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Non-invasive Measurement of Advanced Glycation End-products inthe Skin
Clinical Policy Bulletins Medical Clinical Policy Bulletins
Number: 0841
*Please see amendment for Pennsylvania Medicaid at the end of this CPB.
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 (../1_99/0070.html)
CPB 0381 - Cardiovascular Disease Risk Tests (../300_399/0381.html)
Background
Advanced glycation end-products (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,
Last Review
02/07/2019
Effective: 03/19/2013
Next
Review: 09/26/2019
Review
History
Definitions
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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
Clinical Policy
Bulletin
Notes
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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 non-diabetic 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 AF in the diabetes group was 2.13 ± 0.55, which was significantly higher than in
controls (AF 1.70 ± 0.27, p < 0.05). A significant positive correlation between AF and patients’
age was found for the whole study population (p < 0.05). A significant positive correlation was
also found in diabetic subjects between AF and diabetes duration (p < 0.05) as well as
between AF and hemoglobin A1c (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
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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
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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 % m ale, 35.3 % di abetic, 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.
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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 (2015) evaluated the relationship between SAF, which reflects the accumulation of
AGEs, and the severity of diabetic retinopathy (DR) in patients with type 2 diabetes mellitus
(T2DM). A total of 67 eyes of 67 patients with T2DM 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 auto
fluorescence was measured with an auto-fluorescence reader. Skin auto-fluorescence in the
diabetes patients was significantly higher than in the controls (median 2.5 (interquartile range of
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2.3 to 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 (odds ratio [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 T2DM. They stated that SAF
measurement with an auto-fluorescence 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.
Krul-Poel et al (2015) noted that SAF is a non-invasive measurement of AGE, which are
suggested to be one of the major agents in the pathogenesis and progression of diabetes related
cardiovascular complications. Recently, low vitamin D status has been linked to the progression
of T2DM and cardiovascular disease. These researchers investigated the association between
vitamin D status and SAF in patients with T2DM. In this preliminary report, SAF was measured
non-invasively with an AGE-reader in 245 patients with T2DM treated with lifestyle advice,
metformin and/or sulphonylurea-derivatives. All patients were randomly assigned to receive
either vitamin D 50,000 IU/month or placebo for 6 months. Skin auto-fluorescence was
significantly higher in patients with a serum 25(OH)D less than 50 nmol/L compared to patients
with a serum 25(OH)D greater than 75 nmol/L (2.81 versus 2.41; p < 0.001). Mean serum
25(OH)D was 60.3 ± 23.4 nmol/L and was independently associated with SAF (β -0.006; p <
0.001). Mean vitamin D increased from 60.8 to 103.6 nmol/L in the intervention group; however
no effect was seen on accumulation of skin AGEs after 6 months compared to placebo. The
authors concluded that vitamin D status is independently associated with SAF in patients with
well-controlled T2DM. No effect was seen on the amount of skin AGEs after a short period of 6
months vitamin D supplementation. They stated that further research with longer follow-up and
measurement of circulating AGE is needed to elucidate the causality of the association.
Banser et al (2016) stated that AGEs are considered major contributors to microvascular and
macrovascular complications in adult patients with diabetes mellitus. Advanced glycation end-
products can be measured non-invasively with SAF. These investigators determined SAF values
in children with T1DM and studied correlations between SAF values and HbA1c and mean
HbA1c over the year prior to measurement. In children with T1DM, SAF values were measured
using the AGE Reader. Laboratory and anthropometric values were extracted from medical
charts. Correlations were studied using Pearson's correlation coefficient. Multi-variable linear
regression analysis was conducted to evaluate the effect of multiple study parameters on SAF
values. The mean SAF value was 1.33 ± 0.36 arbitrary units (AU) in children with T1DM (n = 144);
SAF values correlated positively with HbA1c measured at the same time (r = 0.485; p < 0.
