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Clinical Policy Bulletin:
Non-invasive Measurement of Advanced Glycation End-products in the Skin
Number: 0841


Policy

Aetna considers the non-invasive measurement of advanced glycation end-products (AGEs) in the skin experimental and investigational because of insufficient evidence in the peer-reviewed literature.

See also:

CPB 0070 - Diabetic Tests, Programs and Supplies

CPB 0381 - Cardiovascular Disease Risk Tests



Background

Advanced glycation end-productss (AGEs) are modifications of proteins or lipids that have become glycated and oxidized following exposure to aldose sugars; they form in-vivo in hyperglycemic environments and during aging.  Advanced glycation end-products contribute to the pathophysiology of vascular disease in diabetes through accumulation in the vessel walls, where they may perturb cell structure and function.  Advanced glycation end-products have also been hypothesized to play a role in atherosclerosis, acute ischemic stroke, and chronic kidney disease (Macsai, 2012; Tang et al, 2013).  A number of different therapies to inhibit AGEs are under investigation (Goldin et al, 2006).

Gerrits et al (2008) conducted noninvasive skin auto-fluorescence (SAF) in 973 type 2 diabetic patients through use of an autofluorescence reader.  After a mean follow-up period of 3.1 years, baseline SAF was significantly higher in patients who developed microvascular complications, neuropathy, or (micro)albuminuria, but not in patients who developed retinopathy.  This study was the first to observe SAF measurement as an independent predictor of development of microvascular complications in type 2 diabetes.

Hartog et al (2009) investigated whether SAF predicted graft loss following kidney transplantation.  They entrolled a total of 302 renal transplant recipients at a median time of 6.1 years post-transplant.  They followed the study population for 5.2 years for first occurrence of graft loss.  Skin auto-fluorescence predicted graft loss in a Cox regression multivariable analysis (hazard ratio [HR]: 1.83 [1.22 to 2.75], p = 0.003), adjusted for other identified risk-factors such as patient age, creatinine clearance, protein excretion, high sensitivity C-reactive protein, and human leukocyte antigen-DR mismatching.  The investigators concluded that SAF is an independent predictor of graft loss in kidney transplant recipients and that although SAF is not a direct measure of AGEs, the results support a hypothesis that accumulation of AGEs in renal transplant recipients contributes to the development of graft loss.

Smit et al (2010) describe SAF measurement as a noninvasive method of assessing accumulation of AGEs in tissue with low turnover metabolic memory and oxidative stress.  One device for measuring AGEs in tissue is the AGE  Reader®, which measures tissue accumulation of AGEs by means of fluorescence techniques.  It has a light source which illuminates the tissue of interest by exciting fluorescent moieties in the tissue, which will emit light with a different wavelength.  In the used wavelength band, the major contribution in fluorescence comes from fluorescent AGEs and therefore the emitted light is detected using a spectrometer.  Selective discrimination of specific AGEs can be obtained through use of particular technical adaptations including selection of specific wavelength and modulated or pulsed light sources, so that a more selective discrimination of specific AGEs can be obtained (Diagoptics, 2013).

Skin fluorescence was measured in 105 participants of the Pittsburgh Epdemiology of Diabetes Complications Study of Childhood-Onset type 1 diabetes, who had previously undergone electron beam tomograhy scanning for coronary artery calcification.  Study participants’ mean age and diabetes duration were 49 and 40 years, respectively. Measureable coronary artery calcification was found in 71 % of participants and univariately cross-sectionally associated with skin fluorescence.  However, this association was not maintained after age adjustment.  The authors also found that skin fluorescence was both univariately (p < 0.0001) and multi-variately ( p = 0.03) associated with coronary artery calcification severity.  The authors concluded that the relationship between skin fluorescence and coronary artery calcification appears stronger with more severe calcification, suggesting that skin fluorescence may be a useful marker of coronary artery calcificaiton and coronary artery disease risk and potentially may serve as a potential therapeutic target (Conway, 2010).

