Targeting apolipoprotein CIII: potential for reducing cardiovascular risk in type 2 diabetes

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8 July 2015

Results from this cross-sectional study show a link between apolipoprotein (apo)CIII , elevated triglycerides (TG), cardiometabolic risk and increased subclinical atherosclerosis. Consequently, the authors propose that therapeutic inhibition of apoCIII may represent a novel approach to reducing cardiovascular risk in patients with type 2 diabetes.

Qamar A, Khetarpal SA, Khera AV, Qasim A, Rader DJ, Reilly MP. Plasma apolipoprotein C-III levels, triglycerides, and coronary artery calcification in type 2 diabetics. Arterioscler Thromb Vasc Biol 2015;35: DOI: 10.1161/ATVBAHA.115.305415.

STUDY SUMMARY

Objective:

To investigate the relationships between plasma apoCIII, TG levels, and coronary artery calcification (CAC), a measure of subclinical atherosclerosis, in patients with type 2 diabetes.

Study design:

Cross-sectional study

Study population:

1,422 subjects with type 2 diabetes (median age 59 years, 61% white, 58% male, 78% with metabolic syndrome, median baseline low-density lipoprotein [LDL] cholesterol 95 mg/dL or 2.5 mmol/L) but without clinically manifest coronary heart disease (CHD)

Primary variable:

Plasma levels of apoCIII, measured by immunoturbidimetric assay

Secondary variable:

· Plasma levels of lipid-related traits (total, LDL and high-density lipoprotein (HDL) cholesterol and TG)

· Plasma levels of metabolic traits (glycated haemoglobin, fasting glucose, fasting insulin)

· CAC score

Methods:

Spearman rank correlation was used to analyse the association between plasma apoCIII levels and lipid-related and metabolic traits. TG data were logarithmically transformed before analysis. The association was further investigated using a linear regression model with adjustment for age, sex, race, body mass index, alcohol use, glomerular filtration rate, exercise and use of lipid-lowering, and hypoglycaemic treatments. Age, sex, and race-adjusted Tobit conditional regression analysis was used to investigate the association of the logarithmic value of (CAC score+1) and plasma apoCIII levels.

Main results:

· Plasma apoCIII levels were positively associated with plasma total and LDL cholesterol and TG levels. The association between plasma levels of apoCIII and TG was significant in both unadjusted and adjusted analyses (p<0.0001 for all analyses), for all subjects and separately in men and women, p<0.0001).

· The associations between plasma apoCIII levels and fasting glucose and glycated haemoglobin were significant in subjects with plasma TG >150 mg/dL (1.7 mmol/L) but not in those with TG levels below this value.

· Plasma apoC-III levels were positively associated with CAC. Each one standard deviation [SD] increase in plasma apoC-III levels was associated with 78% increase in CAC score (95% confidence interval [CI] 27–250%), p<0.001).This association was attenuated after adjustment for TG levels (Tobit regression ratio 1.43, 95% CI 0.94–2.18; p=0.086) and for very low-density lipoprotein cholesterol (VLDL-C) (Tobit regression ratio 1.14; 95% CI 0.75–1.71; p=0.53). Results were comparable for both combined and sex-stratified analyses.

Authors’ conclusion:

In persons with type 2 diabetes, increased plasma apoCIII is associated with higher TG levels, less favourable cardiometabolic phenotypes, and higher coronary artery calcification, a measure of subclinical atherosclerosis. Therapeutic inhibition of apoCIII may thus be a novel strategy for reducing plasma TG-rich lipoproteins and cardiovascular risk in type 2 diabetes.

COMMENT

This study provides a rationale to support therapeutic targeting of apoCIII to reduce elevated TG, a component of TG-rich lipoproteins, in patients with type 2 diabetes. In summary, the study showed a strong positive association between plasma apoCIII and markers of cardiometabolic risk (TG, fasting glucose and HbA1c), as well as an association between apoCIII levels and subclinical atherosclerosis, as assessed by CAC score. Evidence that this relationship was attenuated after adjustment for TG or VLDL-C, implies that these play an intermediary role in the association of apoCIII with atherosclerosis. The large cohort size, including a sizeable proportion of women and those of non-white ethnicity, and the use of CAC score, an established marker of subclinical atherosclerosis and predictor of clinical coronary heart disease and future cardiac events,1,2 are strengths of the study. However, given ongoing debate about the role of CAC in monitoring progression of coronary heart disease,3 the study does not permit insights into how apoCIII impacts the progression or regression of coronary heart disease as measured by CAC.

ApoCIII inhibits the turnover of plasma TG via multiple mechanisms, including inhibition of lipoprotein lipase activity, delays hepatic clearance of TG-rich lipoproteins, and promotes secretion of VLDL.4,5 Two recent studies have also shown that lifelong exposure to lower plasma TG as a result of carriage of loss-of-function variants of the gene encoding apoCIII (APOC3) is associated with reduced risk of subclinical atherosclerosis and coronary heart disease.6,7 The direct association between plasma apoCIII levels and subclinical atherosclerosis demonstrated here provides clear support for targeting apoCIII to reduce the high residual cardiovascular risk persisting in type 2 diabetes patients despite statin treatment.

References

1. Raggi P, Shaw LJ, Berman DS, Callister TQ. Prognostic value of coronary artery calcium screening in subjects with and without diabetes. J Am Coll Cardiol. 2004;43:1663–9.

2. Detrano R, Guerci AD, Carr JJ et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med. 2008;358:1336–45.

3. Puri R, Nicholls SJ, Shao M et al. Impact of statins on serial coronary calcification during atheroma progression and regression. J Am Coll Cardiol. 2015;65:1273–82.

4. Ginsberg HN, Brown WV. Apolipoprotein CIII: 42 years old and even more interesting. Arterioscler Thromb Vasc Biol. 2011;31:471–3.

5. Rosenson RS, Davidson MH, Hirsh BJ, et al. Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease. J Am Coll Cardiol. 2014;64:2525–40.

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. Blood I, Crosby J, Peloso GM, et al; Tg, Hdl Working Group of the Exome Sequencing Project NHL. Loss-of-function mutations in apoc3, triglycerides, and coronary disease. New Engl J Med 2014;371:22–31.

Key words

apolipoprotein CIII, triglyceride-rich lipoproteins; atherosclerosis; coronary artery calcium, type 2 diabetes; therapy