001), mean HbA1c over the year prior to measurement (r = 0.578; p < 0.001), age (r = 0.337;
p<0.001),duration of T1DM (r = 0.277; p = 0.001), serum triglycerides (r = 0.399; p < 0.001),
and total cholesterol (r = 0.352; p = 0.001); SAF values were significantly higher in patients with
non
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white skin (1.56 versus 1.27 AU, respectively, p = 0.001). The authors concluded that in children
with T1DM, SAF values correlated strongly with single HbA1c and mean HbA1c, making the
non-invasive SAF measurement an interesting alternative to provide information about
cumulative hyperglycemic states. Moreover, they stated that to determine the value of SAF
measurement in predicting long-term microvascular and macrovascular complications, further
prospective follow-up studies are needed.
In a pilot study, Meertens and colleagues (2016) (i) explored the reliability of SAF as an index
of tissue AGEs in patients in the intensive care unit (ICU), (ii) compared its levels to healthy
controls, (iii) described the time course of AGEs and influencing factors during ICU
admission, and (iv) examined their association with disease severity, outcome, and markers
of oxidative stress and inflammation. Serum N"-(carboxyethyl)lysine (CEL), CML, SAF, and
soluble RAGE (sRAGE) were serially measured for a maximum of 7 days in critically ill ICU
patients with multi-organ failure and compared to age-matched healthy controls. Correlations
with (changes in) clinical parameters of disease severity, low-density lipoprotein (LDL) dienes,
and C-reactive protein (CRP) were studied and survival analysis for in-hospital mortality was
performed. A total of 45 ICU patients (age of 59 ± 15 years; 60 % male), and 37 healthy controls
(age of 59 ± 14 years; 68 %) were included. Skin AF measurements in ICU patients were
reproducible (CV right-left arm: 13 %, day-to-day: 10 %), with confounding effects of skin
reflectance and plasma bilirubin levels. Skin AF was higher in ICU patients versus healthy
controls (2.7 ± 0.7 versus 1.8 ± 0.3 au; p < 0.001). Serum CEL (23 ± 10 versus 16 ± 3 nmol/gr
protein; p < 0.001), LDL dienes (19 (15 to 23) versus 9 (8 to 11) μmol/mmol cholesterol; p <
0.001), and sRAGE (1,547 (998 to 2,496) versus 1,042 (824 to 1,388) pg/ml; p = 0.003) were
significantly higher in ICU patients compared to healthy controls, while CML was not different (27
(20 to 39) versus 29 (25 to 33) nmol/gr protein). While CRP and LDL dienes decreased
significantly, SAF and serum AGEs and sRAGE did not change significantly during the first 7
days of ICU admission; CML and CEL were strongly correlated with the sequential organ failure
assessment (SOFA) scores and CML above the median at baseline was associated with
increased risk for mortality (HR 3.3 (1.3 to 8.3); p = 0.01). All other markers did not correlate with
disease severity and did not predict mortality. The authors concluded that the findings of this
study demonstrated that markers for the AGE-RAGE axis were elevated in critically ill patients
compared to healthy controls but remained stable for at least 7 days despite clearly fading
inflammation and oxidative stress. They stated that circulating AGEs may be associated with
disease severity and outcome; and further research should be conducted to elucidate the role of
the AGE-RAGE axis in the exaggerated inflammatory response leading to multi-organ failure and
death, and whether or not this may be a target for treatment.
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Schutte and associates (2016) examined the association of SAF with rate of kidney function
decline in a cohort of patients with peripheral artery disease (PAD). These researchers
performed a post-hoc analysis of an observational longitudinal cohort study. They included 471
patients with PAD, and SAF was measured at baseline. Primary end-point was rate of estimated
glomerular filtration rate (eGFR) decline. Secondary end-points were incidence of eGFR less
than 60 and less than 45 ml/min/1.73 m(2) and rapid eGFR decline, defined as a decrease in
eGFR of greater than 5 ml/min/1.73 m(2)/y. During a median follow-up of 3 years, the mean
change in eGFR per year was -1.8 ± 4.4 ml/min/1.73 m(2)/year. No significant difference in rate
of eGFR decline was observed per 1 arbitrary unit increase in SAF (-0.1 ml/min/1.73 m(2)/y; 95
% confidence interval [CI]: -0.7 to 0.5; p = 0.8). Analyses of the secondary end-points showed
that there was an association of SAF with incidence of eGFR less than 60 and less than 45
ml/min/1.73 m(2) (HR, 1.54; 95 % CI: 1.13 to 2.10; p = 0.006 and HR, 1.76; 95 % CI:, 1.20 to
2.59; p = 0.004, respectively), but after adjustment for age and sex, significance was lost. There
was no association of SAF with rapid eGFR decline. The authors concluded that in this cohort of
patients with PAD, SAF levels did not predict the rate of kidney function decline during follow-up
in this study.
