ReviewSafety and Effect of Very Low Levels of Low-Density Lipoprotein Cholesterol on Cardiovascular Events
Section snippets
Human LDL Cholesterol Levels: Normal Versus Optimal
Data from the early period in life (from gestation to adolescence) and from populations that consume a non-Western diet have provided useful insight into what could be considered the “physiologic lipid levels” in humans. Total cholesterol and LDL cholesterol change as humans age (Table 1).10, 11, 12, 13, 14 During late gestation in utero, the total cholesterol and LDL cholesterol levels reach approximately 55 and 30 mg/dl, respectively, and these levels increase during breastfeeding.10, 11 A
Safety of Very Low LDL Cholesterol Levels
Although these observations generally support the safety of lower LDL cholesterol levels than specified in the current treatment guidelines from North America, Europe, and Australia/New Zealand, some epidemiologic and clinical trial data have led to concern that very low levels of LDL cholesterol might increase the risk of cancer,26, 27 hemorrhagic stroke,27, 28, 29 and non-CV death.7, 27
Data from the Framingham Study were used to examine the relation between lipoprotein levels and non-CHD
Effects of Very Low LDL Cholesterol Levels on CV Risk
The potential of LDL cholesterol reduction to reduce the risk of CV events has been clearly established in secondary prevention, placebo-controlled, statin trials.2, 4, 67, 68 Furthermore, data from more recent trials have favored more-intensive statin therapy instead of less-intensive therapy with respect to a reduction in CV events.7, 69 These findings demonstrate that lowering LDL cholesterol beyond current guidelines imparts incremental clinical benefit in high-risk patients. Studies of
Conclusion
Humans with very low levels of LDL cholesterol (e.g., those with certain forms of FHBL) are generally healthy and have a low risk of CV events. Although the risk of cancer death was greater among those who did not develop atherosclerosis compared to those who did, this was probably because those protected from atherosclerotic death will succumb to other diseases. Cancer risk was not increased in statin-treated subjects attaining a very low level of LDL cholesterol. Furthermore, on the basis of
Acknowledgment
We thank Rick Davis, MS, RPh, Complete Healthcare Communications, Chadds Ford, Pennsylvania (whose work was funded by Amgen, Inc.), and Meera Kodukulla, PhD, Amgen, Inc. (Thousand Oaks, California), for assistance with the writing of our report.
References (78)
- et al.
Baseline low-density lipoprotein cholesterol is an important predictor of the benefit of intensive lipid-lowering therapy: a PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) analysis
J Am Coll Cardiol
(2008) - et al.
Decline in the concentration of low-density lipoprotein-cholesterol in human fetal plasma near term
Metabolism
(1983) - et al.
Thematic review series: brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal
J Lipid Res
(2004) - et al.
Effect of dietary cholesterol on cholesterol synthesis in breast-fed and formula-fed infants
J Lipid Res
(1993) - et al.
Distributions and trends of serum lipid levels among United States children and adolescents ages 4-19 years: data from the Third National Health and Nutrition Examination Survey
Prev Med
(1998) - et al.
30-Year trends in serum lipids among United States adults: results from the National Health and Nutrition Examination Surveys II, III, and 1999–2006
Am J Cardiol
(2010) - et al.
Serum cholesterol, blood pressure, and mortality: implications from a cohort of 361,662 men
Lancet
(1986) - et al.
Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal
J Am Coll Cardiol
(2004) - et al.
Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial
Lancet
(2002) Low serum cholesterol, cancer and other noncardiovascular disorders
Atherosclerosis
(1992)
Time-dependent association of total serum cholesterol and cancer incidence in a cohort of 172,210 men and women: a prospective 19-year follow-up study
Ann Oncol
Lipopolysaccharide and tumor necrosis factor cause a fall in plasma concentration of lecithin: cholesterol acyltransferase in cynomolgus monkeys
J Lipid Res
Hypocholesterolaemia in malignancy due to elevated low-density-lipoprotein-receptor activity in tumour cells: evidence from studies in patients with leukaemia
Lancet
Statins and cancer risk
Am J Med
Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin. The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin)
J Am Coll Cardiol
Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials
Lancet
Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial
Lancet
New mutations in APOB100 involved in familial hypobetalipoproteinemia
J Clin Lipidol
Familial hypobetalipoproteinemia in a hospital survey: genetics, metabolism and non-alcoholic fatty liver disease
Ann Hepatol
Familial hypobetalipoproteinemia
J Lipid Res
Hypobetalipoproteinemia: genetics, biochemistry, and clinical spectrum
Adv Clin Chem
A novel mutation of apolipoprotein B in a French Canadian family with homozygous hypobetalipoproteinemia
J Clin Lipidol
Prospective 10-year evaluation of hypobetalipoproteinemia in a cohort of 772 firefighters and cross-sectional evaluation of hypocholesterolemia in 1,479 men in the National Health and Nutrition Examination Survey I
Metabolism
Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver
J Biol Chem
Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote
Am J Hum Genet
Treating to New Targets (TNT) Study: does lowering low-density lipoprotein cholesterol levels below currently recommended guidelines yield incremental clinical benefit?
Am J Cardiol
Safety and efficacy of atorvastatin-induced very low-density lipoprotein cholesterol levels in patients with coronary heart disease (a post hoc analysis of the treating to new targets [TNT] study)
Am J Cardiol
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
Effect of statin use in patients with acute coronary syndromes and a serum low-density lipoprotein<or=80 mg/dl
Am J Cardiol
Benefit of early statin therapy in patients with acute myocardial infarction who have extremely low low-density lipoprotein cholesterol
J Am Coll Cardiol
Cholesterol and mortality: 30 years of follow-up from the Framingham study
JAMA
The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial Investigators
N Engl J Med
Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group
N Engl J Med
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S)
Lancet
High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial
JAMA
Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein
N Engl J Med
Treating to new targets: I. Intensive lipid lowering with atorvastatin in patients with stable coronary disease
N Engl J Med
Intensifying statin therapy to maximize cardiovascular risk reduction: is 50 the new 70? Goals are getting old
Clin Lipidol
Effects of food availability on serum insulin and lipid concentrations in free-ranging baboons
Am J Primatol
Cited by (0)
See page 1227 for disclosure information.