Apolipoprotein CIII as a residual risk: insights from the OPTIMAL trial

August 2025

According to this latest report from OPTIMAL, apolipoprotein CIII (ApoCIII) promoted the accumulation of lipid plaque components in statin-treated type 2 diabetes patients. These findings highlight ApoCIII as a potential residual risk factor meriting therapeutic intervention in these high-risk patients.

Kitahara S, Kataoka Y, Nicholls SJ, et al. Apolipoprotein CIII in statin-treated type 2 diabetic patients: its implications for plaque progression and instability: the pre-specified analysis from the OPTIMAL randomized controlled trial. Atherosclerosis 2025; https://doi.org/10.1016/j.atherosclerosis.2025.120470

 

STUDY SUMMARY

Objective

To investigate whether ApoCIII affects plaque progression and plaque instability in statin-treated patients with type 2 diabetes.  

 

 

Study design

OPTIMAL (Observation of Coronary Atheroma Progression under Continuous Glucose Monitoring Guidance in Patients with Type 2 Diabetes Mellitus) was a prospective randomized controlled trial using serial Near-Infrared Spectroscopy/ Intravascular Ultrasound (NIRS/IVUS) imaging to compare the efficacy of HbA1c-guided versus continuous glycemic monitoring-guided glycemic management on coronary atherosclerosis in statin-treated type 2 diabetes patients with coronary artery disease. This report describes a prespecified post hoc analysis of this study.

 

 

Study population

In total, 78 patients had data for ApoCIII levels and NIRS/IVUS imaging at baseline and week 48.  

 

 

Main study variables

 

·       Total Atheroma Volume, assessed using IVUS

·       Plaque lipid burden, based on the maximum Lipid Core Burden Index measured over a 4mm segment (maxLCBI4mm) at non-culprit plaques using NIRS.

 

 

Methods

Patients were evaluated according to the change in ApoCIII (categorized as with any increase or without any increase) from baseline to week 48. Absolute changes in NIRS/IVUS parameters were compared using analysis of covariance with adjustment for treatment group, age, gender, baseline sodium glucose cotransporter-2 inhibitor use, and baseline NIRS/IVUS measures. Multiple regression analyses were conducted to evaluate factors associated with the increase in maxLCBI4mm and baseline characteristics associated with any increase in ApoCIII levels.

 

Results

Overall, 37 patients (47.4%) had an increase in ApoCIII at week 48; on-treatment low-density lipoprotein cholesterol (LDL-C) levels in these patients did not differ from those without an increase in ApoCIII (mean ± standard error 1.76±0.55 mmol/L and 1.74±0.55 mmol/L, respectively, p=0.91).

 

Serial changes in IVUS-derived atheroma volume did not indicate any difference between patients with or without any increase in ApoCIII. However, there was greater progression in lipid core burden, as assessed by maxLCBI4mm, in patients with an increase in ApoCIII compared with those without any increase. This difference was evident even after adjustment for baseline maxLCBI4mm and clinical characteristics. Among patients with on-treatment LDL-C levels <1.4 mmol/L, patients with an increase in ApoCIII showed greater progression in maxLCBI4mm than those without any increase in ApoCIII (Table 1). Furthermore, patients with an increase in ApoCIII were less likely to show regression in maxLCBI4mm (16.2% vs. 80.5% in patients without any increase in ApoCIII, p<0.001).

 

Table 1. Change in maxLCBI4mm at week 48, categorized by ApoCIII change at week 48

 

Increase in ApoCIII (n=37)

No increase in ApoCIII (n=41)

p-value

All patients

91.2±24.8

-44.2±23.5

<0.001

LDL-C >/= 1.4 mmol/L

90.3

-38.6

<0.001

LDL-C <1.4 mmol/L

93.3

-70.8

<0.001

Author conclusions

Circulating ApoCIII promoted the accumulation of lipidic plaque components in statin-treated patients with type 2 diabetes, suggesting ApoCIII as a residual risk that requires therapeutic intervention.

Comment

The amount of lipid core within coronary artery plaque is conventionally assessed using the metric maxLCBI4mm. A higher maxLCBI4mm value is indicative of a larger lipid core, which is associated with increased risk of acute coronary syndromes (1). The results from this study implicate ApoCIII as a potential driver of plaque build-up and instability in statin-treated type 2 diabetes patients with coronary artery disease, even among patients at guideline-recommended LDL-C goal.  These findings suggest that ApoCIII may represent a therapeutic target to mitigate residual cardiovascular risk in type 2 diabetes patients.

 

The role of ApoCIII in the regulation of circulating levels of triglycerides is established. ApoCIII increases levels of triglyceride-rich lipoproteins by a combination of inhibition of lipoprotein lipase activity, suppression of the hepatic uptake of triglyceride-rich lipoproteins, and promotion of the assembly and secretion of very low-density lipoprotein particles in the liver (2,3). Furthermore, individuals with type 2 diabetes exhibit higher ApoCIII secretion rate due to increased hepatic expression of this apolipoprotein, driven by hyperglycemia (4); indeed, in this study nearly half of the cohort (47.4%) showed an increase in ApoCIII over 48 weeks.

 

The authors stress that their findings are based on a post hoc analysis in a relatively small sample of patients, with ApoCIII and NIRS measurements conducted only at baseline and week 48 and should therefore be viewed as hypothesis generating. Despite these caveats, the results support ApoCIII as a potential contributor to coronary atherosclerosis and residual cardiovascular risk in type 2 diabetes patients with coronary artery disease. These findings merit further study.

 

References

  1. Schuurman AS , Vroegindewey M , Kardys I et al. Near-infrared spectroscopy-derived lipid core burden index predicts adverse cardiovascular outcome in patients with coronary artery disease during long-term follow-up. Eur Heart J 2018;39:295-302. 
  2. Taskinen MR, Borén J. Why Is apolipoprotein CIII emerging as a novel therapeutic target to reduce the burden of cardiovascular disease? Curr Atheroscler Rep 2016;18(10):59.
  3. Norata GD, Tsimikas S, Pirillo A, Catapano AL. Apolipoprotein C-III: From pathophysiology to pharmacology. Trends Pharmacol Sci 2015;36:675-87.
  4. Caron S, Verrijken A, Mertens I, et al. Transcriptional activation of apolipoprotein CIII expression by glucose may contribute to diabetic dyslipidemia. Arterioscler Thromb Vasc Biol 2011;31:513-9.

Key words: Apolipoprotein CIII; residual cardiovascular risk; type 2 diabetes; lipid plaque burden; coronary atherosclerosis