Majority of LDL-C lowering occurs at the lowest statin dose

Combination Lipid-Altering Drug Therapy with Statins (Harold Bays, MD, FACP)

adherence  |  atorvastatin  |  compliance  |  CURVES  |  efficacy  |  rule of 6  |  simvastatin  |  statins  |  titration  |  treatment practice

Many potential reasons exist as to why patients do not achieve lipid treatment goals. For example, some patients are never treated with any lipid-altering drug. Patient noncompliance may also be a factor. Known, potential, or perceived issues of tolerability and safety of high-dose statins among clinicians and patients may pose therapeutic challenges.

However, the resistance among many clinicians to use the highest doses of statins alone is due to not only concerns about toxicity and intolerability (which most often occur at higher doses), but also the recognition that most LDL-C reduction with statins occurs at the lower doses. In fact, each doubling of the statin dose produces an average additional decrease in LDL-C levels of about 5–6%, based upon the baseline LDL-C value ("rule of 6"). In the example above, atorvastatin 10 mg/day lowered mean LDL-C levels by 38%. Upon titration to 20 mg, 40 mg, and 80 mg, LDL-C levels were lowered only an additional 8%, 5%, and 3% respectively (based upon the baseline, pretreatment LDL-C level) for a total further reduction of 16% with these three titrations. In other words, starting with a mean baseline LDL-C level of 211 mg/dl, atorvastatin 10 mg per day would be expected to lower LDL-C levels to about 131 mg/dl (38% reduction). A three-step doubling of the dose to atorvastatin 80 mg per day would lower the baseline mean LDL-C levels an additional 16% to about 97 mg/dl (38% + 16% = 54% total reduction). The modest percent reduction after the lowest doses is also seen with the above simvastatin example, in which simvastatin 10 mg lowered mean LDL-C levels by 28%, while titration to 20 mg and 40 mg resulted in only an additional 7% and 6% reduction in LDL-C compared with the baseline value.

Finally, many patients with more severe dyslipidemias and/or in need of the most aggressive lipid therapy may not achieve lipid treatment goals even when the highest dose of statin is used. For all of these reasons, combination lipid-altering drug therapy is often indicated to avoid known or potential toxicity with higher doses of statin alone, or when statin monotherapy is insufficiently effective at the higher doses.

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3. Jones P, Kafonek S, Laurora I, Hunninghake D, for the CURVES Investigators. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998;81:582-587.