A study of 140 type 1 diabetic and 57 nondiabetic subjects was conducted to compare AGE accumulation in the skin of patients in a type 1 diabetic and non-diabetic population.  The study also assessed its association with disease duration and metabolic control.  The investigators found that mean autofluorescence in the diabetes group was 2.13 ± 0.55, which was significantly higher than in controls (autofluorescence 1.70 ± 0.27, p < 0.05).  A significant positive correlation between autofluorescence and patients’ age was found for the whole study population (p < 0.05).  A significant positive correlation was also found in diabetic subjects between autofluorescence and diabetes duration (p < 0.05) as well as between autofluorescence and HbA1c levels (p < 0.05).  The authors concluded that autofluorescence measurement may be useful as a secondary method of assessing metabolic control as it reflects glycemic control over a longer period of time than that reflected by HbA1c levels (Samborski et al, 2011).

Beisswenger et al (2012) stated that although measurement of SAF has been promoted as a non-invasive technique to measure skin AGEs, the actual products quantified are uncertain.  They compared specific SAF measurements with analytically determined AGEs and oxidative biomarkers in skin collagen to determine if these measures are correlated with chronological aging and actinic exposure.  Skin autofluorescence was measured at 4 sites on the arms of 40 non-diabetic subjects.  They found poor correlation of AGE-associated fluorescence spectra with AGEs and oxidative products (OPs) in collagen, with only pentosidine correlating with fluorescence at 370(ex)/440(em)nm.  Thus, they concluded that SAF measurements at 370(ex)/440(em) nm and 335(ex)/385(em) nm, except for pentosidine, correlated poorly with glycated and oxidatively modified protein in human skin and do not reflect actinic modification.  A new fluorescence measurement (440(ex)/529(em) nm) appeared to reflect AGEs and OPs in skin.

Hofman et al (2012) noted that AGEs may be involved in aging and development of cardiovascular disease.  They further noted that “whether non-invasive measurement of AGE accumulation in the skin may reflect vessel function and vessel protein modification is unknown”.  The authors isolated collagen types I and III from the veins of 52 patients by proteolysis to analyze the AGE-modifications in the collagens extracted from residual bypass graft material.  The SAF reflected accumulation of AGEs in the body and the pulse wave velocity reflected vessel stiffness.  They measured SAF with an autofluorescence reader.  They noted that the collagen AGE autofluorescence in vein graft material increased with age and the pepsin digestible collagen fraction was significantly less modified in comparison to the collagenase digestible fraction.  Thus, the authors concluded that SAF and pulse wave velocity as non-invasive parameters significantly correlated with the AGE contained in graft material, making them strong predictors of vessel AGE modifications in patients with coronary artery disease.  However, the authors also stated that “whether the analysis of the SAF leads to an improvement of the risk stratification in patients suffering from cardiovascular disease has to be further tested”.

Macsai et al (2012) conducted a study to assess whether SAF is influenced by clinical and treatment characteristics in peritoneal dialysis (PD) patients.  Their cross-sectional study of 198 PD patients involved utilization of a specific AE Reader device.  The authors’ analysis revealed that patients’ age, current diabetes and icodextrine use significantly increased patients’ SAF values (p = 0.015, 0.012, and 0.005, respectively), thus illustrating that in this study group AGE exposure of PD patients with diabetes and on icodextrin solution is increased.  The authors noted that further investigation is required to determine whether this finding is due to the icodextrin itself or to a still unspecified clinical characteristic of PD populations treated with icodextrin.

Noordzij et al (2012) evaluated SAFs in patients with carotid artery stenosis with and without co-existing peripheral arery occlusive disease (PAOD) in 56 carotid artery stenosis and 56 age- and sex- matched healthy controls.  Skin autofluorescence was found to be higher in patients with carotid artery stenosis compared to the control group (mean 2.81 versus 2.46, p = 0.002).  The authors further noted that patients with carotid artery stenosis and PAOD had an even higher SAF than patients with carotid artery stenosis only (mean 3.29 versus 2.66, p = 0.003).  The investigators concluded that SAF is increased in patients with carotid artery stenosis and PAOD, and that the uni-variate and multi-variate associations of SAF with age, smoking, diabetes, renal insufficiency and PAOD suggested that increased SAF can be seen as an indicator of widespread atherosclerosis. 