Hangai and colleagues (2016) evaluated the association of tissue AGE, assessed using SAF,
with coronary artery calcification in Japanese subjects with type 2 diabetes. A total of 122
Japanese subjects with type 2 diabetes enrolled in this cross-sectional study underwent multi-
slice computed tomography for total coronary artery calcium scores (CACS) estimation and
examination with a SAF reader; SAF positively correlated with age, sex, diabetes duration, pulse
wave velocity, systolic blood pressure (SBP), serum creatinine, and CACS. In addition, SAF
results negatively correlated with body mass index (BMI), eGFR, and serum C-peptide
concentration. According to multi-variate analysis, age and SBP showed strong positive
correlation and eGFR showed negative correlation with SAF values. Multiple linear regression
analyses revealed a significant positive correlation between SAF values and logCACS,
independent of age, sex, diabetes duration, HbA1c, BMI, carotid intima-media thickness (IMT),
and BP. However, SAF showed no association with serum levels of AGE, such as CML and 3
deoxyglucosone. The authors concluded that SAF results positively correlated with CACS in
Japanese subjects with type 2 diabetes. They stated that these findings indicated that AGE
plays a role in the pathogenesis of diabetic macro-vascular disease; and measurement of SAF
values may be useful for assessing the severity of diabetic complications in Japanese subjects.
Rajaobelina and co-workers (2017) examined if the accumulation of AGEs measured by SAF
was associated with signs of diabetic peripheral neuropathy (DPN) and to sensitivity, pain, motor
and autonomic function 4 years later in patients with type 1 diabetes. At baseline, 188 patients
(age of 51 years, diabetes duration of 22 years) underwent SAF measurement using the AGE
Reader. Four years later, signs of DPN were defined as the presence of neuropathic pain and/or
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feet sensory loss or foot ulceration. Neurological tests were systematically performed: vibration
perception threshold by neuro-esthesiometry, neuropathic pain by the Douleur Neuropathique en
4 Questions score, muscle strength by dynamometry and electrochemical skin conductance.
Multi-variate analyses were adjusted by age, sex, height, BMI, tobacco, HbA1c , diabetes
duration, eGFR and albumin excretion rate. At the 4-year follow-up, 13.8 % of patients had signs
of DPN. The baseline SAF w as higher in those with signs of DPN (2.5 ± 0.7 versus 2.1 ± 0.5
arbitrary units (AU), p < 0.0005). In the multi-variate analysis, a 1 SD higher SAF at baseline was
associated with an increased risk of signs of neuropathy (OR = 2.68, p = 0.01). All of the
neurological tests were significantly altered in the highest quartile of the baseline SAF (greater
than 2.4 AU) compared with the lowest quartiles after multi-variate adjustment. The authors
concluded that this non-invasive measurement of SAF may have a value for DPN in type 1
diabetes and a potential clinical utility for detection of DPN.
Yamanaka and co-workers (2016) noted that although the accumulation of AGEs of the Maillard
reaction in the body is reported to increase with aging and is enhanced by the pathogenesis of
lifestyle-related diseases such as diabetes, routine measurement of AGEs is not applied to
regular clinical diagnoses due to the lack of conventional and reliable techniques for AGEs
analyses. In the present study, a non-invasive AGEs measuring device was developed and the
association between skin AGEs and diabetic complications was evaluated. To clarify the
association between the duration of hyperglycemia and accumulation of skin fluorophores,
diabetes was induced in mice by streptozotocin. As a result, the fluorophore in the auricle of live
mice was increased by the induction of diabetes. Subsequent studies (168 subjects -- 82
subjects with T2DM and 86 subjects without T2DM) revealed that the fingertip of the middle
finger in the non-dominant hand is suitable for the measurement of the fluorescence intensity by
the standard deviation value. Furthermore, the fluorescence intensity was increased by the
presence of diabetic microvascular complications. The authors concluded that the findings of
this study suggested that the measurement of fluorescence intensity on fingertip is useful for
predicting diabetic microvascular complications; this study provided the first evidence that the
measurement of fluorescence intensity on the fingertip plays an important role in the early
diagnosis and may prevent the pathogenesis of lifestyle-relateddiseases.
