Statins and Cardiovascular Risk: A Deeper Look

Statins are among the most widely used medications in the world. They lower cholesterol by reducing its production in the liver, and they can reduce cardiovascular events in certain high risk populations. However, high cholesterol is rarely a simple cholesterol production problem. In many modern individuals, especially those with metabolic dysfunction, insulin resistance and glucose dysregulation are the primary forces driving elevations in LDL, ApoB, and triglycerides. Understanding these metabolic processes is essential for addressing cardiovascular risk at its root rather than focusing solely on cholesterol numbers.

What Statins Do

Statins inhibit HMG-CoA reductase, the rate limiting enzyme in cholesterol synthesis. This lowers cholesterol production and increases LDL receptor expression, which allows the liver to clear more LDL from circulation. The result is lower LDL concentration, lower ApoB, and modest reductions in triglycerides. Although statins are effective in certain settings, they target only one pathway. Most modern dyslipidemia is caused by metabolic dysfunction rather than excessive cholesterol synthesis alone.

How Insulin Resistance Raises LDL and ApoB

Insulin resistance significantly alters liver metabolism and lipoprotein handling.

Key mechanisms include:

• Increased VLDL Production: High insulin stimulates the liver to release excess VLDL, which later becomes LDL.

• Suppressed Lipoprotein Lipase: Insulin reduces lipoprotein lipase activity. Triglycerides rise, and LDL becomes smaller and denser.

• Impaired LDL Clearance: A fatty, insulin resistant liver has fewer functioning LDL receptors. LDL particles remain in circulation longer, increasing ApoB.

• Activation of Cholesterol Synthesis: Insulin activates the same enzyme that statins inhibit, which increases cholesterol synthesis in insulin resistant individuals.

This metabolic pattern produces elevated triglycerides, low HDL, small dense LDL, and high ApoB. Statins may lower LDL concentration, but they do not resolve these metabolic distortions.

How Dysglycemia Raises LDL and ApoB

Even in individuals without advanced insulin resistance, dysglycemia can significantly increase LDL particle number and alter LDL behavior.

• Increased Liver Fat: Excess glucose is converted to fat in the liver through de novo lipogenesis, increasing VLDL production.

• Glycation of LDL: High glucose glycates LDL particles, making them more oxidized and more atherogenic.

• Poor Clearance of Glycated LDL: Glycated LDL binds poorly to LDL receptors, remaining in circulation longer and raising ApoB.

• Postprandial Dyslipidemia: Glucose instability leads to repeated spikes in VLDL and triglycerides after meals, which raises LDL-P over time.

• Activation of Lipid Synthesis: High glucose activates SREBP-1c, increasing fatty acid and cholesterol synthesis.

This means that many cases of elevated LDL and ApoB are actually driven by glucose related metabolic stress rather than a primary cholesterol problem.

Do Statins Reduce Heart Attack and Stroke?

Statins can reduce cardiovascular events, but the benefit depends heavily on the population.

• Secondary Prevention: Individuals with prior heart attack, stroke, or established cardiovascular disease see a benefit.

• Primary Prevention: In people without established disease, absolute risk reduction tends to be small.

If an individual’s dyslipidemia is driven by insulin resistance or glucose instability, addressing that dysfunction often provides more meaningful improvement in risk than lowering LDL concentration alone.

Statin Side Effects

Statins are widely prescribed, but side effects can be meaningful in some individuals.

• Muscle Symptoms: Myalgia occurs in about 5 to 10 percent of users and is linked to mitochondrial effects and CoQ10 depletion.

• CoQ10 Depletion: Because statins block the mevalonate pathway, CoQ10 levels decline.

• Increased Blood Sugar: Statins raise the risk of new onset diabetes, especially in people with underlying metabolic dysfunction.

• Cognitive Effects: Research is mixed with some demonstrating increase risk of dementia.

• Liver Enzymes: Elevations in AST or ALT may occur.

Nutrient Considerations

Statin use is associated with reductions in:

• Coenzyme Q10

• Vitamin D

• Omega 3 fatty acids

Optimizing these nutrients can reduce muscle symptoms, support mitochondrial function, and improve tolerability.

A Better Approach Than Statins Alone

Many individuals are placed on statins based solely on elevated LDL, even when the deeper cause of the dyslipidemia is metabolic. A more comprehensive and effective strategy includes evaluating and correcting the metabolic patterns that cause atherogenic lipoprotein overproduction.