Current American Association of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan do not refer to advanced glycemic endpoints (Handelsman et al, 2011).  Although there have been recently published case-control, cross-sectional and case series studies on this topic, the breadth of evidence is such that non-invasive measurement of AGEs in the skin remains experimental and investigational at this time.

Chaudhri et al (2013) noted that SAF has been advocated as a quick non-invasive method of measuring tissue AGE, which have been reported to correlate with cardiovascular risk in the dialysis patient.  Most studies have been performed in patients from a single racial group, and these researchers wanted to look at the reliability of SAF measurements in a multi-racial dialysis population and whether results were affected by hemodialysis.  These investigators measured SAF 3 times in both forearms of 139 hemodialysis patients, pre-dialysis and 36 post-dialysis.  A total of 139 patients, 62.2 % male, 35.3 % diabetic, 59 % Caucasoid, mean age of 65.5 ± 15.2 years were studied.  Reproducibility of measurements between the 1st and 2nd measurements was very good (r(2 ) = 0.94, p < 0.001, Bland Altman bias 0.05, confidence limits -0.02 to 0.04).  However, SAF measurements were not possible in 1 forearm in 8.5 % Caucasoids, 25 % Far Asian, 28 % South Asians and 75 % African or Afro Caribbean (p < 0.001).  Mean SAF in the right forearm was 3.3 ± 0.74 arbitrary units (AU) and left forearm 3.18 ± 0.82 AU pre-dialysis, and post-dialysis there was a fall in those patients dialyzing with a left sided arterio-venous fistula (left forearm pre 3.85 ± 0.72 versus post 3.36 ± 0.55 AU, p = 0.012).  The authors concluded that although SAF is a relatively quick non-invasive method of measuring tissue AGE and measurements were reproducible, it was often not possible to obtain measurements in patients with highly pigmented skin.  To exclude potential effects of arterio-venous fistulae, the authors suggested that measurements be made in the non-fistula forearm pre-dialysis.

Hoffman et al (2013) stated that AGEs seem to be involved in aging as well as in the development of cardiovascular diseases.  During aging, AGEs accumulate in extracellular matrix proteins like collagen and contribute to vessel stiffness.  Whether non-invasive measurement of AGE accumulation in the skin may reflect vessel function and vessel protein modification is unknown.  These researchers analyzed the AGE-modifications in the collagens extracted from residual bypass graft material, the SAF reflecting the accumulation of AGEs in the body as well as the pulse wave velocity reflecting vessel stiffness.  Collagen types I and III (pepsin digestible collagen fraction) were isolated from the veins of 52 patients by proteolysis.  The residual collagen fraction was further extracted by collagenase digestion.  Collagen was quantified by hydroxyproline assay and AGEs by the AGE intrinsic fluorescence.  Skin autofluorescence was measured with an autofluorescence reader; pulse wave velocity with the VICORDER.  The collagen AGE autofluorescence in patient vein graft material increased with patient age.  The pepsin digestible collagen fraction was significantly less modified in comparison to the collagenase digestible fraction.  Decreasing amounts of extracted collagenase digestible collagen corresponded with increasing AGE autofluorescence.  Skin autofluorescence and vessel stiffness were significantly linked to the AGE autofluorescence of the collagenase digestible collagen fraction from graft material.  The authors concluded that SAF and pulse wave velocity as non-invasive parameters significantly correlated with the AGE contained in graft material and therefore are strong predictors of vessel AGE modifications in patients with coronary heart disease.  Moreover, they stated that whether the analysis of the SAF leads to an improvement of the risk stratification in patients suffering from cardiovascular disease has to be further tested.

