Statin Topic Review

BySteven Lome, MD

HMG-CoA reductase inhibitors, commonly referred to as statins, are the cornerstone of pharmacologic reduction of elevated low-density lipoprotein cholesterol.

LDL-C is the main contributor to atherosclerotic cardiovascular disease risk. [Grundy SM, et al. J Am Coll Cardiol. 2018;7a;8a]

The safety and efficacy of statins has been established in multiple clinical trials in various populations. Statins, including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, simvastatin and rosuvastatin, are therefore widely used for both primary and secondary prevention of ASCVD.

The statins lower LDL-C by inhibiting an enzyme, HMG-CoA reductase, that catalyzes the rate-limiting step in the synthesis of mevalonate, a cholesterol precursor. This results in reduction of cholesterol synthesis, and increased LDL receptor expression on peripheral cells, thereby reducing the level of circulating LDL-C. Although their main mechanism of action is lowering of LDL-C, statins may also contribute to lower ASCVD rates via other mechanisms, including stabilization of atherosclerotic plaques as well as their anti-inflammatory, immunomodulatory and antithrombotic effects. [Ward NC, et al. Circ Res. 2019;2a-b;6a]

The Table below presents a summary of the LDL-C-reducing potency of each statin and other important information specific to each drug.

The 2018 American College of Cardiology/American Heart Association/Multisociety Guideline on the Management of Blood Cholesterol defines three categories of statin therapy intensity, based on the required degree of LDL-C reduction: [Grundy SM, et al. J Am Coll Cardiol. 2018;10a]

For a target LDL-C reduction of ≥ 50%: High-intensity statin therapy, including any of the following:

Atorvastatin 80 mg (with down titration to 40 mg if 80 mg cannot be tolerated)
Rosuvastatin 20 mg (titration up to 40 mg)
For a target LDL-C reduction of 30% to 49%: Moderate-intensity statin therapy, including any of the following:
Atorvastatin 10 mg (titration up to 20 mg)
Rosuvastatin 10 mg (down titration to 5 mg)
Simvastatin 20 to 40 mg
Pravastatin 40 mg (titration up to 80 mg)
Lovastatin 40 mg (titration up to 80 mg)
Fluvastatin XL 80 mg
Fluvastatin 40 mg twice daily
Pitavastatin 1 to 4 mg

For a target LDL-C reduction of < 30%: Low-intensity statin therapy, including any of the following:

Simvastatin 10 mg
Pravastatin 10 to 20 mg
Lovastatin 20 mg
Fluvastatin 20-40 mg

Indications

The 2018 ACC/AHA/Multisociety cholesterol guideline provides the following recommendations for the use of statins:

1) Recommendations for the primary prevention of ASCVD: [Grundy SM, et al. J Am Coll Cardiol. 2018;20a]

For all patients with an LDL-C level of 190 mg/dL or higher (severe hypercholesterolemia), a high-intensity statin therapy should be initiated regardless of ASCVD risk assessment (Class I recommendation)

For patients 40 to 70 years of age with type 2 diabetes, a moderate-intensity statin therapy should be initiated (Class I recommendation)

For patients 40 to 70 years of age with type 2 diabetes, a high-intensity statin can be useful (Class IIa recommendation) based on risk assessment

For patients 40 to 75 years of age without type 2 diabetes and with an LDL-C level ≥ 70 mg/dL and < 190 mg/dL:

High-intensity statin therapy should be initiated (Class I recommendation) if calculated 10-year ASCVD risk is ≥ 20%
Moderate-intensity statin therapy should be initiated (Class I recommendation) if calculated 10-year ASCVD risk is ≥ 7.5% to <20%, and if risk assessment favors statin therapy
Moderate-intensity statin therapy may be considered (Class IIb recommendation) if calculated 10-year ASCVD risk is between 5% and 7.5%, and “risk enhancers” (such as a high coronary artery calcium [CAC] score) are present [19b]

2) Recommendations for the secondary prevention of ASCVD: [Grundy SM, et al. J Am Coll Cardiol. 2018;12a]

For patients with ASCVD who are at very high risk (defined as a history of multiple major ASCVD events or one major ASCVD event and multiple high-risk conditions):

High-intensity or maximal tolerated statin therapy is indicated (Class I recommendation)
When on maximal statin and with an LDL-C level of ≥ 70 mg/dL, adding ezetimibe is reasonable (Class IIa recommendation)
Ezetimibe should be added before PCSK9 inhibitors are considered (Class IIa recommendation)

For patients with ASCVD who are not at very high risk:

For patients ≤ 75 years of age, a high-intensity statin is indicated (Class I recommendation) with a goal of reducing LDL-C by ≥ 50%; if a high-intensity statin is not tolerated, a moderate-intensity statin therapy is indicated (Class I recommendation); if LDL-C level remains ≥ 70 mg/dL on maximally tolerated statin, adding ezetimibe is reasonable (Class IIb recommendation)
For patients >75 years of age, initiation of moderate- to high-intensity statin therapy is reasonable (Class IIa recommendation), as is continuation of high-intensity statin therapy (Class IIa recommendation)

Side Effects

Statin-associated muscle symptoms are the most common adverse event of statin use, accounting for 72% of statin-related adverse events. Statin-associated muscle symptoms typically include myalgia, myopathy and myositis with elevated creatinine kinase. Actual muscle damage (rhabdomyolysis) is much less common. [Ward NC, et al. Circ Res. 2019;3b] While liver enzyme elevation can occur, the rate of hepatic failure in patients taking statins is the same as in the general population not taking statins, and they are not thought to be truly hepatotoxic.

Two supplemental agents, coenzyme Q10 (CoQ10) and vitamin D, have been proposed for management of statin-associated muscle symptoms. Coenzyme Q10 supplementation demonstrated no benefit compared to the placebo in randomized trials in patients with statin-associated muscle symptoms. [Ward NC, et al. Circ Res. 2019;7a] Some studies, but not all, suggest that vitamin D supplementation in patients who are deficient can relieve myalgias.

Alternative strategies for management of statin-associated muscle symptoms include switching therapy to statins with less intrinsic muscle toxicity (fluvastatin and pravastatin) or using alternate-day dosing or even once-weekly dosing of rosuvastatin.

A recent randomized trial concluded that the majority of symptoms associated with statins were due to nocebo effects. [Howard JP, et al. J Am Coll Cardiol. 2021;1a]

The National Lipid Association Scientific Statement on Statin Intolerance recommends the following [Cheeley MK, et al. J Clin Lipidol. 2022;5a]:

Patients who are nonadherent to their statin therapy or fail to take it consistently should be evaluated for statin intolerance (Class I recommendation).
Because complete statin intolerance is rare, if statin intolerance is suspected, attempt multiple strategies such as lowering the dose, switching statins or moving to non-daily dosing (Class I recommendation).
When choosing a nonstatin therapy, preference should be given to those with data from randomized trials showing reduced risk for CV events (Class I recommendation). As of April 2023, these include ezetimibe, PCSK9 inhibitors, bempedoic acid (Nexletol, Esperion Therapeutics) and icosapent ethyl (Vascepa, Amarin).
In patients with known or suspected statin intolerance at high or very high CV risk, delays in use of lipid-lowering therapy should be avoided, so nonstatin therapy should be considered while trying to determine a tolerable statin regimen (Class IIa recommendation).
It is reasonable to consider the nocebo effect as a possible cause of statin intolerance, but that does not make such symptoms any less clinically relevant (Class IIa recommendation).
It is reasonable to consider nonstatin therapy in patients with complete or partial statin intolerance to assist in lowering atherogenic lipoproteins (Class IIa recommendation).

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