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Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond
Changting Xiao1, Satya Dash1, Cecilia Morgantini1
1Departments of Medicine and Physiology and the Banting & Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada.
Insights
Residual cardiovascular disease (CVD) risk persists despite lowering LDL cholesterol, particularly in patients with diabetes. Targeting triglyceride-rich lipoproteins offers a new frontier for CVD prevention by addressing the atherogenic dyslipidemia complex.
Area of Science:
- Cardiology
- Endocrinology
- Metabolic Syndrome
Background:
- Residual cardiovascular disease (CVD) risk remains a significant challenge in high-risk populations, especially those with diabetes.
- This residual risk is often linked to non-low-density lipoprotein (LDL) lipid abnormalities, collectively termed the "atherogenic dyslipidemia complex."
- This complex, characterized by hypertriglyceridemia, low HDL cholesterol, altered LDL particles, and remnant lipoproteins, is epidemic due to changing demographics and lifestyles.
Purpose of the Study:
- To review the pathophysiology of the atherogenic dyslipidemia complex and its association with insulin resistance, obesity, and type 2 diabetes.
- To explain the limitations of current therapies (fibrates, niacin, CETP inhibitors) in managing this complex.
- To discuss novel therapeutic strategies and the repurposing of existing ones for effective CVD prevention.
Main Methods:
- Literature review of the pathophysiology of atherogenic dyslipidemia.
- Analysis of the efficacy and limitations of current therapeutic agents.
- Exploration of emerging and repurposed treatment strategies.
Main Results:
- The atherogenic dyslipidemia complex is strongly associated with insulin resistance, obesity, and type 2 diabetes, contributing significantly to CVD risk.
- Existing therapies have shown limited success in fully addressing the multifaceted nature of this lipid disorder.
- Targeting triglyceride-rich lipoproteins (TRLs) is identified as a promising strategy.
Conclusions:
- The atherogenic dyslipidemia complex is a major driver of residual CVD risk in diabetic and other high-risk populations.
- A paradigm shift towards targeting TRLs is proposed as a novel and potentially most effective strategy for CVD prevention.
- Modifying TRLs may correct multiple components of the atherogenic dyslipidemia complex, leading to improved cardiovascular outcomes.
Abstract:
Notwithstanding the effectiveness of lowering LDL cholesterol, residual CVD risk remains in high-risk populations, including patients with diabetes, likely contributed to by non-LDL lipid abnormalities. In this Perspectives in Diabetes article, we emphasize that changing demographics and lifestyles over the past few decades have resulted in an epidemic of the "atherogenic dyslipidemia complex," the main features of which include hypertriglyceridemia, low HDL cholesterol levels, qualitative changes in LDL particles, accumulation of remnant lipoproteins, and postprandial hyperlipidemia. We briefly review the underlying pathophysiology of this form of dyslipidemia, in particular its association with insulin resistance, obesity, and type 2 diabetes, and the marked atherogenicity of this condition. We explain the failure of existing classes of therapeutic agents such as fibrates, niacin, and cholesteryl ester transfer protein inhibitors that are known to modify components of the atherogenic dyslipidemia complex. Finally, we discuss targeted repurposing of existing therapies and review promising new therapeutic strategies to modify the atherogenic dyslipidemia complex. We postulate that targeting the central abnormality of the atherogenic dyslipidemia complex, the elevation of triglyceride-rich lipoprotein particles, represents a new frontier in CVD prevention and is likely to prove the most effective strategy in correcting most aspects of the atherogenic dyslipidemia complex, thereby preventing CVD events.
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