Why Low LDL Cholesterol May Increase Diabetes Risk: Rethinking an Old Paradigm

For decades, we’ve been taught a simple rule: lower LDL cholesterol is always better. LDL has been framed as the “bad” cholesterol that clogs arteries, while high LDL is seen as a direct path to heart disease.

But a new large, real-world, six-year study published in Cardiovascular Diabetology surprisingly challenges that story.

The research—following 13,674 adults free of diabetes and heart disease—found something unexpected:

People with the lowest LDL levels had the highest risk of developing type 2 diabetes (T2D),and those with the highest LDL levels had the lowest future diabetes risk.

Even more striking: This pattern was mostly independent of statin use. Statins did raise diabetes risk—but only in people starting with very high LDL (≥131 mg/dL). At lower LDL levels, statins didn’t significantly change the already-increased diabetes risk.

These findings seem confusing—unless we rethink what LDL actually represents in the body.

Two Ways to Interpret These Findings

1. The Traditional Lipid-Centric Perspective

This is the paradigm most people (and many clinicians) still use:

• LDL cholesterol is harmful.

• High LDL = higher cardiovascular risk.

• Lowering LDL is always good.

• If low LDL is associated with diabetes, something must be “wrong” with the study—or it must be purely a statin side effect.

But the study found that the risk–LDL relationship holds even without statins. This leaves a contradiction the lipid paradigm cannot explain:

Why would “healthier” LDL levels predict a higher risk of diabetes?

This is where the traditional model hits its limits.

2. A Metabolic-Adaptation Perspective (A More Coherent Explanation)

Instead of viewing LDL as a toxin, this approach sees LDL as part of a living, adapting metabolic system.

Under stress—whether physical, inflammatory, hormonal, or metabolic—the body needs:

• more cholesterol for membrane repair and hormone synthesis

• more lipid transport for energy redistribution

• more antioxidant and nutrient-carrying lipoproteins

• more flexibility in switching between glucose and fat metabolism

LDL particles help provide these things.

From this viewpoint:

Higher LDL often reflects a system that is still trying to adapt and mobilize resources effectively.Lower LDL can reflect declining metabolic flexibility and shrinking adaptive capacity.

And metabolic inflexibility—the inability to efficiently switch fuels, manage energy, and maintain redox balance—is exactly what precedes insulin resistance and T2D.

So instead of being a marker of good health, very low LDL may be a warning sign of early metabolic exhaustion, especially in people under chronic stress.

Suddenly, the study’s findings are not surprising at all—they are expected.

Why This Matters

1. It challenges the “LDL is always bad” story

LDL isn’t just a cargo pod for cholesterol—it’s a stress-response molecule, an energy-distribution vehicle, and a repair-support system.

This means LDL levels reflect how well your metabolism is coping, not just your heart disease risk.

2. It reframes type 2 diabetes

T2D isn’t simply “too much sugar.”It is a failure of metabolic adaptation—a system that can no longer flexibly use energy.

Lower LDL may be one of the earliest visible signs of this deeper problem.

3. It helps explain statin-associated diabetes

Statins suppress the same pathways the body uses to produce adaptive lipids. This is why people who still have strong adaptive responses (very high LDL) experience the biggest impact of statins on diabetes risk.

For those already in a metabolically constrained state (low LDL), statins don’t change much because the adaptive system is already sluggish.

The Bigger Picture: Moving From a Lipid Paradigm to a Resilience Paradigm

Medicine is slowly shifting from a simple “numbers-based” cholesterol model to a deeper understanding of bioenergetics, stress adaptation, and metabolic resilience.

This study provides another clue:

Health is not defined by how low your LDL goes, but how well your metabolism adapts to ongoing stress.

When we look through that lens, the paradox disappears.

Final Thoughts

This new research challenges us to think differently about LDL—and about chronic metabolic disease more broadly. Instead of assuming that “lower is better,” we should ask a more important question:

What is the body trying to adapt to—and do we have the metabolic reserve to handle it?

When we start thinking in terms of resilience rather than single numbers, the story becomes clearer, the data makes more sense, and prevention becomes far more effective.

Lembo, M., Trimarco, V., Pacella, D., Izzo, R., Jankauskas, S. S., Piccinocchi, R., Gallo, P., Bardi, L., Piccinocchi, G., Morisco, C., Cristiano, S., Esposito, G., Giugliano, G., Manzi, M. V., Santulli, G., & Trimarco, B. (2025). A six-year longitudinal study identifies a statin-independent association between low LDL-cholesterol and risk of type 2 diabetes. Cardiovascular Diabetology, 24, 429. https://doi.org/10.1186/s12933-025-02964-6