Modulation of circulating levels of advanced glycation end products and its impact on intima-media thickness of both common carotid arteries: CORDIOPREV randomised controlled trial

Abstract

Background: Increasing evidence supports the role of advanced glycation end products (AGEs) in atherosclerosis in both diabetic and non-diabetic patients, suggesting that therapeutic strategies targeting AGEs may offer potential benefits in this population. The Mediterranean diet is associated with improved biomarkers and anthropometric measurements related with atherosclerosis in addition to its ability to modulate AGE metabolism. Our aim was to determine whether the reduction in atherosclerosis progression (measured by changes in intima-media thickness of both common carotid arteries (IMT-CC)), observed after consumption of a Mediterranean diet compared to a low-fat diet, is associated with a modulation of circulating AGE levels in patients with coronary heart disease (CHD).

Methods: 1002 CHD patients were divided in: (1) Non-increased IMT-CC patients, whose IMT-CC was reduced or not changed after dietary intervention and (2) Increased IMT-CC patients, whose IMT-CC was increased after dietary intervention. Serum AGE levels (methylglyoxal-MG and Nε-Carboxymethyllysine-CML) and parameters related to AGE metabolism (AGER1 and GloxI mRNA and sRAGE levels) and reduced glutathione (GSH) levels were measured before and after 5-years of dietary intervention.

Results: The Mediterranean diet did not affect MG levels, whereas the low-fat diet significantly increased them compared to baseline (p = 0.029), leading to lower MG levels following the Mediterranean diet than the low-fat diet (p < 0.001). The Mediterranean diet, but not the low-fat diet, produced an upregulation of AGE metabolism, with increased AGER1 and GloxI gene expression as well as increased GSH and sRAGE levels in Non-increased IMT-CC patients (all p < 0.05). Although the Mediterranean diet increased MG levels in Increased IMT-CC patients, this increment was lower compared to the low-fat diet (all p < 0.05).

Conclusions: Our results suggest that an improvement in modulation of AGE metabolism, which facilitates better management of circulating AGE levels, may be one of the mechanisms through which the Mediterranean diet, compared to a low-fat diet, reduces the progression of atherosclerosis in patients with CHD. Trial registration https://clinicaltrials.gov/ct2/show/NCT00924937 , Clinicaltrials.gov number, NCT00924937.

Keywords: Advanced glycation end products; Atherosclerosis; Dietary intervention; Mediterranean diet.

Fig. 1

Screening and randomization flow-chart of the study

Fig. 2

Effect of dietary intervention on IMT-CC in CHD patients classified according to IMT-CC progression. (A) IMT-CC at baseline and after 5-year of dietary intervention; (B) Changes produced between post- and preintervention in IMT-CC after each dietary model. Values are represented as the mean ± standard error. Variables were compared using the analysis of variance (univariate ANOVA) adjusted by age, sex, BMI, hypertension, energy, smoking habits (non-, past- and current smokers), and pharmacological treatments–lipid-lowering therapy, use of antidiabetic drugs and anti-hypertensive drugs. Differences were significant when p < 0.05. *Significant differences between post- and preintervention. #Significant differences between Non-increased IMT-CC and Increased IMT-CC patients. Different common letter superscripts denote significant differences. Non-increased IMT-CC patients, whose IMT-CC was reduced or not changed after dietary intervention (n = 408, 166 in the low-fat diet and 242 in the Mediterranean diet). Increased IMT-CC patients, whose IMT-CC was increased after dietary intervention (n = 401, 211 in the low-fat diet and 190 in the Mediterranean diet). CHD, Coronary heart disease; IMT-CC, intima-media thickness of both common carotid arteries

Fig. 3

Effect of dietary intervention on circulating MG levels and GloxI gene expression in CHD patients classified according to IMT-CC progression. (A) Serum levels of MG at baseline and after 5-year of dietary intervention; (B) Changes produced between post- and preintervention in serum levels of MG after each dietary model; (C) GloxI gene expression at baseline and after 5-year of dietary intervention; B) Changes produced between post- and preintervention in GloxI gene expression after each dietary model. Values are represented as the mean ± standard error. Variables were compared using the analysis of variance (univariate ANOVA) adjusted by age, sex, BMI, hypertension, energy, smoking habits (non-, past- and current smokers), and pharmacological treatments–lipid-lowering therapy, use of antidiabetic drugs and anti-hypertensive drugs. Differences were significant when p < 0.05. *Significant differences between post- and preintervention. #Significant differences between Non-increased IMT-CC and Increased IMT-CC patients. Different common letter superscripts denote significant differences. Non-increased IMT-CC patients, whose IMT-CC was reduced or not changed after dietary intervention (n = 408, 166 in the low-fat diet and 242 in the Mediterranean diet). Increased IMT-CC patients, whose IMT-CC was increased after dietary intervention (n = 401, 211 in the low-fat diet and 190 in the Mediterranean diet). CHD, Coronary heart disease; IMT-CC, intima-media thickness of both common carotid arteries; MG, methylglyoxal; GloxI, glyoxalase I

Fig. 4

Effect of dietary intervention on AGER1 gene expression and sRAGE levels in CHD patients classified according to IMT-CC progression. (A) AGER1 gene expression at baseline and after 5-year of dietary intervention; (B) Changes produced between post- and preintervention in AGER1 gene expression after each dietary model; (C) sRAGE levels at baseline and after 5-year of dietary intervention; (D) Changes produced between post- and preintervention in sRAGE levels after each dietary model. Values are represented as the mean ± standard error. Variables were compared using the analysis of variance (univariate ANOVA) adjusted by age, sex, BMI, hypertension, energy, smoking habits (non-, past- and current smokers), and pharmacological treatments–lipid-lowering therapy, use of antidiabetic drugs and anti-hypertensive drugs. Differences were significant when p < 0.05. *Significant differences between post- and preintervention. #Significant differences between Non-increased IMT-CC and Increased IMT-CC patients. Different common letter superscripts denote significant differences. Non-increased IMT-CC patients, whose IMT-CC was reduced or not changed after dietary intervention (n = 408, 166 in the low-fat diet and 242 in the Mediterranean diet). Increased IMT-CC patients, whose IMT-CC was increased after dietary intervention (n = 401, 211 in the low-fat diet and 190 in the Mediterranean diet). CHD, Coronary heart disease; IMT-CC, intima-media thickness of both common carotid arteries; AGER1, AGE receptor-1; sRAGE: soluble form of receptor for AGEs

Fig. 5

Multiple logistic regression model for predicting changes in IMT-CC regarding modulation of AGEs metabolism by each dietary model. (A) Mediterranean diet (R² = 0.337, constant = 2.552 (p = 0.001)); (B) Low-fat diet (R² = 0.249, constant = 3.270 (p = 0.007)). Squares denote hazard ratios; horizontal lines represent 95% confidence intervals. Predictive variables tested by backward (conditional) method: Age (years), Sex (men and women), Baseline IMT-CC (mm), Changes in Methylglyoxal (mg/mL, Δ post-intervention minus pre-intervention), Changes in GloxI expression (AU, Δ post-intervention minus pre-intervention), Changes in AGER1 expression (AU, Δ post-intervention minus pre-intervention), fasting glucose (mg/dL), HbA1c (%), HDL-cholesterol (mg/dL), triglycerides (mg/dL) and hsCRP levels (mg/mL), smoking habits (non-, past- and current smokers) and medications–lipid-lowering therapy, use of antidiabetic drugs and anti-hypertensive drugs)