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Low LDL cholesterol, PCSK9 and HMGCR genetic variation, and risk of Alzheimer’s disease and Parkinson’s disease: Mendelian randomisation study

BMJ 2017; 357 doi: (Published 24 April 2017) Cite this as: BMJ 2017;357:j1648

Rapid Response:

Evidence Is not Enough to be Safe: Very Low LDL cholesterol

Benn M, et al1 tested the hypothesis that low density lipoprotein (LDL) cholesterol due to genetic variation in the genes responsible for LDL cholesterol metabolism and biosynthesis (PCSK9 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), respectively) is associated with a high risk of Alzheimer's disease, vascular dementia, any dementia, and Parkinson's disease in the general population. Because cholesterol is a major constituent of the brain, it has been suggested that low levels of LDL cholesterol might lead to increased risk of neurological diseases. They observed that low LDL cholesterol levels due to PCSK9 and HMGCR variants had no causal effect on high risk of Alzheimer's disease, vascular dementia, any dementia, or Parkinson's disease; however, low LDL cholesterol levels may have a causal effect in reducing the risk of Alzheimer's disease.

Dys lipidemia is one of major risk factors for cardiovascular disease and dementia.2 It is expected to lower LDL cholesterol levels may reduce both cardiovascular disease and dementia. However, because cholesterol is a major constituent of the brain, too lower LDL cholesterol levels may impair neurocognitive function, dementia, and Alzheimer's disease despite of reduction of cardiovascular disease.

Dr. Robinson demonstrated that LDL cholesterol levels <25 or <15 mg/dl on alirocumab were not associated with an increase in overall treatment-emergent adverse event rates or neurocognitive events, although cataract incidence increased 3 times in the group achieving LDL cholesterol levels <25 mg/dl.3 However, follow-up period is not enough to be safe. LDL cholesterol -lowering is paramount important to reduce cardiovascular (CV) events. How far should we lower LDL cholesterol levels for a lifelong period cost-effectively to prevent CV diseases and simultaneously with safety? Some experts suggest 60 mg/dL would be ideal because that would be required to maintain our body in homeostasis. When fetus is born, LDL cholesterol levels are 40 mg/dL. However, the current study did not report the most concerned issue. Subjects with genetic variants in PCSK9 or HMGCR with reduced LDL levels had similar decreases in CV risk per unit decrease in LDL cholesterol.4,5 In subjects with pre-existing glucose intolerance, variants in both genes were associated with independent and additive effects to increase risk of diabetes (also associated with LDL lowering albeit with smaller effect size than CV risk). PCSK9 inhibitors and statins use distinct mechanisms to lower LDL cholesterol, the common downstream effect that is likely related to both protection against CV disease and promotion of diabetes. It may be extended to other safety issues of neurocognitive function and cataract.

Recently, Dr. Watts demonstrated that in healthy, normolipidemic subjects, evolocumab (420 mg every 2 weeks) decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism. Reductions in intermediate-density lipoprotein and LDL production also contributed to the decrease in LDL particle concentration with evolocumab by a mechanism distinct from that of atorvastatin (80 mg daily).6

Furthermore, dosage of PCSK9 inhibitors and statins used by Western people is much higher than Korean. The most prescribed dosage in Korean is alirocumab (75 mg every 2 weeks) and atorvastatin (10 mg).7 CV benefits and safety issues should be also judged based on an expensive cost.

1. Benn M, Nordestgaard BG, Frikke-Schmidt R, Tybjærg-Hansen A. Low LDL cholesterol, PCSK9 and HMGCR genetic variation, and risk of Alzheimer's disease and Parkinson's disease: Mendelian randomisation study. BMJ 2017;357:j1648.

2. Kim SH, Després JP, Koh KK. Obesity and cardiovascular disease: friend or foe?
Eur Heart J 2016;37:3560-8.

3. Robinson JG, Rosenson RS, Farnier M, et al. Safety of very low low-density lipoprotein cholesterol levels with alirocumab: Pooled data from randomized trials. J Am Coll Cardiol 2017;69:471-82.

4. Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9 and HMGCR and risk
of cardiovascular disease and diabetes. N Engl J Med 2016;375:2144-53.

5. Lotta LA, Sharp SJ, Burgess S, et al. Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: A Meta-analysis.
JAMA 2016;316:1383-91.

6. Watts GF, Chan DC, Dent R, et al. Factorial effects of evolocumab and atorvastatin on lipoprotein metabolism. Circulation 2017;135:338-51.

7. Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Shin EK. Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients. J Am Coll Cardiol 2010;55:1209-16.

Competing interests: No competing interests

09 June 2017
Kwang Kon KOH
Professor of Medicine
Department of Cardiovascular Medicine, Gachon University, Gil Medical Center
774 Beongil 21, Namdongdaero, Namdong-Gu, Incheon, Korea 21565