HMG-CoA Reductase Inhibitors Topic Review

Introduction

Also known as statins, HMG-CoA reductase inhibitors work by inhibiting the synthesis of cholesterol in the liver by the enzyme HMG-CoA reductase. These drugs, which include pravastatin, fluvastatin, atorvastatin, simvastatin and rosuvastatin, are the mainstay of therapy for elevated LDL cholesterol and both primary and secondary prevention of acute coronary syndrome and stroke. Multiple clinical trials have shown a mortality benefit with statin therapy in various populations.

Below is a summary of the HMG-CoA reductase inhibitors, their potency in reducing LDL and other important information specific to each drug. Note that in the American College of Cardiology/American Heart Association Cholesterol Guidelines, therapeutic goals include either moderate intensity therapy (30-50% LDL reduction) or high intensity therapy (> 50% LDL reduction) depending on different factors.

HMG-CoA Reductase Inhibitor
Dose / LDL reduction %

Important Facts

Atorvastatin (Lipitor)

10 mg / 35-39%
20 mg / 43%
40 mg / 50%
80 mg / 55-60%

  • Metabolized in CYP3A4; high drug interaction risk
  • High potency
  • Multiple trials to support CV risk reduction

Cerivastatin (Lipobay, Baycol)

  • Removed from market 2001 due to rhabdomyolysis risk

Fluvastatin (Leschol)

20 mg / 22%
40 mg / 25%
80 mg / 35% 

  • Low potency
  • Few drug interactions

Lovastatin (Mevacor, Altocor)

10 mg / 21%
20 mg / 24-27%
40 mg / 30-31%
80 mg / 40-42% 

  • Low to moderate potency
  • Metabolized in CYP3A4; high drug interaction risk
  • Significantly raises cyclosporine levels in transplant patients

Mevastatin

  • First statin ever isolated; found in Penicillium citrinum
  • Animal testing showed high risk for liver tumors (no human trials)

Pitavastatin (Livalo, Pitava)

1 mg / 29%
2 mg / 36-39%
4 mg / 41-45%

  • Newest statin
  • Moderate potency
  • Few drug interactions

Pravastatin (Pravachol, Lipostatin)

10 mg / 22%
20 mg / 29%
40 mg / 34%
80 mg / 37%

  • Low potency
  • Thought to have fewest side effects
  • Established safety in patients with liver disease
  • Few drug interactions

Rosuvastatin (Crestor)

5 mg / 45%
10 mg / 46-49%
20 mg / 50-55%
40 mg / 55-63%

  • Highest potency available
  • Few drug interactions
  • Multiple trials to support CV risk reduction
  • Best statin to increase HDL cholesterol levels

Simvastatin (Zocor)

5 mg / 26%
10 mg / 29%
20 mg / 38%
40 mg / 30-41%
80 mg / 36-47%

  • Moderate potency
  • High incidence of side effects (myalgias)
  • Metabolized in CYP3A4; high drug interaction risk
  • The 80 mg dose not recommended by FDA in 2011 due to myalgias/interactions

Indications

The ACC/AHA Guidelines for Cholesterol Management, published in November 2013, give four indications for statin therapy.

  1. LDL greater than 190 mg/dL
  2. Clinical atherosclerotic cardiovascular disease (i.e. prior acute coronary syndrome, stable angina, coronary revascularization, stroke/transient ischemic attack, peripheral arterial disease including aneurysmal disease)
  3. Diabetes mellitus type II in patient aged 40 to 75 years with LDL 70 mg/dL to 189 mg/dL without clinical atherosclerotic cardiovascular disease
  4. No clinical atherosclerotic cardiovascular disease OR diabetes mellitus type II, but an estimated 10-year risk of 7.5% or greater (using a specific calculator provided in these guidelines)

Note: The Adult Treatment Panel (ATP) III Guidelines are now outdated.

Side Effects

Myalgias are common with statin therapy. Actual muscle damage including rhabdomyolysis is much less common. Elevated liver enzymes can be seen. However, the rate of hepatic failure in patients taking statins is the same as the general population not taking statins, and thus they are not truly thought to be hepatotoxic.

The two therapies that have been researched to reduce myalgias in patients taking statin therapy (HMG CoA reductase inhibitors) are coenzyme Q10, or CoQ10, and vitamin D.

Two very small trials of coenzyme Q10 had conflicting results regarding the efficacy of this therapy to relieve statin-induced myalgias. Likewise, some studies, but not all, have shown that replacing vitamin D in patients who are deficient can relieve similar myalgias. 

Better strategies include switching therapy to statins with less intrinsic muscle toxicity (fluvastatin and pravastatin) or alternate-day dosing. Some have even had success with once-weekly dosing of rosuvastatin.

References:
Stone NJ, et al. 2013 ACC/AHA Guidelines on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. J Am Coll Cardiol. 2013;doi:10.1016/j.jacc.2013.11.002.