and then to de-escalate, if necessary. Large clinical trials are necessary to get a definitive answer.

In statin intolerant patients, ezetimibe with or without BA is an attractive treatment option. PCSK9 inhibitors may be reserved for very high LDL levels. FH patients pose a problem as their baseline LDL levels are very high and their target LDL levels are very low. LDL apheresis may sometimes be the only option, though often not a practicable solution.

NONSTATIN THERAPIES FOR OTHER DYSLIPIDEMIAS

Very high levels of TG above 500 mg/dL impart a threat of pancreatitis. The treatment should be started urgently with lifestyle measures along with fibrates. If liver or kidney disease is associated, then saroglitazar may be a safer option. Secondary causes of high TG should be identifies and treated.

Low HDL-C can only be raised modestly by proper exercise and diet. All major drug trials failed to show clinical benefit though causing significant rise of HDL levels.

CONCLUSION

Statins are the main stay of therapy of dyslipidemia, which is usually driven by a high LDL level. However, there are occasions where statin are not tolerated, or are not adequate. There are other instances where abnormal levels of lipoproteins other than LDL are the primary dyslipidemia. In all such cases, nonstatin drugs are required. Clinical evidences are rapidly being generated regarding their efficacy and safety. Already there are unprecedented low levels of LDL and are becoming achievable by the use of combination therapies, especially due to PCSK9 inhibitors and inclisiran. Cost is still a barrier for their widespread use. But as Professor Eugene Braunwald predicted a few years ago, a 6 monthly injection of inclisiran to the general population may eventually eradicate ASCVD and will immensely reduce the health budget of all countries.

SUGGESTED READINGS

1.   Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111-88.

2.   Writing Committee; Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Covington AM, et al. 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2022;80(14):1366-418.