What is the natural history of individuals with Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) mutations?

Natural History of PCSK9 Loss-of-Function Mutations

Individuals with PCSK9 loss-of-function mutations are healthy throughout their lives, experience lifelong low LDL-cholesterol levels (as low as 14 mg/dL), have no apparent comorbidities, and benefit from significant protection against cardiovascular disease without any neurocognitive, reproductive, or other organ system impairments. 1

Cardiovascular Outcomes

The most clinically significant finding is marked cardiovascular protection:

• People with PCSK9 loss-of-function mutations experience a significant reduction in cardiovascular events over long-term follow-up compared to those without these mutations 1
• These individuals have markedly reduced rates of atherosclerotic cardiovascular disease (ASCVD) throughout their lifetime 1, 2
• The cardiovascular benefit is directly related to their lifelong exposure to very low LDL-cholesterol levels 1

Lipid Profile Characteristics

LDL-cholesterol levels in affected individuals:

• LDL-C levels vary but can reach as low as 14 mg/dL in compound heterozygotes 1
• These individuals maintain lifelong reduction in LDL-C due to increased numbers of LDL receptors on hepatocyte surfaces, which promotes robust LDL-C clearance from circulation 1
• The mechanism involves reduced PCSK9-mediated degradation of LDL receptors, allowing more receptors to remain functional 1

General Health and Organ Function

Despite PCSK9 expression in multiple organs, loss-of-function mutations cause no apparent harm:

• Although PCSK9 is expressed in the brain, liver, intestine, and kidneys, individuals with these mutations remain healthy without secondary morbidities 1
• A compound heterozygote with 14 mg/dL LDL-C was found to be healthy, fertile, and without any neurocognitive impairment 1
• No comorbidities have been documented in these individuals 1

Diabetes Risk: Conflicting Evidence

There is contradictory evidence regarding diabetes risk:

• One study suggested that PCSK9 variants have an LDL-C-dependent risk for developing diabetes, with an 11% increase in diabetes risk for each 10 mg/dL LDL-C decrease 1
• However, another study did not support any correlation between low LDL-C and type 2 diabetes in individuals with the most frequent PCSK9 loss-of-function variant 1
• To date, no higher rates of diabetes mellitus have been consistently observed among affected individuals in population studies 1

Safety of Very Low LDL-Cholesterol

The natural history demonstrates that very low LDL-C is safe:

• Individuals with PCSK9 loss-of-function mutations have shown no known comorbidity associated with very low LDL-C per se 1
• No higher rates of hemorrhagic stroke have been observed among affected individuals 1
• These findings contrast sharply with other genetic conditions causing very low LDL-C (such as abetalipoproteinemia or familial hypobetalipoproteinemia), which are associated with significant comorbidities including vitamin deficiencies, neurological manifestations, and hepatic steatosis 1

Clinical Implications

This natural history provides strong evidence for therapeutic PCSK9 inhibition:

• The benign natural history of PCSK9 loss-of-function mutations supports that loss of functional PCSK9 in humans is not associated with apparent deleterious effects 3
• This makes PCSK9 an attractive therapeutic target for LDL-C lowering 3
• The lifelong cardiovascular protection observed in these individuals provides the biological rationale for PCSK9 inhibitor therapy in high-risk populations 2, 4