Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy

J Am Coll Cardiol. 2005 Oct 18;46(8):1411-6. doi: 10.1016/j.jacc.2005.04.064.


Objectives: This study sought to evaluate the safety and efficacy of achieving very low calculated low-density lipoprotein (LDL) levels with intensive statin therapy.

Background: Intensive statin therapy reduces clinical events occurring after acute coronary syndrome (ACS) and may result in LDL levels markedly lower than guideline levels. Prior epidemiologic and preclinical studies raise concerns about the safety of very low cholesterol levels.

Methods: The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) study compared intensive therapy (atorvastatin, 80 mg) and moderate therapy (pravastatin, 40 mg) in patients after ACS. Patients treated with atorvastatin were divided by four-month LDL values into groups: >100, >80 to 100 (reference-range-meeting guidelines), >60 to 80, >40 to 60, and <40 mg/dl. Baseline, clinical, and safety data were compared among groups achieving guideline recommendation levels or lower.

Results: Among 1,825 patients with four-month LDL, 91% were at goal (<100 mg/dl). The distribution was >80 to 100 mg/dl (14%), >60 to 80 mg/dl (31%), >40 to 60 mg/dl (34%), and <40 mg/dl (11%). Those with lower LDL levels were more often male, older, and diabetic, and had lower baseline LDL levels. They had prior statin therapy and fewer prior myocardial infarctions (MI). There were no significant differences in safety parameters, including muscle, liver, or retinal abnormalities, intracranial hemorrhage, or death, in the very low LDL groups. The <40 mg/dl and 40 to 60 mg/dl groups had fewer major cardiac events (death, MI, stroke, recurrent ischemia, revascularization).

Conclusions: Compared with patients treated with an accepted LDL goal (80 to 100 mg/dl), there was no adverse effect on safety with lower achieved LDL levels, and apparent improved clinical efficacy. These data identify no intrinsic safety concern of achieving low LDL and, therefore, a strategy of intensive treatment need not be altered in patients achieving very low LDL levels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Angina, Unstable / blood*
  • Angina, Unstable / drug therapy*
  • Atorvastatin
  • Female
  • Heptanoic Acids / therapeutic use*
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Lipoproteins, LDL / blood*
  • Male
  • Middle Aged
  • Myocardial Infarction / blood*
  • Myocardial Infarction / drug therapy*
  • Pravastatin / therapeutic use*
  • Pyrroles / therapeutic use*
  • Syndrome


  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Lipoproteins, LDL
  • Pyrroles
  • Atorvastatin
  • Pravastatin