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Advanced glycation end products via skin autofluorescence as a new biomarker for major adverse cardiovascular events: A meta-analysis of prospective studies

  • Qimou Chen
    Affiliations
    Department of Endocrinology & Metabolism, University-Town Hospital of Chongqing Medical University, Middle Road of University-Town NO.55, Gaoxin District, Chongqing, China
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  • Qiaojuan Huang
    Affiliations
    Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, No. 1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, China
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  • Weiwei Liu
    Affiliations
    Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, No. 1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, China
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  • Xiaoli Zhou
    Correspondence
    Corresponding author.
    Affiliations
    Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, No. 1, Youyi Road, Yuanjiagang, Yuzhong District, Chongqing, China
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Published:February 03, 2022DOI:https://doi.org/10.1016/j.numecd.2022.01.032

      Highlights

      • Whether AGEs can predict cardiovascular events is controversial.
      • The meta-analysis indicates that AGEs via skin autofluorescence can be new biomarker to predict MACE.
      • The same conclusion has been confirmed in the general population, diabetes or nephropathy patients.

      Abstract

      Aims

      This meta-analysis aimed to systematically evaluate the prospective association between advanced glycation end products (AGEs) and major adverse cardiovascular events (MACE).

      Data synthesis

      Prospective studies that reported the association of AGEs (measured by skin autofluorescence) with MACE were searched in PubMed and EMBASE from inception up to July 2021. Multivariable-adjusted hazard ratios (HRs) and their respective 95% confidence intervals (CIs) reflecting the risk of MACE associated with AGEs were determined using random-effects meta-analysis. Fourteen articles with sixteen items involving 79,389 participants were included. A significant association was found between AGEs and MACE (pooled HR: 1.54, 95% CI: 1.31–1.81, I2 = 68%). Moreover, AGEs were associated with a significant increase in fatal cardiovascular disease (CVD) (HR: 1.88, 95% CI: 1.30–2.70) and nonfatal CVD (HR: 1.40, 95% CI: 1.12–1.74). The association between AGEs and MACE was also significant in patients with diabetes (HR: 1.88, 95% CI: 1.31–2.69) and kidney disease (HR: 1.50, 95% CI: 1.16–1.94).

      Conclusions

      This meta-analysis indicates that higher levels of AGEs measured by skin autofluorescence are significantly correlated with a higher pooled risk of MACE, and AGEs are closely related to both nonfatal and fatal cardiovascular events. AGEs are a valuable biomarker for predicting the occurrence of MACE.

      The PROSPERO registration number

      CRD42021279714.

      Keywords

      Abbreviations:

      AGEs (advanced glycation end products), MACE (major adverse cardiovascular events), SAF (skin autofluorescence), HRs (hazard ratios), CKD (chronic kidney disease), T1DM (type 1 diabetes), T2DM (type 2 diabetes), PAD (peripheral artery disease), PCI (percutaneous coronary intervention), MI (myocardial infarction), PTCA (percutaneous transluminal coronary angioplasty), CABG (coronary artery bypass grafting), TIA (transient ischemic attack), CVA (cerebrovascular accident), AU (indicates arbitrary units), ESRD (end-stage renal disease)

      1. Introduction

      Major adverse cardiovascular events (MACE), including recurrent angina pectoris, acute myocardial infarction, severe arrhythmia, heart failure, stroke, and cardiogenic death [
      • Kip K.E.
      • Hollabaugh K.
      • Marroquin O.C.
      • Williams D.O.
      The problem with composite end points in cardiovascular studies: the story of major adverse cardiac events and percutaneous coronary intervention.
      ], are the main causes of death and disease in many countries in the world. Advanced glycation end products (AGEs), a group of heterogeneous molecules, are produced through nonenzymatic glycation and oxidation of proteins, lipids, and nucleic acids [
      • Prasad K.
      • Tiwari S.
      Therapeutic interventions for advanced glycation-end products and its receptor- mediated cardiovascular disease.
      ]. They alter tissue function and mechanical properties through cross-linking intracellular and extracellular matrix proteins [
      • Bidasee K.R.
      • Nallani K.
      • Yu Y.
      • Cocklin R.R.
      • Zhang Y.
      • Wang M.
      • et al.
      Chronic diabetes increases advanced glycation end products on cardiac ryanodine receptors/calcium-release channels.
      ,
      • Bidasee K.R.
      • Zhang Y.
      • Shao C.H.
      • Wang M.
      • Patel K.P.
      • Dincer U.D.
      • et al.
      Diabetes increases formation of advanced glycation end products on Sarco(endo)plasmic reticulum Ca2+-ATPase.
      ] and binding to their cell surface receptors, thereby modulating multiple cellular processes [
      • Yan S.F.
      • Ramasamy R.
      • Schmidt A.M.
      The receptor for advanced glycation endproducts (RAGE) and cardiovascular disease.
      ]. Enhanced formation and accumulation of AGEs have been reported to occur in some pathogenic conditions, such as diabetes mellitus, renal failure, and chronic inflammation, as well as in natural aging [
      • Ajith T.A.
      • Vinodkumar P.
      Advanced glycation end products: association with the pathogenesis of diseases and the current therapeutic advances.
      ]. Meanwhile, lower intake of AGEs has beneficial effects on insulin resistance and high blood cholesterol and reduces the incidence of obesity and associated chronic diseases [
      • Sohouli M.H.
      • Sharifi-Zahabi E.
      • Lari A.
      • Fatahi S.
      • Shidfar F.
      The impact of low advanced glycation end products diet on obesity and related hormones: a systematic review and meta-analysis.
      ,
      • Sohouli M.H.
      • Fatahi S.
      • Sharifi-Zahabi E.
      • Santos H.O.
      • Tripathi N.
      • Lari A.
      • et al.
      The impact of low advanced glycation end products diet on metabolic risk factors: a systematic review and meta-analysis of randomized controlled trials.
      ]. Notably, using the fluorescence properties of some AGEs, the accumulation of these toxins in the skin can be assessed noninvasively using skin autofluorescence (SAF), which is well correlated with the dermal concentrations of AGEs. Therefore, SAF is considered a noninvasive marker of tissue accumulation of AGEs [
      • Perrone A.
      • Giovino A.
      • Benny J.
      • Martinelli F.
      Advanced glycation end products (AGEs): biochemistry, signaling, analytical methods, and epigenetic effects.
      ].
      Recently, accumulating evidence has indicated that AGEs play an important role in the development of cardiovascular diseases (CVDs). Many studies [
      • Raposeiras-Roubin S.
      • Rodino-Janeiro B.K.
      • Paradela-Dobarro B.
      • Grigorian-Shamagian L.
      • Garcia-Acuna J.M.
      • Aguiar-Souto P.
      • et al.
      Fluorescent advanced glycation end products and their soluble receptor: the birth of new plasmatic biomarkers for risk stratification of acute coronary syndrome.
      ,
      • Raposeiras-Roubin S.
      • Rodino-Janeiro B.K.
      • Paradela-Dobarro B.
      • Almansour H.
      • Grigorian-Shamagian L.
      • Reino-Maceiras M.V.
      • et al.
      Advanced glycation end-products as long-term predictors of death and reinfarction after an acute coronary syndrome.
      ,
      • Jensen L.J.
      • Lindberg S.
      • Hoffmann S.
      • Iversen A.Z.
      • Pedersen S.H.
      • Mogelvang R.
      • et al.
      Dynamic changes in sRAGE levels and relationship with cardiac function in STEMI patients.
      ] have confirmed AGEs as valuable biomarkers for predicting the occurrence of cardiovascular events, such as acute coronary syndrome, cardiac function, or cardiogenic death. However, some studies [
      • Lutgers H.L.
      • Gerrits E.G.
      • Graaff R.
      • Links T.P.
      • Sluiter W.J.
      • Gans R.O.
      • et al.
      Skin autofluorescence provides additional information to the UK Prospective Diabetes Study (UKPDS) risk score for the estimation of cardiovascular prognosis in type 2 diabetes mellitus.
      ,
      • Gerrits E.G.
      • Lutgers H.L.
      • Smeets G.H.
      • Groenier K.H.
      • Smit A.J.
      • Gans R.O.
      • et al.
      Skin autofluorescence: a pronounced marker of mortality in hemodialysis patients.
      ,
      • Fraser S.D.
      • Roderick P.J.
      • McIntyre N.J.
      • Harris S.
      • McIntyre C.W.
      • Fluck R.J.
      • et al.
      Skin autofluorescence and all-cause mortality in stage 3 CKD.
      ,
      • Siriopol D.
      • Hogas S.
      • Veisa G.
      • Mititiuc I.
      • Volovat C.
      • Apetrii M.
      • et al.
      Tissue advanced glycation end products (AGEs), measured by skin autofluorescence, predict mortality in peritoneal dialysis.
      ,
      • Shardlow A.
      • McIntyre N.J.
      • Kolhe N.V.
      • Nellums L.B.
      • Fluck R.J.
      • McIntyre C.W.
      • et al.
      The association of skin autofluorescence with cardiovascular events and all-cause mortality in persons with chronic kidney disease stage 3: a prospective cohort study.
      ] have shown that AGEs have no association with cardiovascular events or cardiogenic death. Therefore, a comprehensive analysis of the relationship between AGEs and CVDs is needed to clarify the association between them. Accordingly, we conducted a systematic review and meta-analysis of the most updated evidence to provide substantive insights into the association of AGEs with the risks of MACE.

