Table 1. Steroid Conversion Chart Based on LDL Target

Statins and Clinical Trial Evidence

Statins, discovered in the 1970s, are cholesterol-lowering drugs that inhibit the enzyme HMG-CoA reductase, a key player in cholesterol synthesis in the liver. This inhibition enhances the liver’s production of LDL receptors, which remove LDL and VLDL cholesterol from the bloodstream, effectively lowering serum cholesterol levels. Statins have proven to be highly effective with relatively few side effects. To date, seven statins have been approved for clinical use. Over the past three decades, numerous randomized controlled trials (RCTs) have demonstrated the efficacy and safety of statin therapy in reducing morbidity and mortality associated with atherosclerotic cardiovascular disease (ASCVD). While individual trials have yielded significant findings, meta-analyses combining data from these trials provide the strongest evidence of statins’ benefits.

Meta-analyses indicate that for every 1 mmol/L (39 mg/dL) reduction in LDL-C achieved through statin therapy, there is an approximate 22% reduction in ASCVD events. This relationship holds true across varying levels of LDL-C. However, the efficacy of individual statins varies depending on their intensity of cholesterol-lowering effects. For instance, rosuvastatin is twice as effective as atorvastatin, which itself is twice as effective as simvastatin, on a per-milligram basis. Statins are categorized based on the percentage reduction in LDL-C they achieve, as shown below:

Table 2. Statin intensity therapy

Moderate-intensity statins typically reduce LDL-C by 30–49%, lowering ASCVD risk by approximately one-third. High-intensity statins achieve greater reductions (>50%), translating to a risk reduction of about 50%. However, the absolute risk reduction depends on baseline LDL-C levels. For example, a patient with a baseline LDL-C of 200 mg/dL who achieves a 50% reduction experiences a significant 59% reduction in 10-year ASCVD risk. Conversely, in patients with lower baseline LDL-C levels, the absolute benefit diminishes despite similar percentage reductions. This underscores the principle that while “lower is better,” there are diminishing returns when lowering already low LDL-C levels, necessitating a balance between benefits, risks, and costs.

Non-Statin Cholesterol-Lowering Drugs

Beyond statins, several other agents are available for cholesterol management, each with unique mechanisms and effects.

• Bile Acid Sequestrants: These drugs inhibit bile acid absorption in the intestine, thereby upregulating hepatic LDL receptor activity. They moderately reduce LDL-C and have demonstrated efficacy in reducing CHD risk in patients with elevated baseline LDL-C.
• Ezetimibe: This agent blocks intestinal cholesterol absorption, enhancing hepatic LDL receptor activity. It lowers LDL-C by 15–25% and has shown additive effects when combined with statins. Clinical trials demonstrate its benefit in very high-risk patients, particularly when added to moderate-intensity statin therapy.
• Bempedoic Acid: This prodrug inhibits cholesterol synthesis via adenosine triphosphate-citrate lyase (ACL), leading to LDL receptor upregulation. It lowers LDL-C by 15–25%, with ongoing trials assessing its cardiovascular benefits.
• Niacin and Fibrates: Primarily used for triglyceride reduction, these drugs offer modest LDL-C reductions. Their effects on ASCVD risk vary, with limited incremental benefit when combined with high-intensity statins. Fibrates, particularly fenofibrate, are preferred when used with statins due to a lower risk of myopathy.
• Omega-3 Fatty Acids: These lower triglycerides and have shown mixed results in clinical trials. Icosapent ethyl significantly reduced ischemic events in high-risk, hypertriglyceridemic patients when added to statin therapy, whereas other formulations have not demonstrated similar benefits.

Table 3. Various non statin cholesterol lowering medications

Other emerging therapies include:

• PCSK9 Inhibitors: These drugs inhibit a protein that promotes LDL receptor degradation, resulting in substantial LDL-C reductions. They are effective in high-risk ASCVD patients, particularly those with statin intolerance or very high baseline LDL-C.
• Evinacumab: A monoclonal antibody targeting ANGPTL3, this drug is approved for homozygous familial hypercholesterolemia, reducing LDL-C independently of LDL receptor activity.
• CETP Inhibitors: Although these drugs lower LDL-C and raise HDL-C, clinical trials have shown minimal benefits, and they are not currently FDA-approved.

Reference

Smith MEB, Lee NJ, Haney E, et al. Drug Class Review: HMG-CoA Reductase Inhibitors (Statins) and Fixed-dose Combination Products Containing a Statin: Final Report Update 5 [Internet]. Portland (OR): Oregon Health & Science University; 2009 Nov. Available from: https://www.ncbi.nlm.nih.gov/books/NBK47273/