Vouillarmet et al (2013) examined if AGEs measurement by SAF would be an additional marker for diabetic foot ulceration (DFU) management.  These researchers performed SAF analysis in 66 patients with a history of DFU prospectively included and compared the results with those of 84 control patients with diabetic peripheral neuropathy without DFU.  They then assessed the prognostic value of SAF levels on the healing rate in the DFU group.  Mean SAF value was significantly higher in the DFU group in comparison with the control group, even after adjustment for other diabetes complications (3.2 ± 0.6 arbitrary units versus 2.9 ± 0.6 arbitrary units; p = 0.001).  In the DFU group, 58 (88 %) patients had an active wound at inclusion.  The mean DFU duration was 14 ± 13 weeks.  The healing rate was 47 % after 2 months of appropriate foot care.  A trend for a correlation between SAF levels and healing time in DFU subjects was observed but was not statistically significant (p = 0.06).  The authors concluded that increased SAF levels are associated with neuropathic foot complications in diabetes; and use of SAF measurement to assess foot vulnerability and to predict DFU events in high-risk patients appears to be promising.

Llaurado et al (2014) examined the relationship between AGEs and arterial stiffness (AS) in subjects with type 1 diabetes without clinical cardiovascular events.  A set of 68 patients with type 1 diabetes and 68 age- and sex-matched healthy subjects were evaluated.  Advanced glycation end-products were assessed using serum concentrations of N-carboxy-methyl-lysine (CML) and using SAF; AS was assessed by aortic pulse wave velocity (aPWV), using applanation tonometry.  Patients with type 1 diabetes had higher serum concentrations of CML (1.18 versus 0.96 μg/ml; p = 0.008) and higher levels of SAF (2.10 versus 1.70; p < 0.001) compared with controls.  These differences remained significant after adjustment for classical cardiovascular risk factors.  Skin autofluorescence was positively associated with aPWV in type 1 diabetes (r = 0.370; p = 0.003).  No association was found between CML and aPWV.  Skin autofluorescence was independently and significantly associated with aPWV in subjects with type 1 diabetes (β = 0.380; p < 0.001) after adjustment for classical cardiovascular risk factors.  Additional adjustments for HbA1c, disease duration, and low-grade inflammation did not change these results.  The authors concluded that skin accumulation of autofluorescent AGEs is associated with AS in subjects with type 1 diabetes and no previous cardiovascular events.  They stated that these findings indicated that determination of tissue AGE accumulation may be a useful marker for AS in type 1 diabetes.

Yasuda et al (2014) evaluated the relationship between SAF, which reflects the accumulation of AGEs, and the severity of diabetic retinopathy (DR) in patients with type 2 diabetes.  A total of 67 eyes of 67 patients with type 2 diabetes were enrolled; 67 age-matched non-diabetic subjects served as controls.  Diabetic patients were classified by the severity of their DR: no DR (NDR), non-proliferative DR (NPDR), and proliferative DR (PDR).  Skin autofluorescence was measured with an autofluorescence reader.  Skin autofluorescence in the diabetes patients was significantly higher than in the controls (median 2.5 (interquartile range 2.3-2.7) and 1.8 (1.6 to 2.3) AU, respectively, p < 0.001).  There was a statistically significant increase in SAF along with the increasing severity of DR (from NDR to NPDR: p = 0.034; NPDR to PDR: p < 0.01).  Logistic regression analysis revealed that SAF (OR, 17.2; p < 0.05) was an independent factor indicating the presence of PDR.  The authors concluded that SAF has an independent relationship with PDR in patients with type 2 diabetes.  They stated that SAF measurement with an autofluorescence reader is a non-invasive way to assess the risk of DR; SAF may, therefore, be a surrogate marker candidate for the non-invasive evaluation of DR.

