Use and effectiveness of lipid-modifying drugs

Abstract

Lipid-modifying drugs are widely used to reduce elevated cholesterol concentrations, an important modifiable cause of atherosclerotic cardiovascular disease (ASCVD). Despite their widespread use, recent international trends in lipid-modifying drug utilization—especially for statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors—have not been quantified. Also, it remains uncertain whether statin treatment and achieving very low concentrations of low-density lipoprotein (LDL) and non-high-density lipoprotein (non-HDL) cholesterol are associated with a reduced risk of cardiovascular events and mortality for primary prevention of ASCVD in Chinese adults.

To address these knowledge gaps, pharmaceutical sales data was used to describe trends in lipid-modifying drug utilization in 83 countries. Electronic health record data from Hong Kong was used to describe local statin prescription trends and to conduct two cohort studies assessing the effectiveness of lipid-modifying drugs for primary prevention of ASCVD. The first cohort study directly compared simvastatin and gemfibrozil initiation, while the second assessed concentrations of LDL cholesterol and non-HDL cholesterol two years after statin initiation. From 2008 to 2018, the overall global consumption of lipid-modifying drugs increased at an annual compound rate of 4.13%. Since the approval PCSK9 inhibitors in 2015, the United States has experienced the largest utilization of and expenditure on these drugs. In Hong Kong, the prescribing of statins for primary prevention has increased rapidly and consistently since 2004.

The cohort studies found that simvastatin was associated with a reduced risk of major adverse cardiovascular events (MACE) and all cause mortality compared with gemfibrozil. In statin-treated individuals, LDL cholesterol < 2.6 mmol/L and non- HDL cholesterol < 3.4 mmol/L were associated with a reduced risk of MACE and all cause mortality. The magnitude of the association was generally larger for non-HDL cholesterol than LDL cholesterol, remaining consistent in sensitivity analyses using a three-month and one-year landmark.

This thesis addressed a significant gap in our knowledge of lipid-modifying drug utilization and the effectiveness of statins and gemfibrozil for primary prevention. The findings show improved global access to lipid-modifying drugs, especially statins. Disparities in PCSK9 inhibitor utilization among regions may be a barrier to an adequate response to the burden of disease caused by elevated LDL cholesterol. Increased prescribing of statins in Hong Kong has likely contributed to the observed decline in age-standardized deaths from cardiovascular diseases since 2004. Because ASCVD is a major cause of death in Hong Kong, using statins to achieve a non-HDL cholesterol < 3.4 mmol/L within 3 months of treatment initiation could reduce residual cardiovascular risk in primary prevention.

This research suggests that achieving lower absolute concentrations of non-HDL cholesterol and LDL cholesterol with statins reduces the risk of cardiovascular events and mortality in Chinese adults. It can inform clinicians about the prescribing of lipid- modifying drugs and monitoring of treatment response in Asians. Future studies could include a pragmatic randomized trial for primary prevention to assess the risk of cardiovascular events between patients assigned to a non-HDL cholesterol < 3.4 mmol/L—using a combination of lipid-modifying drugs—versus usual care.