Author + information
- Published online April 18, 2018.
- Kohei Takata, MD, PhD,
- Yu Kataoka, MD, PhD,
- Jordan Andrews, MS,
- Rishi Puri, MBBS, PhD,
- Muhammad Hammadah, MD,
- Bhanu Duggal, MD,
- Samir R. Kapadia, MD,
- E. Murat Tuzcu, MD,
- Steven E. Nissen, MD and
- Stephen J. Nicholls, MBBS, PhD∗ ()
- ↵∗South Australian Health & Medical Research Institute, University of Adelaide, P.O. Box 11060, Adelaide, South Australia 5001, Australia
Ongoing cardiovascular risks in patients with type 2 diabetes mellitus (T2DM), despite the use of statins, need additional therapeutic targets. We investigated whether diabetic dyslipidemia, characterized by hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C), was associated with plaque features in 267 statin-treated patients with T2DM and coronary artery disease who underwent frequency-domain optical coherence tomography (FD-OCT) within the target vessel for percutaneous coronary intervention.
FD-OCT measures and fasting blood biochemical data were compared in subjects stratified by triglyceride-to–HDL-C ratio tertiles. A generalized estimating equations approach was used to consider the intraclass correlation because of the multiple plaques analyzed within a single patient’s data. Multivariate linear regression analyses were performed to identify independent determinants for lipid arc (°) and cholesterol crystal (CC) presence. Receiver-operating characteristic analysis was performed to determine the optimal cutoff value of the triglyceride-to–HDL-C ratio for lipid-rich plaque containing CC. The Institutional Review Board of the Cleveland Clinic (Cleveland, Ohio) approved this retrospective study. All statistical analyses were performed using SPSS version 17.0 software (SPSS, Inc., Chicago, Illinois).
A total of 482 nonculprit and 325 culprit plaques were analyzed within 423 imaged target vessels. Nonculprit and culprit plaques in patients with a higher triglyceride-to–HDL-C ratio exhibited a larger lipid burden and a higher frequency of CC (Figures 1A and 1B). Patients with a higher triglyceride-to–HDL-C ratio had a larger total lipid index (1,309.6 mm° vs. 2,933.4 mm° vs. 4,105.6 mm°; p = 0.005), by calculating the sum of the lipid index within the entire imaged vessel. After adjusting for age, sex, risk factors, medications, glycosylated hemoglobin (HbA1c), and lipids, the triglyceride-to–HDL-C ratio was an independent determinant of lipid arc (β coefficient = 0.38; p = 0.01) and CC (β coefficient = 0.50; p = 0.008), whereas low-density lipoprotein cholesterol (LDL-C) and HbA1c levels were not associated with these measures. Furthermore, the triglyceride-to–HDL-C ratio was still associated with lipid arc, even in patients with LDL-C <70 mg/dl (p = 0.04) or HbA1c <7.0% (p = 0.03). The optimal cutoff value of the triglyceride-to–HDL-C ratio predicting lipid-rich plaques containing CC was 6.0 (area under the curve: 0.80; sensitivity 87.5%; specificity 80.3%; positive and negative predictive values of 75.0% and 92.3%, respectively; positive and negative likelihood ratio of 4.37 and 0.15, respectively; diagnostic odds ratio of 29.13; Youden index 0.678). During a 2-year observational period, there was a trend toward a higher frequency of cardiovascular events in patients with a higher triglyceride-to–HDL-C ratio (log-rank p = 0.12).
Previous studies have demonstrated the relationship of the triglyceride-to–HDL-C ratio with cardiovascular events, a finding suggesting that triglyceride-to–HDL-C ratio is a potential proatherogenic marker. In the current study analyzing statin-treated subjects with T2DM, the triglyceride-to-HDL-C ratio was associated with vulnerable plaque features, thus providing further evidence for a proatherogenic role of diabetic dyslipidemia even with statin therapy. Mechanistically, hypertriglyceridemia corresponds essentially to an increased content of atherogenic lipoproteins, which enhance the inflammatory response and foam cell formation. A diminished capacity of HDL-mediated cholesterol efflux capacity was observed in parallel with increases in triglyceride content in HDL. These properties could induce the accumulation of substantial amount of lipid materials and CC, thereby promoting plaque vulnerability.
LDL-C levels were not associated with FD-OCT measures in our study. Another study reported vulnerable plaque features in diabetic subjects despite achieving low LDL-C levels (1). Furthermore, small LDL particle concentration, but not LDL-C level, was a significant contributor to diabetic atheroma progression (2). Given that small LDL particles often accompany low HDL-C and elevated triglyceride levels, current observations may reflect the relative importance of mixed dyslipidemia in addition to LDL-C in patients with T2DM.
Subanalyses of large clinical trials and meta-analysis have elucidated the benefit of fibrates in diabetic patients with characteristics of diabetic dyslipidemia. Recently, pemafibrate, a novel peroxisome proliferator–activated receptor alpha modulator, was shown to cause a robust reduction in triglyceride levels and an increase in HDL-C levels when the drug was used with background statin therapy (3). Whether modulating an elevated triglyceride-to–HDL-C ratio with pemafibrate will stabilize diabetic atheroma requires further investigation.
Several caveats should be noted. This is a cross-sectional study, which may have limited our ability to detect causal relationships. FD-OCT imaging was conducted according to operators’ discretion. We excluded 110 plaques because of poor image quality. This exclusion may cause selection bias. The relationship of current findings with clinical outcomes remains unknown.
In conclusion, the triglyceride-to–HDL-C ratio, but not LDL-C, was associated with vulnerable plaque features in diabetic subjects with coronary artery disease who were taking statins. These observations may indicate that diabetic dyslipidemia is a potential residual cardiovascular risk.
Please note: Dr. Nissen has received research support to perform clinical trials through the Cleveland Clinic Coordinating Center for Clinical Research from Pfizer, AstraZeneca, Novartis, Roche, Daiichi-Sankyo, Takeda, Sanofi-Aventis, Resverlogix, and Eli Lilly; and is a consultant or advisor for many pharmaceutical companies but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction. Dr. Nicholls has received speaking honoraria from AstraZeneca, Pfizer, Merck Schering-Plough, and Takeda; has received consulting fees from AstraZeneca, Abbott, Atheronova, Esperion, Amgen, Novartis, Omthera, CSL Behring, Boehringer Ingelheim, Pfizer, Merck Schering-Plough, Takeda, Roche, NovoNordisk, LipoScience, and Anthera; and has received research support from the National Health and Medical Research Council of Australia, Amgen, Esperion, The Medicines Company, Sanofi-Regeneron, Anthera, AstraZeneca, Cerenis, Eli Lilly, InfraReDx, Roche, Resverlogix, Novartis, Amgen, and LipoScience. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
- Kataoka Y.,
- Hammadah M.,
- Puri R.,
- et al.
- Nicholls S.J.,
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