• Identify Whether the Dyslipidemia Is Metabolic: Patterns such as elevated triglycerides, low HDL, and high triglyceride to HDL ratios indicate that the problem is insulin resistance or glucose instability rather than cholesterol production.

• Improve Insulin Sensitivity and Reduce Glucose Instability: Because insulin resistance and dysglycemia increase VLDL output and reduce LDL clearance, improving metabolic health often lowers LDL and ApoB more effectively than medication alone. Strategies include whole food nutrition, adequate protein intake, consistent meal composition, stabilizing carbohydrate intake, reducing ultra processed foods, resistance training, weight loss when appropriate, and improving gut health.

• Correct Nutrient Imbalances: Low vitamin D, low magnesium, low CoQ10, low omega 3 fatty acids, and low B vitamins impair healthy lipid metabolism and increase statin side effects.

• Consider Alternatives or Adjuncts When Needed: Options include lower dosing, alternate day dosing, omega 3 supplementation, and mitochondrial support.

• Focus on ApoB and LDL-P Rather Than LDL Alone: ApoB reflects particle number and is a better indicator of atherogenic risk than LDL concentration alone.

Statins lower LDL concentration but do not improve glucose instability, inflammation, nutrient deficiencies, endothelial health, or metabolic dysfunction. Addressing these areas is essential for true cardiovascular protection.

Root Cause Approach

Because insulin resistance and glucose instability drive most dyslipidemia, addressing metabolic health is the most effective strategy for improving lipid markers and lowering cardiovascular risk.

Helpful interventions include:

• stabilizing daily blood sugar patterns

• improving carbohydrate quality and timing

• reducing ultra processed foods

• increasing soluble fiber

• increasing omega-3 fatty acids

• anti-inflammatory diet

• resistance training

• reducing visceral fat

• improving gut health

• reducing stress and improving sleep

  
  

These approaches reduce VLDL production, improve LDL clearance, reduce glycation, and lower inflammation.

Summary

Statins can be helpful tools in the right clinical setting, especially for individuals with established cardiovascular disease. However, elevated LDL and ApoB are often symptoms of deeper metabolic dysfunction. Insulin resistance, dysglycemia, and glucose instability frequently drive the liver to overproduce lipoproteins and impair their clearance. If these metabolic issues are not corrected, statins may lower LDL concentration but may not fully address the processes that promote plaque formation.

A holistic, metabolic approach that stabilizes glucose, improves insulin sensitivity, reduces inflammation, and restores nutrient balance offers a more complete path to cardiovascular health.

References

Adiels M. Overproduction of lipoproteins in insulin resistance. Curr Opin Lipidol. 2008.https://pubmed.ncbi.nlm.nih.gov/18460911/

Berliner JA. Atherosclerosis and oxidized LDL. N Engl J Med. 1997.https://pubmed.ncbi.nlm.nih.gov/8721615/

Estruch R. PREDIMED trial. N Engl J Med. 2013.https://www.nejm.org/doi/full/10.1056/NEJMoa1800389

Ginsberg HN. Insulin resistance and lipoprotein metabolism. J Clin Invest. 2000.https://www.jci.org/articles/view/10762

Glueck CJ. Vitamin D deficiency and statin intolerance. Am J Cardiol. 2011.https://pubmed.ncbi.nlm.nih.gov/21728907/

Istvan ES. Statin mechanism of action. Science. 2001.https://pubmed.ncbi.nlm.nih.gov/11349148/

Jenkins AJ. Pathophysiology of glycated LDL. Diabetologia. 2004.https://pmc.ncbi.nlm.nih.gov/articles/PMC9904536/

Marcoff L, Thompson PD. CoQ10 and statin myopathy. Curr Opin Cardiol. 2007.https://pubmed.ncbi.nlm.nih.gov/17560286/

Parks EJ. Mechanisms linking glucose to lipogenesis. Annu Rev Nutr. 2002.https://www.cambridge.org/core/services/aop-cambridge-core/content/view/417FADEAD26CEF5C4C0652667876B8D7/S0007114502001022a.pdf/dietary-carbohydrates-effects-on-lipogenesis-and-the-relationship-of-lipogenesis-to-blood-insulin-and-glucose-concentrations.pdf

Sattar N. Statins and diabetes risk. Lancet. 2010.https://pubmed.ncbi.nlm.nih.gov/20167359/

Taskinen MR. Diabetic dyslipidemia and atherogenicity. Arterioscler Thromb Vasc Biol. 2012.https://pubmed.ncbi.nlm.nih.gov/25706066/