How Low Is Too Low for Suppressing the Lipid Profile With Statins?

Jodi H. Walker, BS, PharmD, BCPS


March 06, 2009

Target levels of LDL cholesterol keep going down, but should we use higher doses of statins to achieve those goals?

Response from Jodi H. Walker, BS, PharmD, BCPS
Adjunct Faculty, Albany College of Pharmacy, Albany, New York; Clinical Pharmacy Specialist, VA Medical Center, Bath, New York

Although hyperlipidemia is a modifiable cardiovascular disease (CVD) risk factor, about 40 million American adults are at high risk due to total cholesterol levels of 240 mg/dL or higher.[1,2] The most recent guidelines, issued by the Third National Cholesterol Educational Program Adult Treatment Panel (NCEP ATP III), identified low-density lipoprotein cholesterol (LDL-C) as the prime target for lipid intervention to prevent CVD, with optimal LDL-C levels being below 100 mg/dL.[3] An optional goal of 70 mg/dL was proposed for those at very high risk for atherosclerosis.[4]

Hydroxymethylglutaryl- coenzyme A (HMG-CoA) reductase inhibitors, otherwise known as "statins," have been found to be the most effective means for lowering LDL-C. Recent studies have shown a clear reduction in clinical events in patients treated with high doses of statins to lower the LDL-C well below the target goals.

A recent study, called The Pravastatin or Atorvastatin Evaluation and Infection Therapy - Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22), evaluated the safety and efficacy of intensive statin therapy (atorvastatin 80 mg daily) on LDL-C levels in patients after acute coronary syndrome.[5] Results were divided by 4-month LDL-C values into groups: > 100, > 80 to 100, > 60 to 80, > 40 to 60, and < 40 mg/dL. Among 1825 patients, the < 40 mg/dL and 40-60 mg/dL groups had fewer major cardiac events. Compared with patients whose LDL-C goal was 80-100 mg/dL, lower LDL-C levels did not cause increased adverse effects. Patients with lower LDL-C had fewer cardiac events but no significant difference in overall mortality.

The Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE) trial evaluated the effect of LDL-C levels 80 mg/dL or below in patients with a history of known heart disease treated with intensive atorvastatin therapy. Overall cardiac events were reduced by 17% in the study patients compared with usual care. Risk for nonfatal myocardial infarction was reduced by 47%.[6] This study, along with PROVE IT - TIMI 2, demonstrated the superior benefit of LDL-C lowering below current guidelines in high-risk patients.

Statin doses should be no higher than needed to prevent or minimize adverse effects. The debate, however, continues over what is the "magic" LDL-C number, and how low is too low? The goal line seems to keep moving, yet it remains controversial as to when the benefits stop. Some of the benefits of statin use may also be due to anti-inflammatory properties. Greater reductions in C-reactive protein, a marker associated with inflammation, and LDL-C values due to intensive statin treatment may be related to a slower progression of atherosclerosis compared with moderate statin therapy in patients with coronary artery disease.[7]

Although lower LDL-C reduces cardiovascular risk, the risks for liver enzyme elevations and muscle damage must be taken into consideration based on the dose of the statin used. It is well documented that higher statin doses can promote higher rates of elevated liver enzymes. However, no significant relationship between elevated liver enzymes or rhabdomyolysis and the degree of LDL-C reduction exists. Lower LDL-C may be associated with an increased risk of cancer, which may offset the cardiovascular benefits of low LDL-C.[8]

Overall, statins are very safe and the benefits are significant both in elderly and younger patients.[9] A recent study found that statin use was not associated with an increase in malignancy, liver enzymes, or rhabdomyolysis. In addition, LDL-C levels as low as 40 mg/dL appeared safe and improved survival.[4]

The safety implication rests in how the LDL-C level is lowered. Although there is no limit to how low the LDL-C should be, thought should be given to the possibility of using multiple drugs at moderate doses instead of maximizing the statin dosage and risking side effects. Combination therapy can often achieve the goal LDL-C.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.