The Statin Rule of 6

You Get the Most (per mg of drug) With the Least

Statins produce remarkable reductions in low density lipoprotein cholesterol (LDL-C) concentrations by blocking 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) reductase, the rate-limiting enzyme in cholesterol production. Blocking HMG CoA reductase decreases cholesterol levels in the hepatocyte. This increases hepatic production of LDL receptors, which increases hepatic uptake of cholesterol and thereby reduces blood LDL-C.  

Statins produce the biggest reduction in LDL-C, per mg of drug, at low drug doses. (Figure) 

In fact, after the initial dose, doubling the statin dose reduces LDL-C only an additional ~6% of the baseline value. This is called the “statin rule of 6”. As an example, suppose my LDL-C was 200 mg/dl, and you started me on 20 mg daily of pravastatin. That dose reduces LDL-C ~25%, so my LDL-C goes from 200 to 150 mg/dl. But you, as my clinician, decide that is not enough, so you double the dose of pravastatin to 40 mg daily. Doubling the pravastatin dose does not produce an additional 50 mg/dl decrease, but only an additional ~6% of the 200 baseline value or a 12 mg/dl LDL-C reduction. My LDL-C goes from 150 to 138 mg/dl. The reduction of LDL-C with doubling of the statin is even less at higher doses of the most potent statins. Increasing rosuvastatin from 20 to 40 mg/day or atorvastatin from 40 to 80 mg/day only reduces LDL-C an additional ~3 to 4% of the baseline value. Increasing the dose does increase the risk of statin associated muscle symptoms. So, the best approach is to use the lowest statin dose necessary to achieve the desired LDL-C.

Or to add ezetimibe. Ezetimibe decreases intestinal absorption of cholesterol. Ezetimibe produces a 20% reduction in LDL-C when used alone and a 24% reduction when combined with a statin, probably because statins increase intestinal cholesterol absorption. 

Ezetimibe is under-utilized because of the misinterpretation of two studies. I have discussed this previously.¹ The ENHANCE or “Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression” Study examined carotid intimal medial thickness (CIMT) in patients with familial hypercholesterolemia who were treated with simvastatin 80 mg daily or simvastatin plus ezetimibe. ² There was no difference in CIMT after treatment, but CIMT was normal in both groups at baseline. It was probably normal because subjects were recruited from lipid management centers where they had been expertly managed. The study was interpreted as showing that ezetimibe did not work.  I thought it showed that it’s hard to make a normal CIMT more normal. The IMPROVE-IT or “Improved Reduction of Outcomes: Vytorin Efficacy International Trial” randomized patients with an acute coronary syndrome to simvastatin 40 mg/day with or without ezetimibe.³ The study was criticized because it had to be extended to a median follow-up of 6 years to accrue a sufficient number of cardiac events. This was interpreted as demonstrating that ezetimibe was weak, but there was a 2% absolute reduction in cardiovascular events from 34.7 to 32.7% (p=0.016). I think the study took so long because the LDL-C values were low at the start in all patients so the difference between the simvastatin with or without ezetimibe groups was small, 53.7 vs. 69.6 mg/dL. It is hard to get a big difference in cardiovascular events when the differences in LDL-C are small.

I know that ezetimibe is not a statin and statins have achieved almost mystical status at reducing cardiovascular events, but most data show that anything that reduces LDL-C by increasing LDL receptor activity reduces cardiac events.⁴ Ezetimibe reduces intestinal cholesterol absorption, which decreases hepatocyte cholesterol levels, which increases LDL receptor activity, just like statins. 

So, the take home messages?  Remember the statin rule of 6, and consider adding ezetimibe to your statin treatment regimen before proceeding to more expensive treatment strategies.

1. https://www.hcplive.com/view/ezetimibe-a-lipid-lowering-drug-for-older-patients-and-older-cardiologists

2. Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358(14):1431-1443.

3. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397.

 4.Sabatine  MS, Wiviott  SD, Im  K, Murphy  SA, Giugliano  RP.  Efficacy and safety of further lowering of low-density lipoprotein cholesterol in patients starting with very low levels: a meta-analysis.  JAMA Cardiol. 2018;3(9):823-828.