HbA1c, coronary atheroma progression and cardiovascular events

Background Hemoglobin A1c (HbA1c) reflects long-term glycemic control and is associated with an increased risk of cardiovascular events among diabetic and non-diabetic patients. The specific impact of HbA1c upon atheroma progression and incident cardiovascular events relative to the presence of other cardiovascular risk factors remains uncertain. Purpose We tested the hypothesis that on-treatment HbA1c levels independently associate with coronary atheroma progression measured with serial intravascular ultrasonography (IVUS) and major adverse cardiovascular events (MACE: death, myocardial infarction, cerebrovascular accident, coronary revascularization, or hospitalization for unstable angina) rates. Methods We performed a post-hoc pooled analysis of data from eight prospective, randomized trials involving serial coronary IVUS. HbA1c was measured at baseline and the average of the follow-up values was taken. The percent atheroma volume (PAV) was calculated as the proportion of the entire vessel wall occupied by atherosclerotic plaque, throughout the segment of interest. Using multivariable mixed modeling, we determined the association of HbA1c with annualized change in PAV. Cox proportional hazard models were used to assess the association of HbA1c with incidence of MACE. Results Among 2,791 patients, mean age was 58.9±9 years and 29.1% were women. Mean on-treatment low-density lipoprotein (LDL)-cholesterol was 80.2±33.7 mg/dl and median on-treatment triglycerides (TG) were 125.5 (94.7, 170.2) mg/dl. Mean baseline and follow-up HbA1c was 6.2±1.2% and 6.3±1.2%, respectively. Overall, there was no net significant annualized change in PAV (0.15±0.21, p=0.47). In a fully adjusted multivariable analysis (following adjustment of age, sex, body mass index (BMI), systolic blood pressure, smoking, LDL- and high-density lipoprotein cholesterol, TG levels, peripheral artery disease, trial, region, and baseline PAV), higher on-treatment HbA1c levels were independently associated with annualized changes in PAV [beta-estimate (95% confidence interval): 0.13 (0.07, 0.19), p<0.001]. On-treatment HbA1c levels were significantly and independently associated with incidence of MACE [hazard ratio (95% confidence interval): 1.17 (1.07, 1.28), p<0.001]. Conclusions Independent of achieved cholesterol levels, vascular risk factors and BMI, greater HbA1c levels significantly associate with coronary atheroma progression and clinical outcomes. These results support the notion of a direct, specific effect of glycemic control upon the natural history of coronary atheroma and atherosclerotic events, supporting the rationale of therapies designed to directly modulate it. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Iryna Dykun was supported by the German Research Foundation

Comparison of coronary atherosclerotic features in response to achieving LDL-C <55 mg/dl between non-diabetic and diabetic patients: insights from the REASSURE-NIRS registry