      2. Methods

      The meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and was registered in PROSPERO under the registration number CRD42021279714.

      2.1 Search strategy

      We searched the PubMed and EMBASE databases from inception up to July 2021. We used the controlled vocabulary supplemented with keywords to search for prospective studies that evaluated the association between AGEs and the risk of MACE. There is no standard definition for MACE, and the definition varies by study; most studies include MI and cardiogenic death to define MACE [
      • Kip K.E.
      • Hollabaugh K.
      • Marroquin O.C.
      • Williams D.O.
      The problem with composite end points in cardiovascular studies: the story of major adverse cardiac events and percutaneous coronary intervention.
      ]. In the current study, MACE were indicated by a composite of myocardial infarction, stroke, heart failure, other ischemic cardiovascular events, arterial vascular surgery, or cardiogenic death, as presented in Table 1. Details of the search strategy are shown in the supplemental material.
      Table 1Basic characteristics of eligible studies.
      Author (Year)TimeCountryFollow-up duration, yType of patientsñAge, yAGEs, AUDefinition of MACEs, n (%)Relative risk (95% CI)Adjustment factors
      Meerwaldt [
      • Meerwaldt R.
      • Lutgers H.L.
      • Links T.P.
      • Graaff R.
      • Baynes J.W.
      • Gans R.O.
      • et al.
      Skin autofluorescence is a strong predictor of cardiac mortality in diabetes.
      ]
      2007Netherlands5T1DM4845.0 ± 15.01.6 ± 0.5Fatal events; 11 (22.9)OR; 2.00 (1.30–2.70)Age, mean A1C, creatinine, hypertension, hemodialysis treatment, triglycerides, CHD at baseline.
      T2DM6961.0 ± 13.02.1 ± 0.3Fatal events; 23 (33.3)OR; 2.90 (1.30–4.40)Age, creatinine, hypertension, hemodialysis treatment, triglycerides, LDL, BMI, CHD at baseline.
      Lutgers [
      • Lutgers H.L.
      • Gerrits E.G.
      • Graaff R.
      • Links T.P.
      • Sluiter W.J.
      • Gans R.O.
      • et al.
      Skin autofluorescence provides additional information to the UK Prospective Diabetes Study (UKPDS) risk score for the estimation of cardiovascular prognosis in type 2 diabetes mellitus.
      ]
      2009Netherlands3T2DM96766.0 ± 11.02.8 ± 0.8Non-fatal events: MI, CABG, PCI, CVA, amputation, percutaneous transluminal angioplasty, bypass surgery; 75 (7.8)and fatal events; 44 (4.6)HR; 1.21 (0.82–1.79)Microvascular complications, macrovascular complications, and 10 years UKPDS risk score.
      Gerrits [
      • Gerrits E.G.
      • Lutgers H.L.
      • Smeets G.H.
      • Groenier K.H.
      • Smit A.J.
      • Gans R.O.
      • et al.
      Skin autofluorescence: a pronounced marker of mortality in hemodialysis patients.
      ]
      2012Netherlands4.9ESRD10565.1 ± 14.63.16 ± 0.88Fatal events; 34 (32.4)HR; 1.26 (0.63–2.52)Serum albumin, DM, preexisting CVD, renal replacement therapy duration at baseline, age, pulse pressure, hematocrit, serum phosphorus, and PTH.
      Arsov [
      • Arsov S.
      • Trajceska L.
      • van Oeveren W.
      • Smit A.J.
      • Dzekova P.
      • Stegmayr B.
      • et al.
      Increase in skin autofluorescence and release of heart-type fatty acid binding protein in plasma predicts mortality of hemodialysis patients.
      ]
      2013Macedonia3ESRD16956.0 ± 13.03.2 ± 0.9Fatal events; 32 (18.9)HR; 3.01 (1.47–6.17)Age, sex, CVD history, diabetes, hypertension, HbSAg, hemodialysis duration, hs-CRP, MPO, H-FABP, albumin.
      Fraser [
      • Fraser S.D.
      • Roderick P.J.
      • McIntyre N.J.
      • Harris S.
      • McIntyre C.W.
      • Fluck R.J.
      • et al.
      Skin autofluorescence and all-cause mortality in stage 3 CKD.
      ]
      2014UK3.6CKD3170773.0 ± 9.02.7 ± 0.7Fatal events; 69 (4.0)HR; 2.96 (0.95–4.71)Age, sex, CVD, diabetes, smoking, BMI, eGFR, albuminuria, and hemoglobin.
      Furuya [
      • Furuya F.
      • Shimura H.
      • Takahashi K.
      • Akiyama D.
      • Motosugi A.
      • Ikegishi Y.
      • et al.
      Skin autofluorescence is a predictor of cardiovascular disease in chronic kidney disease patients.
      ]
      2014Japan3ESRD6460.90 ± 13.203.40 ± 0.91Non-fatal events; 21 (32.8)OR; 2.96 (1.26–8.16)Sex, age, hemodialysis duration, DM, hypertension, dyslipidemia, Alb, LDL, TG, PTH, CRP, Hb, HbA1c.
      Kimura [
      • Kimura H.
      • Tanaka K.
      • Kanno M.
      • Watanabe K.
      • Hayashi Y.
      • Asahi K.
      • et al.
      Skin autofluorescence predicts cardiovascular mortality in patients on chronic hemodialysis.
      ]
      2014Japan6ESRD12865.1 ± 11.62.3 ± 0.9Fatal events; 19 (14.8)HR; 3.97 (1.67–9.43)Gender, age, dialysis duration, diabetes, carotid IMT, albumin, pentosidine, high-sensitivity C-reactive protein, pre-existing CVD.
      Lisanne [
      • de Vos L.C.
      • Mulder D.J.
      • Smit A.J.
      • Dullaart R.P.
      • Kleefstra N.
      • Lijfering W.M.
      • et al.
      Skin autofluorescence is associated with 5-year mortality and cardiovascular events in patients with peripheral artery disease.
      ]
      2014Netherlands5.1PAD25266.0 ± 11.02.7 ± 0.7Fatal & non-fatal events: cardiovascular death and non-MI or stroke; 62 (25)HR; 1.50 (1.04–2.17)Cardiovascular risk factors and the use of lipid-lowering drugs.
      Siriopol [
      • Siriopol D.
      • Hogas S.
      • Veisa G.
      • Mititiuc I.
      • Volovat C.
      • Apetrii M.
      • et al.
      Tissue advanced glycation end products (AGEs), measured by skin autofluorescence, predict mortality in peritoneal dialysis.
      ]
      2015Romania2.5ESRD30456.7 ± 14.43.6 ± 0.8Fatal events: coronary heart disease, sudden death, and stroke; 21 (6.9)HR; 1.22 (0.69–2.16)None.
      Céphise [
      • Velayoudom-Cephise F.L.
      • Rajaobelina K.
      • Helmer C.
      • Nov S.
      • Pupier E.
      • Blanco L.
      • et al.
      Skin autofluorescence predicts cardio-renal outcome in type 1 diabetes: a longitudinal study.
      ]
      2016France4T1DM24351.2 ± 16.72.13 ± 0.58Non-fatal events: MI, stroke, gangrene, revascularization procedures; 14 (5.7)OR; 4.84 (1.31–17.89)Age, sex, BMI, tobacco, diabetes duration, hypertension, HbA1c, AER, eGFR.
      Blanc-Bisson [
      • Blanc-Bisson C.
      • Velayoudom-Cephise F.L.
      • Cougnard-Gregoire A.
      • Helmer C.
      • Rajaobelina K.
      • Delcourt C.
      • et al.
      Skin autofluorescence predicts major adverse cardiovascular events in patients with type 1 diabetes: a 7-year follow-up study.
      ]
      2018France7T1DM23251.5 ± 16.725.0 ± 4.1Non-fatal events: MI, limb amputation, revascularization procedures; 22 (9.5)HR; 4.13 (1.30–13.07)Age, sex, diabetes duration, BMI, hypertension, smoking status, albumin excretion rates, statin treatment, and a previous history of MACE.
      Yozgatli [
      • Yozgatli K.
      • Lefrandt J.D.
      • Noordzij M.J.
      • Oomen P.H.N.
      • Brouwer T.
      • Jager J.
      • et al.
      Accumulation of advanced glycation end products is associated with macrovascular events and glycaemic control with microvascular complications in Type 2 diabetes mellitus.
      ]
      2018Netherlands5.1T2DM514642.77Non-fatal events: coronary heart disease, CVA, PAD:189 (37%)HR; 1.28 (1.03–1.60)The UKPDS risk score
      Waateringe [
      • van Waateringe R.P.
      • Fokkens B.T.
      • Slagter S.N.
      • van der Klauw M.M.
      • van Vliet-Ostaptchouk J.V.
      • Graaff R.
      • et al.
      Skin autofluorescence predicts incident type 2 diabetes, cardiovascular disease and mortality in the general population.
      ]
      2019Netherlands6Ordinary72,88043.7 ± 12.025.8 ± 4.1Non-fatal events: MI, PTCA, stent positioning, CABG, TIA, CVA, intermittent claudication, or peripheral artery vascular surgery; 1258 (1.7)OR; 1.33 (1.16–1.54)Age, sex, waist, glucose, SBP, cholesterol, triacylglycerol, eGFR, smoke.
      Shardlow [
      • Shardlow A.
      • McIntyre N.J.
      • Kolhe N.V.
      • Nellums L.B.
      • Fluck R.J.
      • McIntyre C.W.
      • et al.
      The association of skin autofluorescence with cardiovascular events and all-cause mortality in persons with chronic kidney disease stage 3: a prospective cohort study.
      ]
      2020UK6CKD3170772.9 ± 9.02.6 ± 0.6Non-fatal events: MI, stroke, TIA, cardiac failure, revascularization; 485 (28.4)HR; 1.12 (1.01–1.23)Age, sex, DM, previous CVD, hypertension, smoke, BP, BMI, eGFR, UACR, albumin, uric acid, cholesterol, hemoglobin, hsCRP
      CKD3170772.9 ± 9.02.6 ± 0.6Fatal events; 105 (6.1)HR; 1.12 (0.92–1.35)Age, sex, previous CVD, BMI, eGFR, UACR, albumin, uric acid, cholesterol, hsCRP
      CKD, chronic kidney disease; T1DM, type 1 diabetes; T2DM, type 2 diabetes; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; MI, myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty; CABG, coronary artery bypass grafting; TIA, transient ischemic attack; CVA, cerebrovascular accident; AU, indicates arbitrary units; ESRD, end-stage renal disease; PTH, phosphorus and parathyroid hormone; eGFR, estimated glomerular filtration rate; AER, urinary albumin excretion rate; hsCRP, high-sensitivity C reactive protein; UACR, urine albumin to creatinine ratio; IMT, intima-media thickness; HbSAg, hepatitis B surface antigen; MPO, myeloperoxidase; H-FABP, heart-type fatty acid binding protein.

