Triglycerides: From “Secondary” to Center Stage in Cardiovascular Prevention

For decades, cardiovascular prevention has revolved around one dominant target: LDL cholesterol. Triglycerides were often treated as a side note—something to “clean up” after LDL-C goals were met, or a marker of poor lifestyle rather than a causal driver of disease.

That framing is now changing.

A recent state-of-the-art review by Toth and Banach, on behalf of the International Lipid Expert Panel, positions 2025 as a turning point: the year triglycerides moved from a secondary lipid abnormality to a primary therapeutic target in their own right.

And this shift is not cosmetic. It is grounded in three powerful developments.

1. Strong causal biology: Triglycerides are not innocent bystanders

Large genetic studies, Mendelian randomization analyses, and long-term cohort data now converge on a clear conclusion:

Triglyceride-rich lipoproteins and their remnants are causally involved in atherosclerotic cardiovascular disease.

These particles are not simply “fat in the blood.” They:

• Carry large amounts of cholesterol per particle

• Penetrate the arterial wall

• Promote endothelial dysfunction and inflammation

• Drive residual cardiovascular risk even when LDL-C is well controlled

Importantly, this explains a familiar clinical paradox: patients with “perfect” LDL numbers who still suffer heart attacks, strokes, or progressive vascular disease.

Triglycerides—and more precisely, triglyceride-rich remnants—fill that explanatory gap.

2. Precision genetic stratification: not all hypertriglyceridemia is the same

Another reason triglycerides were historically neglected is that they were treated as a single, messy category. The new framework changes that.

The review emphasizes the importance of genetic and mechanistic stratification, particularly distinguishing:

• Familial Chylomicronemia Syndrome (FCS) is a rare, monogenic disorder caused by absent lipoprotein lipase activity, leading to extreme triglyceride levels and recurrent pancreatitis.

• Multifactorial chylomicronemia and metabolic hypertriglyceridemia are much more common, driven by insulin resistance, obesity, diabetes, medications, and polygenic risk.

Why does this matter?

Because treatment response depends on the mechanism.

Therapies that work in metabolic hypertriglyceridemia often fail completely in FCS.

Treating both as the same condition delayed effective care for years.

Precision diagnosis now allows precision therapy.

3. Powerful new therapies: targeting lipid metabolism upstream

Perhaps the most transformative change is therapeutic.

The article highlights a new generation of treatments that act upstream in lipoprotein metabolism, rather than simply lowering LDL-C or mildly reducing triglyceride synthesis.

ApoC-III inhibitors: a breakthrough for severe disease

RNA-based therapies targeting apolipoprotein C-III can reduce triglycerides by 50–80%, even in patients with no functional lipoprotein lipase. Most importantly, they dramatically reduce the risk of acute pancreatitis in FCS.

As a result, international guidelines now recommend ApoC-III inhibitors as first-line therapy in genetically confirmed FCS, rather than as a last resort.

This is a rare example of a lipid disorder moving from dietary restriction and risk management to true disease-modifying treatment.

Beyond ApoC-III

Other emerging approaches—ANGPTL3 inhibition, FGF21 analogs, and even gene-editing strategies—signal a broader transition:

From downstream lipid numbers → to regulation of lipid flux, clearance, and metabolic allocation

A conceptual shift: triglycerides as an active driver, not a passive marker

Taken together, these developments force a rethink of cardiovascular prevention.

Triglycerides are no longer:

• A secondary lab abnormality

• A lifestyle scolding tool

• A residual risk footnote

They are now recognized as:

• Causally linked to vascular disease

• Biologically distinct across patient groups

• Directly targetable with mechanism-based therapies

This does not replace LDL-C lowering—it completes it.

Why this matters for patients and clinicians

For patients, this shift explains why some people “do everything right” and still get sick—and why new treatments may finally address that risk.

For clinicians, it demands a more nuanced question:

What kind of triglyceride problem is this—and what mechanism is driving it?

For the field of cardiometabolic medicine, it signals a broader evolution: from static targets to dynamic, pathway-informed intervention.

Triglycerides have entered the spotlight—not as a trend, but as a long-overdue correction.

Toth PP, Banach M, on behalf of the International Lipid Expert Panel. 2025: The year in cardiovascular disease – the year of triglyceride-lowering therapies. Can we effectively reduce triglyceride-related residual cardiovascular disease and pancreatitis risk? Archives of Medical Science, 2025.