Focus – Potential for combination therapy targeting APOC3 and LDL-C

April 2025

Results from this genetic association study including over 400,000 UK Biobank subjects provide the first evidence that combined intervention against APOC3- and LDL-C-lowering targets could offer improved benefit for lipid profiles and reduction in coronary heart disease risk over monotherapy. These findings merit study in clinical trials.

Wang W, Li R, Song Z, Huang N, et al. Joint associations of APOC3 and LDL-C–lowering variants with the risk of coronary heart disease. JAMA Cardiol. doi:10.1001/jamacardio.2025.0195

STUDY SUMMARY

Objective:	To investigate 1) whether genetically predicted lower apolipoprotein C3 (APOC3) is associated with reduction in cardiovascular risk, and 2) if the combined exposure to APOC3-lowering and low-density lipoprotein cholesterol (LDL-C)–lowering variants is associated with a reduction in the risk of coronary heart disease (CHD).
Study design:	Population-based genetic association study with 2 × 2 factorial mendelian randomization
Study population:	401, 548 subjects of European ancestry (mean age 56.9 years; 54% female) in the UK Biobank study. The cohort had a mean (standard deviation) LDL-C level of 138.1 (33.7) mg/dL and median (interquartile range) triglyceride level of 132.5 (93.6-191.6) mg/dL.
main study variable:	Plasma lipid and lipoprotein levels, and risk for CHD.
Methods:	The study developed genetic scores to mimic the effects of triglyceride-lowering APOC3, and LDL-C lowering 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors. A mendelian randomization design was used to assess the causal associations between genetically predicted lower APOC3, PCSK9, and HMGCR concentrations with lipids and clinical outcomes. A 2 × 2 factorial mendelian randomization study was then performed to evaluate the joint association of median-dichotomized APOC3 genetic score and HMGCR/PCSK9 genetic scores with circulating lipids, lipoproteins and CHD.

RESULTS

Over a median follow-up of 12.5 years, there were 25,199 CHD cases. Genetically lower APOC3 concentration was associated with lower levels of triglycerides, LDL-C, apolipoprotein B (apoB), total cholesterol and remnant cholesterol, and a higher level of HDL-C. Associations with genetically lower PCSK9 and HMGCR were similar to those of APOC3, except for triglycerides and HDL-C.
Genetically lower APOC3 and LDL-C targets (HMGCR and PCSK9) were associated with comparable reduction in CHD risk per 10 mg/dL decrease in apoB (Table 1). Combined exposure to genetically lower APOC3 and PCSK9, or genetically lower APOC3 and HMGCR was each associated with a lower risk of CHD.

Table 1. Association of genetically lower AP0C3, PCSK9 and HMGCR with lipid levels and CHD risk

	Change (95% CI) in triglyceride (mg/dL)	Change (95% CI) In LDL-C (mg/dL)	Odds ratio (95% CI)
Lower APOC3*	-142.99 (-146.74, -139.24)	-11.33 (-12.76, -9.91)	0.70 (0.59-0.83)
Lower PCSK9*	1.54 (-0.37, 3.45)	-14.52 (-15.24, -13.80)	0.71 (0.65-0.77)
Lower HMGCR*	-3.27 (-6.48, -0.06)	-16.01 (-17.22, -14.80)	0.85 (0.73, 0.98)
Joint associations
APOC3 PCSK9 APOC3/PCSK9			0.96 (0.92-0.99) 0.93 (0.90-0.97) 0.90 (0.86-0.93)
HMGCR HMGCR/APOC3			0.97 (0.94-1.01) 0.93 (0.90-0.97)

* Per 10 mg/dL decrease in apoB; CI confidence interval

Authors’ conclusion:

Genetically predicted lower APOC3 was associated with a reduced risk of CHD that is comparable with that associated with lower PCSK9 per unit decrease in ApoB. Combined exposure to APOC3 and LDL-C–lowering variants was associated with an additive reduction in CHD risk. Future studies are warranted to investigate the therapeutic potential of these combined therapies, particularly among high-risk patients who cannot achieve therapeutic targets with existing lipid-lowering therapies.

COMMENT

Management of lipid-related cardiovascular risk has focused on LDL-C, primarily with statin treatment, and latterly PCSK9 inhibition. Despite attainment of LDL-C goal with these efficacious therapies, a high residual risk persists especially among patients with elevated triglyceride levels (1-4). As the triglyceride level is a recognized surrogate for triglyceride-rich lipoproteins and their remnants, implicated as cardiovascular risk factors (5), new treatments are needed to target this residual risk.

APOC3, a key regulator of plasma triglyceride metabolism, has emerged as a potential target for therapeutic intervention, supported by genetic epidemiologic studies which showed that loss-of-function gene variants of APOC3 were associated with lower levels of triglycerides and a lower risk of cardiovascular disease (6,7). Clinical trials have shown that treatment with novel APOC3 inhibitors lowers triglycerides effectively (8-10); however, whether this benefit translates to reduction in cardiovascular risk is uncertain. Moreover, there is no evidence that their addition to LDL-C lowering therapy can improve cardiovascular risk reduction.

The results from this genetic association study provide the first evidence to support this hypothesis. There was greater benefit on lipid profiles and reduction in CHD risk with exposure to both APOC3 lowering and LDL-C lowering variants compared with exposure to LDL-C lowering variants alone. The study results are strengthened by the size of the cohort, the use of a mendelian randomization design to minimize the risk of confounding, as well as the use of validated genetic scores to simulate the effects of APOC3 and LDL-C–lowering therapies. The authors do, however, recognize that the effects of lowering therapies mimicked by these genetic scores reflect cumulative lifetime exposure and might differ from that expected in short-term clinical trials. Despite these limitations, the results support further investigation of the potential of combination therapy targeting both APOC3 and LDL-C to reduce residual cardiovascular risk.

References

1. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-63.
2. Langsted A, Madsen CM, Nordestgaard BG. Contribution of remnant cholesterol to cardiovascular risk. J Intern Med 2020;288:116-27.
3. Varbo A, Benn M, Tybjærg-Hansen A, et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427-36.
4. Schwartz GG, Abt M, Bao W, et al. Fasting triglycerides predict recurrent ischemic events in patients with acute coronary syndrome treated with statins. J Am Coll Cardiol 2015;65:2267-75.
5. Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies — a consensus statement from the European Atherosclerosis Society. Eur Heart J 2021;42:4791-806.
6. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;371:32-41.
7. TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014;371:22-31.
8. Tardif JC, Karwatowska-Prokopczuk E, Amour ES, et al. Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridemia and at high cardiovascular risk. Eur Heart J 2022;43:1401-12.
9. Kosmas CE, Bousvarou MD, Tsamoulis D, et al. Novel RNA-Based Therapies in the management of dyslipidemias. Int J Mol Sci 2025; 26: 1026.
10. Ahmad M, Hegele RA. Molecular therapeutics in development to treat hyperlipoproteinemia. Mol Diagn Ther 2025; doi: 10.1007/s40291-024-00768-0.

Key words

apolipoprotein C3; triglyceride-rich lipoproteins; mendelian randomization; residual cardiovascular risk