Icosapent Ethyl and Residual Cardiovascular Risk: What NMR Reveals Beyond Triglycerides
A prospective, multicentre real-world study shows that icosapent ethyl therapy is associated with favourable changes in atherogenic lipoprotein particles and in an integrated marker of systemic inflammation. The key is to look beyond the conventional lipid profile.
The clinical challenge: residual risk despite LDL-lowering therapy
Modern cardiovascular prevention has achieved substantial reductions in LDL cholesterol through statins, ezetimibe and therapies targeting PCSK9. However, even when LDL cholesterol is intensively treated, residual cardiovascular risk remains and is not always adequately captured by the conventional lipid profile.
Hypertriglyceridaemia is one of the signals associated with this residual risk. Its biological significance, however, extends beyond an isolated increase in circulating triglycerides. Elevated triglycerides are commonly accompanied by an increased concentration of triglyceride-rich lipoproteins, accumulation of remnant particles, changes in LDL and HDL size and composition, and a more atherogenic metabolic and inflammatory environment.
This complexity may help explain why lowering triglyceride concentrations alone does not necessarily translate into fewer cardiovascular events. Understanding what happens to the particles carrying these lipids — and to the biological pathways accompanying dyslipidaemia — may provide a more complete picture.
What does NMR add to the conventional lipid profile?
Proton nuclear magnetic resonance (1H-NMR) spectroscopy enables a more detailed characterisation of the lipoprotein system. In the IPE-NMR study, serum samples were analysed using a Bruker 600 MHz spectrometer and the Liposcale® test, which provides information on particle number, size and composition across large, medium and small VLDL, LDL and HDL subclasses.
The same NMR spectra were also used to quantify Glyc-Acetyl, an integrated signal derived from N-acetyl groups of circulating acute-phase glycoproteins. This measurement provides information related to low-grade systemic inflammation.
Study design: real-world clinical practice
IPE-NMR was an open-label, multicentre, prospective observational study conducted in Spain between December 2024 and September 2025 under real-world clinical practice conditions.
Eligible patients were receiving secondary cardiovascular prevention, optimised lipid-lowering therapy and met the clinical criteria for treatment with icosapent ethyl.
Participants received icosapent ethyl 2 g twice daily. Baseline measurements were compared with follow-up measurements obtained after at least four months of therapy. Of 71 patients recruited, 62 completed paired NMR assessments and were included in the analysis.
First finding: a globally disrupted lipoprotein profile at baseline
Before treatment, the study population showed abnormalities extending well beyond elevated triglyceride concentrations. NMR analysis identified triglyceride enrichment in both VLDL and HDL fractions, increased remnant cholesterol, elevated VLDL particle concentrations and small LDL particles, together with increased Glyc-Acetyl concentrations.
These findings illustrate an important feature of residual hypertriglyceridaemia: metabolic alterations may be distributed across several lipoprotein characteristics — including particle number, size and lipid composition — that are not directly visible in a conventional lipid panel.
Response to icosapent ethyl was heterogeneous
Across the overall cohort, triglyceride concentrations decreased significantly, with an average reduction of approximately 24%. However, the magnitude of the response varied substantially between individuals.
To explore this variability, participants were stratified into tertiles according to the percentage change in triglycerides:
- Tertile 1: non-responders, defined as patients with an increase in triglycerides or a reduction of less than 10%.
- Tertile 2: mean triglyceride reduction of approximately 21.6%.
- Tertile 3: mean triglyceride reduction of approximately 38%.
Changes in lipoprotein parameters and Glyc-Acetyl were related to the magnitude of triglyceride lowering. The responder analysis therefore included 42 patients who achieved a triglyceride reduction of at least 10%.
What changed among responders?