      2.2 Study selection

      The relevant studies were selected by two investigators (Q.C. and Q.H.) independently, and any conflicts were resolved by consensus or consultation with a third investigator (Z.X.). The inclusion criteria were as follows: (1) prospective studies; (2) not reviews, letters, editorials, and case reports; (3) the exposure was AGEs measured by the SAF; (4) the outcome was MACE; (5) the studies were published in English. The exclusion criteria were as follows: (1) nonhuman studies; (2) clinical trials or case-control studies; (3) participants' age ≤18 years; (4) there were no experimental data in the publications; (5) the estimates were presented without hazard ratio (HR) or other information that allowed calculation of HR; (6) the outcomes were microvascular events (including nephropathy, retinopathy, and neuropathy), atherosclerosis, aortic stiffness, hypertension, venous thrombus, or atrial fibrillation.
      The investigators selected potentially eligible publications through a preliminary review of the titles and abstracts as well as detailed reading of the full text. When more than one study provided data from the same sample, we selected the most detailed results, the largest sample size, or the longer follow-up data.

      2.3 Data extraction

      Two authors (Q.C. and Q.H) extracted the data independently using a standardized spreadsheet. The following information was extracted from the included studies: first author, year of publication, country and follow-up duration, sample sizes, patients’ baseline information (patient type, male percentage, age, and the level of AGEs), and outcomes of interest (MACE). Any inconsistencies were resolved through discussion with a third author (X.Z.).

      2.4 Quality assessment

      The quality of evidence was rated using the Newcastle–Ottawa Scale tool [
      • Stang A.
      Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses.
      ]. The content of assessment included three domains: selection, comparability, and outcome. Detailed rules are shown in Table S1. The scores ranged from 0 to 9 points, with 7–9 points as high quality, 5 to 6 points as medium quality, and 0 to 4 points as poor quality.

      2.5 Statistical analysis

      HR estimates adjusted for the maximum number of covariates from the included studies were pooled using a random-effects meta-analysis. Forest plots were drawn to intuitively visualize the HRs and corresponding 95% confidence intervals (CIs) across studies for each outcome using a random-effects model. The Cochrane Q statistic and the I2 statistic were calculated to evaluate heterogeneity across the included studies, P < 0.10 was deemed to be statistically significant, and the percentages of I2 were divided into 0–25%, 26–50%, 51–75%, and 76–100%, which were considered as low, modest, moderate, and high probability of heterogeneity, respectively [
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ]. In addition, sensitivity analyses were performed by excluding studies one at a time. When the new HRs are modified to CI of the original profile estimate, the results of the sensitivity analysis are considered meaningful. Funnel plots, Egger's test, and Begg's test were used to evaluate publication bias. When publication bias was indicated, the trim-and-fill method was used to assess whether the results were stable. All analytical procedures were conducted with Review Manager (RevMan) Version 5.3 (The Cochrane Collaboration) and STATA version 17.0 (StataCorp, 4905 Lakeway Dr, College Station, TX 77845, USA).