In a cross-sectional analysis, van Waateringe and colleagues (2017) examined the association
between SAF and the presence of metabolic syndrome (MetS) as well as its individual
components in a general population. This study included 78,671 non-diabetic subjects between
18 and 80 years of age who participated in the LifeLines Cohort Study and had SAF
measurement obtained non-invasively using the AGE Reader. MetS was defined according to
the revised NCEP ATP III criteria. Students unpaired t-test was used to test differences between
groups. Both logistic and linear regression analyses were performed in order to test associations
between the individual MetS components and SAF. Subjects with MetS had higher SAF (2.07 ±
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0.45 AU) compared to individuals without MetS (1.89 ± 0.42 AU) (p < 0.001). There was a
positive association between the number of MetS components and higher SAF Z-scores (p <
0.001). Individuals in the highest SAF tertile had a higher presence of MetS (OR 2.61; 95 % CI:
2.48 to 2.75) and some of the individual components compared to subjects in the lowest SAF
tertile. After correction for age, gender, creatinine clearance, HbA1c and smoking status, only
elevated BP and low HDL cholesterol remained significantly associated with higher SAF (p =
0.02 and p = 0.001, respectively). The authors concluded that SAF was associated with the
presence of MetS and some of its individual components. In addition, increasing SAF Z-scores
were observed with a higher number of MetS components. Moreover, they stated that
prospective studies are needed to establish whether SAF can be used as an (additional)
screening tool to predict both cardiovascular disease and T2DM in high-risk populations.
Da Moura and associates (2017) noted that SAF has been demonstrated to be a biomarker of
cumulative skin AGEs and potentially may be a better predictor for the development of chronic
complications and mortality in diabetes than glycated hemoglobin A1c. However, there are
several confounding factors that should be assessed prior to its broader application: these
include presence of other fluorescent compounds in the skin that might be measured (e.g.,
fluorophores), skin pigmentation and use of skin creams.
Franca and colleagues (2017) noted that chronic kidney disease (CKD) is associated with high
morbidity and mortality rates, main causes related with cardiovascular disease (CVD) and bone
mineral disorder (CKD-BMD). Uremic toxins, as AGEs, are non-traditional cardiovascular risk
factor and play a role on development of CKD-BMD in CKD. The measurement of SAF is a non
invasive method to assess the level of AGEs in tissue, validated in CKD patients. In a pilot
study, these researchers analyzed AGEs measured by SAF levels (AGEs-SAF) and its relations
with CVD and BMD parameters in hemodialysis (HD) patients. A total of 20 prevalent HD
patients (HD group) and healthy subjects (control group, n = 24), performed biochemical tests
and measurements of anthropometric parameters and AGEs-SAF. In addition, HD group
performed measurement of intact parathyroid hormone (iPTH), trans-thoracic echocardiogram
(TTE) and radiographies of pelvis and hands for vascular calcification score. AGEs-SAF levels
were elevated both in HD and control subjects ranged according to the age, although higher at
HD than control group. Single high-flux HD session did not affect AGEs-SAF levels. AGEs-SAF
levels were not related to ventricular mass, interventricular septum or vascular calcification in HD
group. AGEs-SAF levels were negatively associated with serum iPTH levels. The authors
concluded that this study detected a negative correlation of AGEs-SAF with serum iPTH,
suggesting a role of AGEs on the pathophysiology of bone disease in HD prevalent patients.
The nature of this relation and the clinical application of this non-invasive methodology for
evaluation AGEs deposition must be confirmed and clarified in future studies. The authors
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stated that this pilot study had several drawbacks. Potential influences of ethnicity and diet
limited definitive conclusions. In addition, these investigators did not perform AGEs analysis on
serum or bone histo-morphometric studies.