Introduction Current ESC guideline recommends achieving LDL-C &lt;1.4 mmol/l in very high-risk subjects. Despite fabvourable anti-atherosclerotic effects of lowering LDL-C, its efficacy is diminished in type 2 diabetic patients. Whether response of coronary atheroma to on-treatment LDL-C &lt;1.4 mmol/l differs in diabetic and non-diabetic subjects has not been elucidated yet. Methods The REASSURE-NIRS registry is an on-going multi-center registry to enroll CAD subjects receiving PCI under the guidance of near-infrared spectroscopy/intravascular ultrasound (NIRS/IVUS: DualProTM, Nipro, Tokyo, Japan) imaging. Culprit lesions in 557 CAD patients who already received a statin were evaluated by NIRS/IVUS. Maximum 4-mm-lipid-core burden-index (maxLCBI4mm) and plaque calcification grade at culprit sites were measured. Calcification grade at each 1-mm cross-sectional image was defined as follows: calcium arc 0° = 0, 0–90° = 1, 90–180° = 2, 180–270° = 3, 270–360° = 4. MaxLCBI4mm and the averaged calcification grade were compared in diabetic and non-diabetic subjects stratified according to on-treatment LDL-C level, respectively. Result The proportion of diabetic (n=293, HbA1c; 6.9±0.9%) and non-diabetic patients (n=264) with on-treatment LDL-C &lt;1.4 mmol/l was 8.54 and 16.67%, respectivey (p=0.01). In non-diabetic patients, achieving LDL-C &lt;1.4mmol/L was associated with a lower maxLCBI4mm, whereas, in diabetic patients, maxLCBI4mm was numerically smaller under achieving LDL-C &lt;1.4 mmol/l, but this comparison did not meet statistical significance (Figure 1). Furthermore, a greater degree of calcification grade in non-diabetic patients was observed in association with on-treatment LDL-C level (Figure 2). However, plaque calcification at diabetic coronary atheroma was not necessarily induced under achieving stricter LDL-C goal. Subgroup analysis demonstrated that diabetic patients with body mass index ≥25 (odds ratio = 0.15; 95% CI: 0.18–1.19, p=0.04), estimated glomerular filtration rate &lt;60 (mL/min/1.73m2) (odds ratio = 0.31; 95% CI: 0.10–0.90, p=0.03) and non-insulin use (odds ratio = 0.36; 95% CI: 0.14–0.87, p=0.02) benefit from achieving LDL-C &lt;1.4 mmol/l. Conclusion Achieving LDL-C &lt;1.4 mmol/l was associated with more stabilized atheroma in non-diabetic patients with CAD, whereas these favourable effects were not observed in diabetic subjects. Our findings suggest the potential need to modify additional atherogenic risks for stabilizing diabetic coronary atheroma under achieving LDL-C &lt;1.4 mmol/l. FUNDunding Acknowledgement Type of funding sources: None. Figure 1 Figure 2

Association of Serum Lipoprotein (a) Levels and Coronary Atheroma Volume by Intravascular Ultrasound

Background Lp(a) (lipoprotein (a)) is a risk factor for cardiovascular events, but the mechanism of increased risk is uncertain. This study evaluated the relationship between Lp(a) and coronary atheroma volume by intravascular ultrasound. Methods and Results This was a post hoc analysis of 6 randomized trials of coronary atheroma by intravascular ultrasound. The population was stratified into high (≥60 mg/dL) and low (<60 mg/dL) baseline serum Lp(a). The primary outcome was baseline coronary percent atheroma volume. A mixed model adjusted for baseline low density lipoprotein, ApoB (apoliporotein B100), non‐high density lipoprotein, sex, age, race, history of myocardial infarction, statin use, and intravascular ultrasound study was used to provide estimates of baseline plaque burden. Of 3943 patients, 17.3% (683) had Lp(a) ≥ 60 mg/dL and 82.7% (3260) had Lp(a) < 60 mg/dL. At baseline, uncorrected low density lipoprotein level (107.7 ± 32.0 versus 99.1 ± 31.5) and statin therapy (99.0% versus 97.0%) were higher in patients with high Lp(a) levels, but low density lipoprotein corrected for Lp(a) was lower (80.6 ± 32.0 versus 94.0 ± 31.4) in patients with high Lp(a) levels. Percent atheroma volume was significantly higher in the high Lp(a) group in unadjusted (38.2% [32.8, 43.6] versus 37.1% [31.4, 43.1], P =0.01) and risk‐adjusted analyses (38.7%±0.5 versus 37.5%±0.5, P <0.001). There was a significant association of increasing risk‐adjusted percent atheroma volume across quintiles of Lp(a) (Lp(a) quintiles 1‐5; 37.3 ± 0.5%, 37.2 ± 0.5%, 37.3 ± 0.5%, 38.0 ± 0.5%, 38.5 ± 0.5%, P =0.002). Conclusions Elevated Lp(a) is independently associated with increased percent atheroma volume. Further work is needed to clarify the relationship of Lp(a)‐lowering treatment with cardiovascular outcomes.