      3. Results

      3.1 Characteristics of the included studies

      In total, 9523 potentially relevant publications were identified. Of these, 3672 studies were removed as duplicates. After screening titles and abstracts, 547 studies were identified for a more detailed evaluation. After further examinations, we finally included 14 studies [
      • Lutgers H.L.
      • Gerrits E.G.
      • Graaff R.
      • Links T.P.
      • Sluiter W.J.
      • Gans R.O.
      • et al.
      Skin autofluorescence provides additional information to the UK Prospective Diabetes Study (UKPDS) risk score for the estimation of cardiovascular prognosis in type 2 diabetes mellitus.
      ,
      • Gerrits E.G.
      • Lutgers H.L.
      • Smeets G.H.
      • Groenier K.H.
      • Smit A.J.
      • Gans R.O.
      • et al.
      Skin autofluorescence: a pronounced marker of mortality in hemodialysis patients.
      ,
      • Fraser S.D.
      • Roderick P.J.
      • McIntyre N.J.
      • Harris S.
      • McIntyre C.W.
      • Fluck R.J.
      • et al.
      Skin autofluorescence and all-cause mortality in stage 3 CKD.
      ,
      • Siriopol D.
      • Hogas S.
      • Veisa G.
      • Mititiuc I.
      • Volovat C.
      • Apetrii M.
      • et al.
      Tissue advanced glycation end products (AGEs), measured by skin autofluorescence, predict mortality in peritoneal dialysis.
      ,
      • Shardlow A.
      • McIntyre N.J.
      • Kolhe N.V.
      • Nellums L.B.
      • Fluck R.J.
      • McIntyre C.W.
      • et al.
      The association of skin autofluorescence with cardiovascular events and all-cause mortality in persons with chronic kidney disease stage 3: a prospective cohort study.
      ,
      • Meerwaldt R.
      • Lutgers H.L.
      • Links T.P.
      • Graaff R.
      • Baynes J.W.
      • Gans R.O.
      • et al.
      Skin autofluorescence is a strong predictor of cardiac mortality in diabetes.
      ,
      • Arsov S.
      • Trajceska L.
      • van Oeveren W.
      • Smit A.J.
      • Dzekova P.
      • Stegmayr B.
      • et al.
      Increase in skin autofluorescence and release of heart-type fatty acid binding protein in plasma predicts mortality of hemodialysis patients.
      ,
      • Furuya F.
      • Shimura H.
      • Takahashi K.
      • Akiyama D.
      • Motosugi A.
      • Ikegishi Y.
      • et al.
      Skin autofluorescence is a predictor of cardiovascular disease in chronic kidney disease patients.
      ,
      • Kimura H.
      • Tanaka K.
      • Kanno M.
      • Watanabe K.
      • Hayashi Y.
      • Asahi K.
      • et al.
      Skin autofluorescence predicts cardiovascular mortality in patients on chronic hemodialysis.
      ,
      • de Vos L.C.
      • Mulder D.J.
      • Smit A.J.
      • Dullaart R.P.
      • Kleefstra N.
      • Lijfering W.M.
      • et al.
      Skin autofluorescence is associated with 5-year mortality and cardiovascular events in patients with peripheral artery disease.
      ,
      • Velayoudom-Cephise F.L.
      • Rajaobelina K.
      • Helmer C.
      • Nov S.
      • Pupier E.
      • Blanco L.
      • et al.
      Skin autofluorescence predicts cardio-renal outcome in type 1 diabetes: a longitudinal study.
      ,
      • Blanc-Bisson C.
      • Velayoudom-Cephise F.L.
      • Cougnard-Gregoire A.
      • Helmer C.
      • Rajaobelina K.
      • Delcourt C.
      • et al.
      Skin autofluorescence predicts major adverse cardiovascular events in patients with type 1 diabetes: a 7-year follow-up study.
      ,
      • Yozgatli K.
      • Lefrandt J.D.
      • Noordzij M.J.
      • Oomen P.H.N.
      • Brouwer T.
      • Jager J.
      • et al.
      Accumulation of advanced glycation end products is associated with macrovascular events and glycaemic control with microvascular complications in Type 2 diabetes mellitus.
      ,
      • van Waateringe R.P.
      • Fokkens B.T.
      • Slagter S.N.
      • van der Klauw M.M.
      • van Vliet-Ostaptchouk J.V.
      • Graaff R.
      • et al.
      Skin autofluorescence predicts incident type 2 diabetes, cardiovascular disease and mortality in the general population.
      ] with 16 items involving 79,388 patients in the current meta-analysis. The flowchart is shown in Fig. 1.
      Figure 1
      Figure 1Flowchart of the results of the literature search and study selection.
      All 14 eligible articles were derived from prospective studies, whose baseline characteristics are shown in Table 1. Five studies investigated associations of diabetes with CVD events [
      • Lutgers H.L.
      • Gerrits E.G.
      • Graaff R.
      • Links T.P.
      • Sluiter W.J.
      • Gans R.O.
      • et al.
      Skin autofluorescence provides additional information to the UK Prospective Diabetes Study (UKPDS) risk score for the estimation of cardiovascular prognosis in type 2 diabetes mellitus.
      ,
      • Meerwaldt R.
      • Lutgers H.L.
      • Links T.P.
      • Graaff R.
      • Baynes J.W.
      • Gans R.O.
      • et al.
      Skin autofluorescence is a strong predictor of cardiac mortality in diabetes.
      ,
      • Velayoudom-Cephise F.L.
      • Rajaobelina K.
      • Helmer C.
      • Nov S.
      • Pupier E.
      • Blanco L.
      • et al.
      Skin autofluorescence predicts cardio-renal outcome in type 1 diabetes: a longitudinal study.
      ,
      • Blanc-Bisson C.
      • Velayoudom-Cephise F.L.
      • Cougnard-Gregoire A.
      • Helmer C.
      • Rajaobelina K.
      • Delcourt C.
      • et al.
      Skin autofluorescence predicts major adverse cardiovascular events in patients with type 1 diabetes: a 7-year follow-up study.
      ,
      • Yozgatli K.
      • Lefrandt J.D.
      • Noordzij M.J.
      • Oomen P.H.N.
      • Brouwer T.
      • Jager J.
      • et al.
      Accumulation of advanced glycation end products is associated with macrovascular events and glycaemic control with microvascular complications in Type 2 diabetes mellitus.
      ], seven studies investigated associations of nephropathy with CVD events [
      • Gerrits E.G.
      • Lutgers H.L.
      • Smeets G.H.
      • Groenier K.H.
      • Smit A.J.
      • Gans R.O.
      • et al.
      Skin autofluorescence: a pronounced marker of mortality in hemodialysis patients.
      ,
      • Fraser S.D.
      • Roderick P.J.
      • McIntyre N.J.
      • Harris S.
      • McIntyre C.W.
      • Fluck R.J.
      • et al.
      Skin autofluorescence and all-cause mortality in stage 3 CKD.
      ,
      • Siriopol D.
      • Hogas S.
      • Veisa G.
