Do remnant cholesterol and triglycerides cause cardiometabolic multimorbidity?

Q: How large was the observational remnant-cholesterol sample?

334,030 eligible participants (365,577 for triglycerides).

Q: What SNP set was used?

13 biologically relevant SNPs as genetic instruments.

Q: HR for T2D at remnant cholesterol ≥1.0 mmol/L?

2.46 (95% CI 2.23–2.71) vs <0.4 mmol/L.

In >300,000 UK Biobank participants, higher remnant cholesterol and triglycerides tracked—and MR supported a causal role in—progression to cardiometabolic multimorbidity, especially IHD plus type 2 diabetes.

Source

Elevated blood remnant cholesterol and triglycerides are causally related to the risks of cardiometabolic multimorbidity

Zhao Y, Zhuang Z, Li Y, et al. · Nature communications · 2024

doi.org/10.1038/s41467-024-46686-x Read the full paper ↗91 citationscc by

Study at a glance

Design: Mendelian randomisation — UK Biobank multistate cohort plus one-sample Mendelian randomisation using 13 triglyceride-rich-lipoprotein SNPs.
N: N=334030 · Observational: 334,030 (remnant cholesterol) and 365,577 (triglycerides); MR: 376,712 and 411,930.
Population: UK Biobank adults free of diabetes, ischemic heart disease, and stroke at baseline (lipid-lowering users excluded from observational analyses).
Outcome: Progression from first cardiometabolic disease to multimorbidity (especially IHD plus type 2 diabetes), plus causal ORs from MR.

Structured fields used in claim comparison tables when every cited study has a complete layer.

What they did

Used multistate models from first cardiometabolic disease (diabetes, IHD, or stroke) to multimorbidity, then one-sample MR with 13 biologically relevant SNPs in hundreds of thousands of UK Biobank participants.

What they found

Remnant cholesterol ≥1.0 vs <0.4 mmol/L: T2D HR 2.46 and IHD HR 1.63. Triglycerides ≥2.3 mmol/L: T2D HR 3.54. Causal TG ORs per 1.0 mmol/L were 1.21 (any multimorbidity) and 1.24 (IHD–T2D); remnant cholesterol ORs per 0.29 mmol/L were 1.23 and 1.26. Associations were for IHD and diabetes, not stroke.

The limits

What it doesn't show

Single baseline lipids, possible instrument pleiotropy, and a healthier-than-average UK Biobank sample still limit how far causal estimates travel.

Key terms

Remnant cholesterol: Cholesterol in triglyceride-rich leftover lipoproteins after chylomicron/VLDL lipolysis.
Cardiometabolic multimorbidity: At least two of type 2 diabetes, ischemic heart disease, and stroke.
IHD-T2D multimorbidity: Concurrence of ischemic heart disease and type 2 diabetes, the trajectory most tied to remnants/TG.
Multistate model: Survival model of transitions from disease-free → first disease → multimorbidity.
Mendelian randomisation: Uses 13 triglyceride-rich-lipoprotein SNPs as instruments for lifelong lipid differences.
GRS: Genetic risk score rescaled to a 0.98 SD (1.0 mmol/L TG) lipid increment.

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Primary causal design was:

Common questions

How large was the observational remnant-cholesterol sample?

334,030 eligible participants (365,577 for triglycerides).

What SNP set was used?

13 biologically relevant SNPs as genetic instruments.

HR for T2D at remnant cholesterol ≥1.0 mmol/L?

2.46 (95% CI 2.23–2.71) vs <0.4 mmol/L.

Causal OR for IHD–T2D per 1.0 mmol/L triglycerides?

1.24 (95% CI 1.06–1.46).