Related Experiment Video
Updated: Mar 20, 2026
Author Spotlight: Understanding Retinal Vessel Resilience and Disease Progression
Published on: January 12, 2024
HDL Cholesterol as a Residual Risk Factor for Vascular Events and All-Cause Mortality in Patients With Type 2
Shahnam Sharif1, Yolanda van der Graaf2, Hendrik M Nathoe3
1Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
Insights
In type 2 diabetes patients, low HDL cholesterol (HDL-c) is not a risk for cardiovascular events. However, higher HDL-c unexpectedly increases risk in those with very low LDL cholesterol (LDL-c) levels (<2.0 mmol/L).
Area of Science:
- Cardiology
- Endocrinology
- Metabolic Diseases
Background:
- Low high-density lipoprotein cholesterol (HDL-c) is often considered a cardiovascular risk factor.
- The role of HDL-c as a residual risk factor in patients with type 2 diabetes, especially under intensive low-density lipoprotein cholesterol (LDL-c) management, requires further investigation.
Purpose of the Study:
- To determine if low HDL-c is a risk for cardiovascular disease and mortality in type 2 diabetes patients.
- To assess if HDL-c remains a residual risk factor when LDL-c treatment goals are met or intensive lipid-lowering therapy is used.
Main Methods:
- A prospective cohort study of 1,829 type 2 diabetes patients from the SMART cohort.
- Cox proportional hazard models were used to analyze the risk of HDL-c on cardiovascular events and all-cause mortality.
- Analyses were stratified by LDL-c levels (<2.0, 2.0-2.5, >2.5 mmol/L) and lipid-lowering therapy intensity, with adjustments for multiple clinical factors.
Main Results:
- No overall association was found between plasma HDL-c and cardiovascular events (HR 0.97) or all-cause mortality (HR 0.99).
- Subgroup analysis revealed effect modification by plasma LDL-c levels.
- In patients with LDL-c <2.0 mmol/L, higher HDL-c was associated with increased risk for all-cause mortality (HR 1.14) and cardiovascular events (HR 1.10).
- Conversely, in patients with LDL-c between 2.0-2.5 mmol/L, higher HDL-c showed a reduced risk for cardiovascular events (HR 0.85).
Conclusions:
- In high-risk type 2 diabetes patients with very low LDL-c (<2.0 mmol/L), higher baseline HDL-c is paradoxically linked to increased cardiovascular events and mortality.
- This finding contrasts with the risk observed in patients with LDL-c levels between 2.0-2.5 mmol/L, suggesting a complex interplay between HDL-c and LDL-c in diabetes management.
Objective:
To evaluate whether low HDL cholesterol (HDL-c) levels are a risk factor for cardiovascular disease and mortality in patients with type 2 diabetes and whether it remains a residual risk factor when attaining low LDL cholesterol (LDL-c) treatment goals or when LDL-c is treated with intensive lipid-lowering therapy.
Research Design And Methods:
We performed a prospective cohort study of 1,829 patients with type 2 diabetes included in the Second Manifestations of ARTerial disease (SMART) cohort. Cox proportional hazard models were used to evaluate the risk of HDL-c on cardiovascular events and all-cause mortality. Analyses were performed in strata of LDL-c levels (<2.0, 2.0-2.5, and >2.5 mmol/L) and lipid-lowering therapy intensity and were adjusted for age, sex, BMI, smoking, alcohol, LDL-c, triglycerides, systolic blood pressure, estimated glomerular filtration rate, glucose, and HbA1c.
Results:
A total of 335 new cardiovascular events and 385 deaths occurred during a median follow-up of 7.0 years (interquartile range 3.9-10.4). No relation was found between plasma HDL-c and cardiovascular events (hazard ratio [HR] 0.97, 95% CI 0.93-1.01) or all-cause mortality (HR 0.99, 95% CI 0.96-1.03). Subgroup analysis supported effect modification by plasma LDL-c levels. In patients with LDL-c levels <2.0 mmol/L, higher HDL-c was related to higher risk for all-cause mortality (HR 1.14, 95% CI 1.07-1.21). Higher HDL-c was also related to higher risk for cardiovascular events in patients with LDL-c levels <2.0 mmol/L (HR 1.10, 95% CI 1.07-1.21) in contrast to patients with LDL-c levels between 2.0 and 2.5 mmol/L (HR 0.85, 95% CI 0.75-0.95) and >2.5 mmol/L (HR 0.96, 95% CI 0.91-1.00).
Conclusions:
In high-risk patients with type 2 diabetes with LDL-c levels <2.0 mmol/L, higher HDL-c at baseline is unexpectedly related to a higher risk for cardiovascular events and all-cause mortality in contrast to high-risk patients with type 2 diabetes with LDL-c levels between 2.0 and 2.5 mmol/L.
Related Concept Videos
01:22Diabetes Mellitus: Type 2 and Gestational
01:30Coronary Artery Disease I: Introduction
01:36Carbohydrate Metabolism
Starch accounts for approximately 60% of the carbohydrates consumed by humans. Since amylase enzymes cannot function in the stomach's acidic environment, starch can only be digested in the mouth and small intestine. Simple sugars are found naturally in milk and fruits in...
01:26Coronary Artery Disease IV: Preventive Measures
01:29Cholesterol: Significance and Regulation
Considering cholesterol and...
01:26Atherosclerosis III: Management