      • Mititiuc I.
      • Volovat C.
      • Apetrii M.
      • et al.
      Tissue advanced glycation end products (AGEs), measured by skin autofluorescence, predict mortality in peritoneal dialysis.
      ,
      • Shardlow A.
      • McIntyre N.J.
      • Kolhe N.V.
      • Nellums L.B.
      • Fluck R.J.
      • McIntyre C.W.
      • et al.
      The association of skin autofluorescence with cardiovascular events and all-cause mortality in persons with chronic kidney disease stage 3: a prospective cohort study.
      ,
      • Arsov S.
      • Trajceska L.
      • van Oeveren W.
      • Smit A.J.
      • Dzekova P.
      • Stegmayr B.
      • et al.
      Increase in skin autofluorescence and release of heart-type fatty acid binding protein in plasma predicts mortality of hemodialysis patients.
      ,
      • Furuya F.
      • Shimura H.
      • Takahashi K.
      • Akiyama D.
      • Motosugi A.
      • Ikegishi Y.
      • et al.
      Skin autofluorescence is a predictor of cardiovascular disease in chronic kidney disease patients.
      ,
      • Kimura H.
      • Tanaka K.
      • Kanno M.
      • Watanabe K.
      • Hayashi Y.
      • Asahi K.
      • et al.
      Skin autofluorescence predicts cardiovascular mortality in patients on chronic hemodialysis.
      ], one study was conducted in the general population [
      • van Waateringe R.P.
      • Fokkens B.T.
      • Slagter S.N.
      • van der Klauw M.M.
      • van Vliet-Ostaptchouk J.V.
      • Graaff R.
      • et al.
      Skin autofluorescence predicts incident type 2 diabetes, cardiovascular disease and mortality in the general population.
      ], and another study investigated peripheral vascular disease [
      • de Vos L.C.
      • Mulder D.J.
      • Smit A.J.
      • Dullaart R.P.
      • Kleefstra N.
      • Lijfering W.M.
      • et al.
      Skin autofluorescence is associated with 5-year mortality and cardiovascular events in patients with peripheral artery disease.
      ]. In all studies, the level of AGEs was evaluated through SAF. The included studies were published from 2007 to 2020. The sample sizes of the included patients ranged from 48 to 72,880, whose average ages were 43.7–73.0 years. The proportion of males ranged from 39.0 to 73.4%. The mean or median follow-up period ranged from 2.5 to 7 years. The mean baseline levels of AGEs ranged from 1.6 AU to 25.8 AU. Twelve studies [
      • Lutgers H.L.
      • Gerrits E.G.
      • Graaff R.
      • Links T.P.
      • Sluiter W.J.
      • Gans R.O.
      • et al.
      Skin autofluorescence provides additional information to the UK Prospective Diabetes Study (UKPDS) risk score for the estimation of cardiovascular prognosis in type 2 diabetes mellitus.
      ,
      • Gerrits E.G.
      • Lutgers H.L.
      • Smeets G.H.
      • Groenier K.H.
      • Smit A.J.
      • Gans R.O.
      • et al.
      Skin autofluorescence: a pronounced marker of mortality in hemodialysis patients.
      ,
      • Fraser S.D.
      • Roderick P.J.
      • McIntyre N.J.
      • Harris S.
      • McIntyre C.W.
      • Fluck R.J.
      • et al.
      Skin autofluorescence and all-cause mortality in stage 3 CKD.
      ,
      • Siriopol D.
      • Hogas S.
      • Veisa G.
      • Mititiuc I.
      • Volovat C.
      • Apetrii M.
      • et al.
      Tissue advanced glycation end products (AGEs), measured by skin autofluorescence, predict mortality in peritoneal dialysis.
      ,
      • Shardlow A.
      • McIntyre N.J.
      • Kolhe N.V.
      • Nellums L.B.
      • Fluck R.J.
      • McIntyre C.W.
      • et al.
      The association of skin autofluorescence with cardiovascular events and all-cause mortality in persons with chronic kidney disease stage 3: a prospective cohort study.
      ,
      • Meerwaldt R.
      • Lutgers H.L.
      • Links T.P.
      • Graaff R.
      • Baynes J.W.
      • Gans R.O.
      • et al.
      Skin autofluorescence is a strong predictor of cardiac mortality in diabetes.
      ,
      • Arsov S.
      • Trajceska L.
      • van Oeveren W.
      • Smit A.J.
      • Dzekova P.
      • Stegmayr B.
      • et al.
      Increase in skin autofluorescence and release of heart-type fatty acid binding protein in plasma predicts mortality of hemodialysis patients.
      ,
      • de Vos L.C.
      • Mulder D.J.
      • Smit A.J.
      • Dullaart R.P.
      • Kleefstra N.
      • Lijfering W.M.
      • et al.
      Skin autofluorescence is associated with 5-year mortality and cardiovascular events in patients with peripheral artery disease.
      ,
      • Velayoudom-Cephise F.L.
      • Rajaobelina K.
      • Helmer C.
      • Nov S.
      • Pupier E.
      • Blanco L.
      • et al.
      Skin autofluorescence predicts cardio-renal outcome in type 1 diabetes: a longitudinal study.
      ,
      • Blanc-Bisson C.
      • Velayoudom-Cephise F.L.
      • Cougnard-Gregoire A.
      • Helmer C.
      • Rajaobelina K.
      • Delcourt C.
      • et al.
      Skin autofluorescence predicts major adverse cardiovascular events in patients with type 1 diabetes: a 7-year follow-up study.
      ,
      • Yozgatli K.
      • Lefrandt J.D.
      • Noordzij M.J.
      • Oomen P.H.N.
      • Brouwer T.
      • Jager J.
      • et al.
      Accumulation of advanced glycation end products is associated with macrovascular events and glycaemic control with microvascular complications in Type 2 diabetes mellitus.
      ,
      • van Waateringe R.P.
      • Fokkens B.T.
      • Slagter S.N.
      • van der Klauw M.M.
      • van Vliet-Ostaptchouk J.V.
      • Graaff R.
      • et al.
      Skin autofluorescence predicts incident type 2 diabetes, cardiovascular disease and mortality in the general population.
      ] were performed in Europe (Macedonia, UK, The Netherlands, France, and Romania), and two studies [
      • Furuya F.
      • Shimura H.
      • Takahashi K.
      • Akiyama D.
      • Motosugi A.
      • Ikegishi Y.
      • et al.
      Skin autofluorescence is a predictor of cardiovascular disease in chronic kidney disease patients.
      ,
      • Kimura H.
      • Tanaka K.
      • Kanno M.
      • Watanabe K.
      • Hayashi Y.
      • Asahi K.
      • et al.
      Skin autofluorescence predicts cardiovascular mortality in patients on chronic hemodialysis.
      ] were conducted in an Asian country (Japan).
      For all the included studies, the average Newcastle–Ottawa Scale scores ranged from 6 to 9, indicating medium-to-high methodological quality (Additional file: Table S1).

