A vaccine-like strategy to lower LDL with a once-yearly dose of an siRNA to inhibit PCSK9 has the potential to dramatically reduce lifetime risk of cardiovascular events by as much as two-thirds – depending on baseline LDL and the age at which therapy is started, according to Brian A. Ference, MD, MPhil, MSc, FACC, presenting findings from the NATURE-PCSK9 study at ESC Congress 2021.

Using a method to estimate the causal effect of each mmol-year of cumulative exposure to lower LDL due to genetic variants in PCSK9 and other genes, NATURE-PCSK9 investigators evaluated the effect of lowering LDL using a once-yearly dose of a PCSK9 siRNA compared with usual care beginning at age 30, 40, 50 or 60 years of age on the lifetime risk of cardiovascular events up to 80 years of age. The primary outcome was age at first occurrence of a major coronary event, defined as the first occurrence of a fatal or non-fatal MI, or coronary revascularization. The secondary outcome was age at first occurrence of a major cardiovascular event, defined as the first occurrence of major coronary event or ischemic stroke. Safety outcomes focused on lifetime risk of developing type 2 diabetes or any cancer.

All told, 445,765 patients, none of whom had a diagnosis of atherosclerotic cardiovascular disease, diabetes or cancer before the age of 30 years, participated in the study. The average age was 68 years and 54% were women. The mean baseline LDL level was 3.5 mmol/L (136 mg/dl). Overall results, compared with usual care, found the vaccine-like strategy produced a sustained 34% time-averaged reduction in plasma LDL. A step-wise increase in the proportional reduction in lifetime risk of cardiovascular events was also observed with each earlier decade of life that LDL lowering was started. For example, treating men starting at age 60 was associated with a 27% reduction in lifetime risk, but starting treatment at age 30 was associated with a 52% reduction in risk. Similar results were observed among women.

In other findings, a significantly greater expected reduction in lifetime risk at all ages was observed with starting a once-yearly dose of a PCSK9 siRNA at age 40, compared with more aggressive twice-yearly doses of an siRNA starting at age 55 years. "This finding suggests that the residual risk of cardiovascular events observed among persons being treated with an LDL lowering therapy started later in life may be due to the cumulative exposure to LDL and the corresponding plaque burden that develops prior to the initiation of LDL lowering treatment," the researchers said.

Additionally, men and women with higher baseline LDL levels had a greater expected proportional reduction in lifetime risk of cardiovascular events in response to once- or twice-yearly doses of a PCSK9 siRNA at all ages, as compared with those who had lower baseline LDL levels. However, Ference and colleagues said all participants, regardless of LDL levels, had large, expected reductions in lifetime risk including participants and had step-wise greater expected reductions in lifetime risk with each decade earlier that LDL lowering was started.

"These findings motivate a greater focus on lowering LDL earlier in life," Ference said.

Clinical Topics: Cardiovascular Care Team, Dyslipidemia, Lipid Metabolism, Novel Agents

Keywords: ESC Congress, ESC21, ACC International, PCSK9 protein, human, Proprotein Convertase 9, RNA, Small Interfering, Diabetes Mellitus, Type 2, Brain Ischemia, Stroke, Atherosclerosis, Plaque, Atherosclerotic, Neoplasms

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