Among the 42 responders, several components of the atherogenic lipoprotein profile improved alongside a reduction in Glyc-Acetyl.
| Parameter | Baseline | Follow-up | p value |
|---|---|---|---|
| Total triglycerides | 2.09 mmol/L | 1.32 mmol/L | <0.0001 |
| VLDL-TG | 1.29 mmol/L | 0.85 mmol/L | <0.0001 |
| Remnant cholesterol | 0.95 mmol/L | 0.74 mmol/L | <0.0001 |
| Total VLDL-P | 82 nM | 56.4 nM | <0.0001 |
| Small VLDL-P | 71.1 nM | 50.2 nM | <0.0001 |
| Small LDL-P | 648 nM | 630 nM | 0.0015 |
| HDL-TG | 0.19 mmol/L | 0.17 mmol/L | 0.0002 |
| Glyc-Acetyl | 1529 µM | 1401 µM | <0.0001 |
1. Fewer triglyceride-rich lipoproteins and remnants
One of the clearest findings was a reduction in VLDL particle concentrations across all subclasses, with a particularly marked decrease in small VLDL particles. Remnant cholesterol also decreased significantly.
Cholesterol-rich remnants are relevant to atherogenesis and represent one component of residual cardiovascular risk that is not fully captured by LDL cholesterol alone.
2. A reduction in small LDL particles
Total LDL particle concentration remained largely unchanged, which is consistent with a population already receiving intensive LDL-lowering therapy. However, a statistically significant reduction in small LDL particle concentrations was observed among responders.
This finding highlights one advantage of advanced lipoprotein profiling: an intervention may modify the distribution of lipoprotein subclasses without producing similarly large changes in conventional lipid measurements.
3. Reduced triglyceride enrichment of HDL
HDL triglyceride content decreased, as did the HDL triglyceride-to- cholesterol ratio. In hypertriglyceridaemia, lipid exchange promotes the formation of triglyceride-enriched HDL particles, meaning that these results are consistent with a change in HDL lipid composition.
4. Lower Glyc-Acetyl: insight into systemic inflammation
One of the most notable findings was the significant decrease in Glyc-Acetyl, with greater reductions observed among patients with more pronounced triglyceride lowering.
Glyc-Acetyl integrates NMR signals derived from N-acetyl groups of circulating glycoproteins and provides a stable readout related to low-grade systemic inflammation.
The result is consistent with the hypothesis that the biological effects associated with icosapent ethyl may extend beyond changes in triglyceride concentrations. However, because IPE-NMR was an observational study, these findings cannot by themselves establish a causal anti-inflammatory mechanism.
What do these findings mean clinically?
IPE-NMR does not demonstrate that measuring these NMR-derived variables will itself improve clinical outcomes, nor does it establish that the observed lipoprotein and Glyc-Acetyl changes are causal mediators of the cardiovascular benefit associated with icosapent ethyl.
What the study does provide is a much more detailed biological characterisation of the metabolic changes associated with treatment. In a secondary prevention population with intensively treated LDL cholesterol and persistent hypertriglyceridaemia, a favourable triglyceride response was accompanied by simultaneous changes in VLDL particles, remnants, small LDL particles, HDL composition and Glyc-Acetyl.
Conclusion
IPE-NMR expands our understanding of the metabolic changes associated with icosapent ethyl therapy in patients with established atherosclerotic cardiovascular disease and residual hypertriglyceridaemia.
Among patients with a triglyceride response, treatment was associated with favourable changes across multiple features of the lipoprotein profile, together with a reduction in Glyc-Acetyl.
The study highlights that residual cardiovascular risk may involve an interconnected network of abnormalities in lipoprotein particle number, lipid composition and inflammatory processes , and that NMR-based profiling can characterise components of this network that are not captured by the conventional lipid profile.
Amigó N, Dalli-Peydró E, Díaz-Díaz JL, Oterino A, Cabau L, Ballestín-Ballestín J, Garcia-Moll X, Masana L, on behalf of the IPE-NMR study group. Impact of icosapent ethyl on serum lipo- and glycoprotein profiles assessed by 1H-NMR. A real-world observational study (IPE-NMR). Nutrition, Metabolism and Cardiovascular Diseases. 2026. DOI: 10.1016/j.numecd.2026.104852