      3.2 Association of AGEs with MACE

      Overall, all 14 studies with 16 items reported MACE as outcomes, including nonfatal or fatal cardiovascular events. In the pooled analysis of 16 items, a significant positive association was observed between AGEs and MACE (HR: 1.54, 95% CI: 1.31–1.81), with high heterogeneity (I2 = 68%, P < 0.0001). Meanwhile, the subgroup analyses based on different events showed a stronger positive association between AGEs and MACE in fatal CVD (HR: 1.88, 95% CI: 1.30–2.70) than in nonfatal CVD (HR: 1.40, 95% CI: 1.12–1.74). However, there was still significant heterogeneity in each subgroup (fatal CVD: I2 = 79%, P < 0.0001; nonfatal CVD: I2 = 62%, P = 0.02) (Fig. 2).
      Figure 2
      Figure 2Association between AGEs and MACE: stratified by specific disease outcomes (fatal events; nonfatal events; fatal events & nonfatal events) [the hazard ratios (HRs) were pooled using random-effects meta-analysis].

      3.3 Association of AGEs with MACE in diabetic patients

      Four of the included studies investigated the association of AGEs with MACE in diabetic patients [
      • Lutgers H.L.
      • Gerrits E.G.
      • Graaff R.
      • Links T.P.
      • Sluiter W.J.
      • Gans R.O.
      • et al.
      Skin autofluorescence provides additional information to the UK Prospective Diabetes Study (UKPDS) risk score for the estimation of cardiovascular prognosis in type 2 diabetes mellitus.
      ,
      • Meerwaldt R.
      • Lutgers H.L.
      • Links T.P.
      • Graaff R.
      • Baynes J.W.
      • Gans R.O.
      • et al.
      Skin autofluorescence is a strong predictor of cardiac mortality in diabetes.
      ,
      • Velayoudom-Cephise F.L.
      • Rajaobelina K.
      • Helmer C.
      • Nov S.
      • Pupier E.
      • Blanco L.
      • et al.
      Skin autofluorescence predicts cardio-renal outcome in type 1 diabetes: a longitudinal study.
      ,
      • Blanc-Bisson C.
      • Velayoudom-Cephise F.L.
      • Cougnard-Gregoire A.
      • Helmer C.
      • Rajaobelina K.
      • Delcourt C.
      • et al.
      Skin autofluorescence predicts major adverse cardiovascular events in patients with type 1 diabetes: a 7-year follow-up study.
      ,
      • Yozgatli K.
      • Lefrandt J.D.
      • Noordzij M.J.
      • Oomen P.H.N.
      • Brouwer T.
      • Jager J.
      • et al.
      Accumulation of advanced glycation end products is associated with macrovascular events and glycaemic control with microvascular complications in Type 2 diabetes mellitus.
      ]. Our random-effects meta-analysis showed that higher AGEs increased MACE, regardless of the type of diabetes (HR: 1.88, 95% CI: 1.31–2.69, I2 = 69%, P = 0.007). These analyses indicated that type 1 diabetes mellitus (HR: 2.61, 95% CI: 1.50–4.55) more effectively increased MACE than type 2 diabetes mellitus (HR: 1.52, 95% CI: 1.02–2.27). Moreover, significant heterogeneity was found among these studies (Fig. 3).
      Figure 3
      Figure 3Association between AGEs and MACE in diabetic patients: stratified by the type of patients [the hazard ratios (HRs) were pooled using random-effects meta-analysis]. T1DM, type 1 diabetes; T2DM, type 2 diabetes.