In a multi-center study, Stirban and associates 92018) examined if SAF correlated with measures
of diabetic peripheral neuropathy (DPN). A total of 497 consecutive individuals with diabetes
mellitus were studied. Forearm SAF was measured using the AGE Reader (Groningen, The
Netherlands); DPN was assessed using the Toronto Clinical Neuropathy Score (TCNS), the
Neuropathy Symptoms Score (NSS) and the Neuropathy Disability Score (NDS). According to
the TCNS, SAF (arbitrary units - AU) was increased in individuals with DPN (TCNS greater
than 5): 2.59 ± 0.56 AU compared with those without DPN (TCNS less than or equal to 5):
2.45 ± 0.53 AU, (p = 0.04) and significantly increased with the severity of DPN (p = 0.028). Higher
SAF was detected in individuals with neuropathic deficits (NDS greater than 2): 2.58 ± 0.56 AU
versus those without deficits (NDS less than or equal to 2): 2.45 ± 0.53 AU, (p = 0.009) as well as
in individuals with symptoms (NSS greater than 2): 2.54 ± 0.56 AU versus those without
symptoms (NSS less than or equal to 2): 2.40 ± 0.47 AU, (p = 0.022). The authors concluded that
accumulation of AGE in skin was increased in individuals with DPN and progressed with the
severity of DPN. They sated that SAF measurement might help in identifying subjects at high
risk for having DPN. The findings need to be validated by further investigations.
CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":
Code Code Description
E08.00 - E13.9 Diabetes mellitus
The above policy is based on the following references:
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diabetic patients at risk for developing microvascular complications. Diabetes Care.
2008;31(3):517-521.
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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
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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
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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.
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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.
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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.
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measurement and the clinical validation. Groningen, The Netherlands: Diagoptics;
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2013.
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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.
www.aetna.com/cpb/medical/data/800_899/0841.html Proprietary 13/15
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. 2015;40(3):338-345.
20. Krul-Poel YH, Agca R, Lips P, et al. Vitamin D status is associated with skin
autofluorescence in patients with type 2 diabetes mellitus: A preliminary report.
Cardiovasc Diabetol. 2015;14:89.
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measured in skin, vs. HbA1c in children with type 1 diabetes mellitus. Pediatr Diabetes.
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of advanced glycation endproducts and its association with oxidative stress,
inflammation, disease severity, and mortality during ICU admission in critically ill
patients: Results from a prospective pilot study. PLoS One. 2016;11(8):e0160893.
23. Schutte E, de Vos LC, Lutgers HL, et al. Association of skin autofluorescence levels with
kidney function decline in patients with peripheral artery disease. Arterioscler Thromb
Vasc Biol. 2016;36(8):1709-1714.
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with coronary artery calcification in Japanese subjects with type 2 diabetes as assessed
by skin autofluorescence. J Atheroscler Thromb. . 2016;23(10):1178-1187.
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four years later in type 1 diabetes. Diabetes Metab Res Rev. 2017;33(2).
26. Yamanaka M, Matsumura T, Ohno R, et al. Non-invasive measurement of skin
autofluorescence to evaluate diabetic complications. J Clin Biochem Nutr.
2016;58(2):135-140.
27. van Waateringe RP, Slagter SN, van Beek AP, et al. Skin autofluorescence, a non-
invasive biomarker for advanced glycation end products, is associated with the
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28. Da Moura Semedo C, Webb M, Waller H, et al. Skin autofluorescence, a non-invasive
marker of advanced glycation end products: Clinical relevance and limitations.
Postgrad Med J. 2017;93(1099):289-294.
29. Franca RA, Esteves ABA, Borges CM, et al. Advanced glycation end-products (AGEs)
accumulation in skin: Relations with chronic kidney disease-mineral and bone disorder.
J Bras Nefrol. 2017;39(3):253-260.
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30. Stirban AO, Bondor CI, Florea B, et al. Skin autofluorescence: Correlation with
measures of diabetic sensorimotor neuropathy. J Diabetes Complications.
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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.
Copyright © 2001-2019 Aetna Inc.
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AETNA BETTER HEALTH® OF PENNSYLVANIA
Amendment to Aetna Clinical PolicyBulletin Number: 0841 Non
invasive Measurement of Advanced Glycation End-products in the Skin
There are no amendments for Medicaid.
www.aetnabetterhealth.com/pennsylvania updated 02/07/2019
Proprietary
