Unveiling the association between low-density lipoprotein cholesterol lowering and fracture risk : real-world evidence from a target trial emulation study.

AIMS: High serum low-density lipoprotein cholesterol (LDL-C) levels are associated with increased risk of fracture; however, it remains unclear whether lowering LDL-C reduces fracture risk, and, if so, whether the magnitude of LDL-C reduction is linearly associated with fracture risk. This study aimed to evaluate the relation between the degree of LDL-C reduction and fracture risk. METHODS: This population-based cohort study included individuals aged 40 to 90 years who initiated statins for hyperlipidaemia from IQVIA Medical Research Data primary care database in the UK (2000 to 2022). The primary outcome was hip fracture. Secondary outcomes included composite fracture and major osteoporotic fracture. A hypothetical target trial was emulated to assess the effect of achieving a LDL-C level of 1.8 to 2.6 mmol/L or < 1.8 mmol/L versus > 2.6 mmol/L induced by statin initiation within one year on the risk of incident and recurrent fractures over five years. RESULTS: Among 165,242 people with hyperlipidaemia initiating statins (mean age 62.6 years, 51.1% female), the five-year risk of incident hip fracture was lower in the 1.8 to 2.6 mmol/L arm (0.53%) and in the < 1.8 mmol/L arm (0.52%) than the > 2.6 mmol/L LDL-C arm (0.65%). The corresponding hazard ratios (HRs) were 0.77 (95% CI 0.65 to 0.91) and 0.68 (95% CI 0.54 to 0.86), respectively. A similar decreased risk of recurrent hip fracture was observed for the 1.8 to 2.6 mmol/L arm (HR = 0.79, 95% CI 0.39 to 1.58) and < 1.8 mmol/L arm (HR = 0.32, 95% CI 0.15 to 0.66), respectively. Additionally, lowering LDL-C levels reduced the risks of composite fracture and major osteoporotic fracture. CONCLUSION: In this population-based cohort study, LDL-C lowering was associated with a decreased risk of fracture in individuals with hyperlipidaemia. This decreased risk appeared to be associated with the extent of LDL-C lowering, suggesting that the therapeutic paradigm of 'lower is better' could be advantageous for fracture prevention in individuals with hyperlipidaemia.