      3.4 Association of AGEs with MACE in renal patients

      Similarly, when the available studies were stratified by renal patients [
      • Gerrits E.G.
      • Lutgers H.L.
      • Smeets G.H.
      • Groenier K.H.
      • Smit A.J.
      • Gans R.O.
      • et al.
      Skin autofluorescence: a pronounced marker of mortality in hemodialysis patients.
      ,
      • Fraser S.D.
      • Roderick P.J.
      • McIntyre N.J.
      • Harris S.
      • McIntyre C.W.
      • Fluck R.J.
      • et al.
      Skin autofluorescence and all-cause mortality in stage 3 CKD.
      ,
      • Siriopol D.
      • Hogas S.
      • Veisa G.
      • Mititiuc I.
      • Volovat C.
      • Apetrii M.
      • et al.
      Tissue advanced glycation end products (AGEs), measured by skin autofluorescence, predict mortality in peritoneal dialysis.
      ,
      • Shardlow A.
      • McIntyre N.J.
      • Kolhe N.V.
      • Nellums L.B.
      • Fluck R.J.
      • McIntyre C.W.
      • et al.
      The association of skin autofluorescence with cardiovascular events and all-cause mortality in persons with chronic kidney disease stage 3: a prospective cohort study.
      ,
      • Arsov S.
      • Trajceska L.
      • van Oeveren W.
      • Smit A.J.
      • Dzekova P.
      • Stegmayr B.
      • et al.
      Increase in skin autofluorescence and release of heart-type fatty acid binding protein in plasma predicts mortality of hemodialysis patients.
      ,
      • Furuya F.
      • Shimura H.
      • Takahashi K.
      • Akiyama D.
      • Motosugi A.
      • Ikegishi Y.
      • et al.
      Skin autofluorescence is a predictor of cardiovascular disease in chronic kidney disease patients.
      ,
      • Kimura H.
      • Tanaka K.
      • Kanno M.
      • Watanabe K.
      • Hayashi Y.
      • Asahi K.
      • et al.
      Skin autofluorescence predicts cardiovascular mortality in patients on chronic hemodialysis.
      ], a significant association between AGEs and MACE was found after pooling effect sizes (HR: 1.50, 95% CI: 1.16–1.94, I2 = 67%, P = 0.003). In addition, AGEs showed a stronger positive association with MACE in hemodialysis patients (HR: 2.09, 95% CI: 1.28–3.42) than in non-hemodialysis patients (HR: 1.13, 95% CI: 1.01–1.27) (Fig. 4). Notably, no significant heterogeneity was found in the subgroup (hemodialysis patients: I2 = 55%, P = 0.06; non-hemodialysis patients: I2 = 16%, P = 0.30).
      Figure 4
      Figure 4Association between AGEs and MACE in renal patients: stratified by the type of patients [the hazard ratios (HRs) were pooled using random-effects meta-analysis].

      3.5 Sensitivity analysis

      Sensitivity analysis was performed by excluding individual studies each time to detect the impact of individual data on pooled HR. The pooled HR estimates did not change significantly in the range or direction (Additional file: Fig. S1). The results from sensitivity analysis indicated that our results were robust.

      3.6 Publication bias

      The funnel plots used to assess the publication bias are shown in Supplementary Fig. S2. The funnel plot showed asymmetry, indicating publication bias, which was also confirmed with Egger's test (P = 0.000) and Begg's test (P = 0.000) (Fig. S3). Using the trim and fill method in the random-effects model, the results did not change significantly after the addition of 5 studies (HR: 1.38; 95% CI: 1.17–1.63). The direction of the results was not different from that of the original results, suggesting that the outcome was stable (Fig. S4).