 
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes not covered for indications listed in the CPB:
0233T Skin advanced glycation endproducts (AGE) measurement by multi-wavelength fluorescent spectroscopy
ICD-9 codes not covered for indications listed in the CPB:
249.00 - 250.93 Diabetes mellitus


The above policy is based on the following references:
  1. Goldin A, Beckman, JA, Schmidt AM, Creager MA. Advanced glycation end products: Sparking the development of diabetic vascular injury. Circulation. 2006;114:597-605.
  2. Gerrits EG, Lutgers HL, Kleefstra N, et al. Skin autofluorescence: a tool to identify type 2 diabetic patients at risk for developing microvascular complications. Diabetes Care. 2008;31(3):517-521.
  3. Hartog JW, Gross S, Oterdoom LH, et al. Skin-autofluorescence is an independent predictor of graft loss in renal transplant recipients. Transplantation. 2009;87(7):1069-1077.
  4. Conway B, Edmundowicz D, Matter N, et al. Skin fluorescence correlates strongly with coronary artery calcification severity in type 1 diabetes. Diabetes Technol Ther. 2010;12(5):339-345.
  5. Smit AJ, Gerrits EG. Skin autofluorescence as a measure of advanced glycation endproduct deposition: a novel risk marker in chronic kidney disease. Curr Opin Nephrol Hypertens. 2010;19(6):527-533.
  6. Handelsman Y, Mechanick, JI, Blonde, L, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan. Endocrine Practice. 17(Suppl 2); March/April, 2011.
  7. Samborski P, Naskręt D, Araszkiewicz A, et al. Assessment of skin autofluorescence as a marker of advanced glycation end product accumulation in type 1 diabetes. Pol Arch Med Wewn. 2011;121(3):67-72.
  8. Beisswenger PJ, Howell S, Mackenzie T, et al. Two fluorescent wavelengths, 440(ex)/520(em) nm and 370(ex)/440(em) nm, reflect advanced glycation and oxidation end products in human skin without diabetes. Diabetes Technol Ther. 2012;14(3):285-292.
  9. Hofmann B, Adam AC, Jacobs K, et al. Advanced glycation end product associated skin autofluorescence: A mirror of vascular function? Exp Gerontol. 2013;48(1):38-44.
  10. Mácsai E. Skin autofluorescence measurement in the clinical practice of diabetology and nephrology. Orv Hetil. 2012 Oct 21;153(42):1651-1657.
  11. Mácsai E, Benke A, Cseh A, Vásárhelyi B. Factors influencing skin autofluorescence of patients with peritoneal dialysis. Acta Physiol Hung. 2012;99(2):216-222.
  12. Noordzij MJ, Lefrandt JD, Loeffen EA, et al.Skin autofluorescence is increased in patients with carotid artery stenosis and peripheral artery disease. Int J Cardiovasc Imaging. 2012;28(2):431-438.
  13. Diagoptics, Inc. Detailed information about advanced glycation endproducts, the AGE measurement and the clinical validation. Groningen, The Netherlands: Diagoptics; 2013. Available at: http://www.diagnoptics.com/en/professionals/. Accessed January 8, 2013.
  14. Tang SC, Wang YC, Li YI, et al. Functional role of soluble receptor for advanced gycation end products in stroke. Arterioscler Thromb Vasc Biol. 2013;33(3):585-594.
  15. Chaudhri S, Fan S, Davenport A. Pitfalls in the measurement of skin autofluorescence to determine tissue advanced glycosylation content in haemodialysis patients. Nephrology (Carlton). 2013;18(10):671-675.
  16. Hofmann B, Adam AC, Jacobs K, et al. Advanced glycation end product associated skin autofluorescence: A mirror of vascular function? Exp Gerontol. 2013;48(1):38-44.
  17. Vouillarmet J, Maucort-Boulch D, Michon P, Thivolet C. Advanced glycation end products assessed by skin autofluorescence: A new marker of diabetic foot ulceration. Diabetes Technol Ther. 2013;15(7):601-605.
  18. Llaurado G, Ceperuelo-Mallafre V, Vilardell C, et al. Advanced glycation end products are associated with arterial stiffness in type 1 diabetes. J Endocrinol. 2014;221(3):405-413.
  19. Yasuda M, Shimura M, Kunikata H, et al. Relationship of skin autofluorescence to severity of retinopathy in type 2 diabetes. Curr Eye Res. 2014 May 28:1-8 [Epub ahead of print]


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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.
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