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Global burden and causal analysis of LDL-C-related cardiovascular diseases: A GBD 2021 and Mendelian randomization

Jiling Zhang¹, Yandan Wu¹, Yanyan Zhang²

¹Department of Laboratory Medicine,Beijing Shunyi District Hospital, Beijing, 101300, China.

Nutrition, Metabolism, and Cardiovascular Diseases : NMCD

|March 20, 2026

Insights

High LDL-C is a significant risk factor for cardiovascular diseases (CVDs). Despite declining death rates, the overall burden of LDL-C-related CVDs is increasing, necessitating targeted interventions.

Area of Science:

Epidemiology
Cardiovascular Medicine
Genetics

Background:

High low-density lipoprotein cholesterol (LDL-C) is a primary driver of cardiovascular diseases (CVDs), contributing significantly to the global health burden.
Understanding the trends and causal factors of LDL-C-related CVDs is crucial for public health strategies.

Purpose of the Study:

To quantify the global burden of LDL-C-related CVDs using the Global Burden of Disease (GBD) 2021 study.
To establish causal relationships between LDL-C and CVDs through Mendelian randomization (MR) analyses.

Main Methods:

Utilized GBD 2021 data to analyze the impact of high LDL-C on CVDs, employing Estimated Annual Percentage Change (EAPC) for trend analysis.
Applied frontier analysis to compare national performances against minimum risk levels and used BAPC modeling for future projections.
Conducted MR analyses to investigate the causal links between LDL-C and specific CVDs, including ischemic heart disease (IHD) and ischemic stroke.

Main Results:

From 1990 to 2021, Disability-Adjusted Life Years (DALYs) for LDL-C-related CVDs increased by 45.7%, while age-standardized death rates (ASDR) decreased by 33.2% globally.
MR analysis confirmed a causal relationship between LDL-C and IHD, but not ischemic stroke.
Significant variations in ASDR trends and national performances were observed, with some nations showing improvement and others requiring more progress.

Conclusions:

High LDL-C is a modifiable risk factor for IHD, a subset of CVDs.
Despite decreasing age-standardized death rates, the absolute global burden of LDL-C-related CVDs is rising.
Integrated GBD and MR findings underscore the urgent need for targeted LDL-C interventions, particularly for vulnerable populations.

Read full analysis

Abstract

Background And Aim:

High low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular diseases (CVDs), contributing substantially to global disease burden. We aimed to quantify the global burden of LDL-C-related CVDs and establish causal relationships through integrated Global Burden of Disease(GBD) and Mendelian randomization(MR) analyses.

Methods And Results:

We analyzed the impact of high LDL-C on CVDs burden using GBD 2021. Estimated Annual Percentage Change(EAPC) was used to delineate trends, while frontier analysis compared national performances against the minimum risk level adjusted for sociodemographic factors. BAPC modeling projected trends to 2036. MR examined the causal relationship between LDL-C (and its subtypes) and CVDs (ischemic heart disease(IHD) and ischemic stroke).The absolute increase in DALYs (45.7% increase from 1990 to 2021) contrasts sharply with the decline in ASDR (-33.2%), with a global EAPC of -1.47. This downward trend is consistent with that of the age-standardized mortality rate (ASMR) and is particularly pronounced among older individuals.In 2021, Nauru had the highest ASMR, while Israel showed the most significant reduction.Frontier analysis highlighted improvements in Somalia, Ethiopia, Rwanda, Burkina Faso, and Niger, but Lithuania, the US, Germany, Finland, and Monaco need more progress. Projections indicate ASMR will decrease by 2036 without targeted measures. MR analysis revealed a causal link between LDL-C and IHD, but not ischemic stroke.

Conclusion:

High LDL-C is a modifiable risk factor for CVDs (IHD). Despite declining ASDR and ASMR globally from 1990 to 2021, the absolute burden is rising. MR and GBD findings call for immediate targeted LDL-C interventions to reduce the burden on vulnerable populations.

Keywords:

Cardiovascular diseases Disability-adjusted life years Global burden of disease (GBD)High LDL-C Mendelian randomization

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