      4. Discussion

      Although previous studies have inconsistent findings on the relationship between AGEs and cardiovascular events, some meta-analyses [
      • Cavero-Redondo I.
      • Soriano-Cano A.
      • Alvarez-Bueno C.
      • Cunha P.G.
      • Martinez-Hortelano J.A.
      • Garrido-Miguel M.
      • et al.
      Skin autofluorescence-indicated advanced glycation end products as predictors of cardiovascular and all-cause mortality in high-risk subjects: a systematic review and meta-analysis.
      ,
      • Sharifi-Zahabi E.
      • Sharafabad F.H.
      • Abdollahzad H.
      • Malekahmadi M.
      • Rad N.B.
      Circulating advanced glycation end products and their soluble receptors in relation to all-cause and cardiovascular mortality: a systematic review and meta-analysis of prospective observational studies.
      ,
      • Varikasuvu S.R.
      • Sulekar H.
      • Aloori S.
      • Thangappazham B.
      The association of non-invasive skin autofluorescence measurements with cardiovascular and all-cause mortality in hemodialysis patients: a meta-analysis.
      ,
      • Adamopoulos C.
      • Farmaki E.
      • Spilioti E.
      • Kiaris H.
      • Piperi C.
      • Papavassiliou A.G.
      Advanced glycation end-products induce endoplasmic reticulum stress in human aortic endothelial cells.
      ] published in recent years concluded that there was a clear correlation between AGEs and cardiovascular and all-cause mortality. Different from the previously published meta-analyses, we included newer studies with larger sample sizes in this meta-analysis. Our results suggest that the level of AGEs measured by SAF is significantly correlated with MACE, and higher AGEs indicate a higher risk of cardiovascular events (fatal or nonfatal CVD), regardless of the general population, patients with diabetes, or those with kidney diseases.
      We further found that AGEs mainly produce biological effects (e.g., causing CVDs) through two mechanisms [
      • Adamopoulos C.
      • Farmaki E.
      • Spilioti E.
      • Kiaris H.
      • Piperi C.
      • Papavassiliou A.G.
      Advanced glycation end-products induce endoplasmic reticulum stress in human aortic endothelial cells.
      ,
      • Fishman S.L.
      • Sonmez H.
      • Basman C.
      • Singh V.
      • Poretsky L.
      The role of advanced glycation end-products in the development of coronary artery disease in patients with and without diabetes mellitus: a review.
      ,
      • Oleniuc M.
      • Secara I.
      • Onofriescu M.
      • Hogas S.
      • Voroneanu L.
      • Siriopol D.
      • et al.
      Consequences of advanced glycation end products accumulation in chronic kidney disease and clinical usefulness of their assessment using a non-invasive technique - skin autofluorescence.
      ,
      • Zieman S.J.
      • Kass D.A.
      Advanced glycation end product crosslinking in the cardiovascular system: potential therapeutic target for cardiovascular disease.
      ]. First, AGEs directly modify the structure of proteins, lipids, and nucleic acids to change their functions. Second, AGEs combine with the specific receptors to cause structural changes and functional disturbances of the artery endothelial and cardiac muscle cells. It has been confirmed that AGEs can increase or decrease the activity of various enzymes [
      • Ren X.
      • Ren L.
      • Wei Q.
      • Shao H.
      • Chen L.
      • Liu N.
      Advanced glycation end-products decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells.
      ], modify mitochondrial proteins of vascular endothelial cells [
      • Neviere R.
      • Yu Y.
      • Wang L.
      • Tessier F.
      • Boulanger E.
      Implication of advanced glycation end products (Ages) and their receptor (Rage) on myocardial contractile and mitochondrial functions.
      ], and cross-link with collagen and elastic proteins [
      • Sell D.R.
      • Monnier V.M.
      Molecular basis of arterial stiffening: role of glycation - a mini-review.
      ], directly quenching nitric oxide activity [
      • Ren X.
      • Ren L.
      • Wei Q.
      • Shao H.
      • Chen L.
      • Liu N.
      Advanced glycation end-products decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells.
      ], which all can induce vascular inflammation and compliance. The mitogen-activated protein kinase, nuclear factor kappa B, and other pathways and cytokine activation can also be induced by AGEs-RAGE to aggravate vascular injury [
      • Ren X.
      • Ren L.
      • Wei Q.
      • Shao H.
      • Chen L.
      • Liu N.
      Advanced glycation end-products decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells.
      ], resulting in intravascular lipid accumulation.
      The reasons for limiting the method of measuring AGEs levels in this meta-analysis are based on the following points. AGEs have a high degree of heterogeneity, and their detection methods include chromatographic analysis, ELISA, immunohistochemistry, radioimmunity, and immunofluorescence spectroscopy. However, there is a lack of effective, convenient, rapid, and unified detection methods in the clinic [
      • Perrone A.
      • Giovino A.
      • Benny J.
      • Martinelli F.
      Advanced glycation end products (AGEs): biochemistry, signaling, analytical methods, and epigenetic effects.
      ]. The serological method and immunofluorescence are the main methods to measure AGEs in clinical studies, and the serum level of AGEs is affected by endogenous, exogenous, and other factors [
      • Bodiga V.L.
      • Eda S.R.
      • Bodiga S.
      Advanced glycation end products: role in pathology of diabetic cardiomyopathy.
      ]. There may be transient fluctuations, and there is a certain deviation in the prediction of long-term prognosis and disease occurrence. The cross-linking between AGEs and dermis collagen is a chronic process, and the deposition level is more correlated with the occurrence and development of the disease. Based on the fluorescence characteristics of some of the accumulated AGEs in the dermis, SAF can detect the accumulation of AGEs in the skin noninvasively. Moreover, some studies have confirmed that SAF is associated with the accumulation of AGEs in the skin measured by skin biopsies [
      • Meerwaldt R.
      • Links T.
      • Graaff R.
      • Thorpe S.R.
      • Baynes J.W.
      • Hartog J.
      • et al.
      Simple noninvasive measurement of skin autofluorescence.
      ]. Although SAF indirectly estimates the accumulation of AGEs in humans, because of its low cost, simplicity, noninvasively, and reproducibility, it has been widely used in clinical research of AGEs in many countries. To avoid the difference and heterogeneity caused by different detection methods, the levels of AGEs were all measured by immunofluorescence in the studies included in this meta-analysis.
      Our study also has several notable limitations. First, although we conducted a detailed literature search, the relatively small amount of included articles restricted our ability to perform more subgroup analyses (e.g., stratified by age, body mass index, sex, participant characteristics, CVD subtypes, and disease status) and determine the source of heterogeneity. Although we attempted to do a subgroup analysis of the type of diabetes and the severity of nephropathy, limited experimental data make the results difficult to be convincing. Obviously, more high-quality prospective studies are needed. Second, most of the studies included in this study focused on people with diabetes, kidney disease, hypertension, or even hemodialysis. Those diseases have a significant effect on the development of CVD. Therefore, the correlation between the AGEs and CVD events might have been affected. It is necessary to further confirm and test the validity of the conclusion with different types of people as the participants. Third, this meta-analysis used MACE as the outcome, and MACE was defined as myocardial infarction, stroke, heart failure, other ischemic cardiovascular events, arterial vascular surgery, or cardiogenic death. However, some included studies used few of these diseases or only fatal events as outcomes, which might lead to the underestimation of the association between AGEs and MACE. Four, we selected multivariate-adjusted outcomes in the original articles, and the confounding factors in each article varied from study to study; thus, the residual confounding factors could not be completely excluded. Nevertheless, we examined the prospective association of AGEs with CVD outcomes by summarizing the latest evidence. We also additionally included studies on AGEs and cardiovascular risk in the general population and explored the relationship between AGEs and fatal or nonfatal cardiovascular events.

      5. Conclusions

      In conclusion, this meta-analysis indicates that the high level of AGEs measured using SAF is associated with a significant increase in MACE, whether fatal or nonfatal cardiovascular events. Moreover, the conclusion is significantly supported by findings in patients with diabetes and kidney disease. Our findings suggest that AGEs are a valuable biomarker for predicting the occurrence of MACE.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Ethics approval and consent to participate

      Not applicable.

      Consent for publication

      Not applicable.

      Availability of data and materials

      All data relevant to the study are included in the article or uploaded as an additional file. No more additional data are available.

      Authors' contributions

      Study concept and design: QC, QH, WL, XZ. Acquisition, analysis, or interpretation of data: All authors. Drafting of manuscript: QC. Critical revision of the manuscript for important intellectual content: XZ. Statistical analysis: QC. Supervision: XZ. All authors read and approved the final manuscript.

      Declaration of competing interest

      The authors declare that they have no competing interests.

      Acknowledgements

      Thank all the authors for their hard work and the help and support given by Chongqing Medical University .

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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