Abstract
Aim:
We evaluated the associations of two biomarkers of hyperglycemia—hemoglobin A1c(HbA1c) and glycated albumin—with lower extremity disease in US adults overall and by diabetes status.
Methods:
We conducted a cross-sectional study of adult participants aged ≥40 years who attended the National Health and Nutrition Examination Survey(NHANES) 1999–2004 (unweighted N=5,785). We used logistic regression to evaluate the associations of HbA1c and glycated albumin with lower extremity disease: peripheral neuropathy (assessed by monofilament test), peripheral artery disease (assessed by ankle-brachial index), history of foot ulcer, or amputation. All analyses were weighted and accounted for the complex NHANES sample survey design.
Results:
The prevalence of lower extremity disease was 17.4% (15.9% in adults without diabetes and 33.2% in adults with diabetes). HbA1c and glycated albumin were not significantly associated with lower extremity disease in adults without diabetes. However, we observed significant associations of both HbA1c (OR 1.19 per 1-% point increase, 95%CI 1.06–1.34) and glycated albumin (OR 1.06 per 1-% point increase, 95%CI 1.02–1.10) with lower extremity disease in adults with diabetes after adjustment. The patterns of association were similar for HbA1c and glycated albumin (P-for-seemingly-unrelated-regression=0.60), with strong linear associations observed at high (diabetic) levels of both biomarkers.
Conclusions:
Our study suggests the importance of diabetes prevention and glycemic control in adults with diabetes to reduce the burden of lower extremity disease.
Keywords: hemoglobin A1c, glycated albumin, lower extremity disease, peripheral neuropathy, peripheral artery disease, amputation
Introduction
Peripheral artery disease (PAD) and peripheral neuropathy (PN) are both lower extremity diseases that can lead to substantial morbidity including foot ulcer, amputation, and mortality [1–3]. The prevalence of lower extremity disease is closely associated with diabetes status; a previous report using data from the National Health and Nutrition Examination Survey (NHANES) demonstrated that the prevalence of PAD and PN was approximately twice as high for individuals with diagnosed diabetes compared to the overall population [4]. Diabetes status and glycemic biomarkers including hemoglobin A1c (HbA1c) and glycated albumin have been independently associated with lower extremity disease in past studies [5–15]. A prior analysis of data from NHANES data showed strong associations of diabetes with PN and PAD [16].
HbA1c is the standard measure of hyperglycemia used to monitor glycemic control in persons with diabetes and was first recommended for diagnosis of diabetes in 2010 [17]. Glycated albumin was cleared in 2017 by the US FDA for use as a biomarker of diabetes control and reflects the percentage of total serum albumin that is glycated [18]. Because the rate of glycation is higher and turnover of albumin is faster than hemoglobin, glycated albumin better reflects short-term (2–3 week) glycemic control [19]. Glycated albumin has been shown to be useful in predicting risk of diabetes and is related to a number of microvascular and macrovascular complications [20, 21], even among people without a diagnosis of diabetes [22–24]. Some experts have proposed that glycated albumin may be useful as a complementary or alternative test to hyperglycemia to HbA1c, particularly in persons with renal comorbidities, anemia, or hemoglobinopathies, where HbA1c is not reliable [20, 25]. While glycated albumin is not currently routinely used in the clinical setting in the US, it is readily available by standard laboratories and community-based reference standards have been established [26].
We undertook the present study to validate the associations of HbA1c and glycated albumin with lower extremity disease in the general population of US adults. We aimed to evaluate these associations overall and stratified by diabetes status [8].
Methods
Study population
We conducted a cross-sectional study of the associations of glycated albumin and HbA1c with lower extremity disease in adult participants aged ≥40 years who attended the mobile examination center for NHANES 1999–2004. We measured glycated albumin in all participants who consented for the use of their blood samples in future studies. We excluded participants with missing glycated albumin or HbA1c data (N=833), missing ankle-brachial index (ABI) measurements or PN data (N=1967), or missing covariates (N=190). We also excluded on outlier and participants who had non-pristine blood samples due to poor assay performance in samples that had undergone multiple freeze-thaw cycles (N=369) [27]. The final population for analysis consisted of 5,785 participants. All participants provided written informed consent and all protocols including the measurement of glycated albumin in stored serum samples were approved by the ethics review board of the National Center for Health Statistics.
HbA1c and Glycated Albumin
HbA1c was measured as part of the original NHANES 1999–2004 survey in whole blood samples by the University of Missouri-Columbia laboratory on Primus Automated high performance liquid chromatography system, model CLC330 (Primus I) or CLC385 (Primus IV).
We measured glycated albumin in stored surplus serum specimens. Laboratory testing was completed between 2018–2020 at the University of Maryland School of Medicine (Baltimore, Maryland, USA). Stored frozen specimens were shipped to the Clinical Chemistry Research Lab at the University of Maryland and glycated albumin was measured using a method by Asahi Kasei Pharma (Lucica-GA-L) adapted to the Siemens Dimension Vista 1500 (Siemens Healthcare Diagnostics). The glycated albumin result is expressed as a percentage of total albumin (Formula: [((glycated albumin concentration in g/dL / serum albumin concentration in g/dL)/1.14)*100] + 2.9)).
Outcomes
The primary outcome was the presence of any lower extremity disease, defined as PN, PAD, or a self-reported history of non-healing foot ulcer, an observed foot ulcer, or a minor or major amputation. PN and PAD were assessed in the mobile examination center using standardized protocols by trained study personnel [28]. PN was assessed using standard 10-g monofilament testing with a 5.07 Semmes-Weinstein nylon monofilament mounted on a plastic handle [29]. All participants underwent monofilament testing at three sites of each foot, and PN was defined as having at least one insensate site on either foot [29]. In NHANES, ABI was calculated by measuring the systolic blood pressure at the right brachial artery and at both posterior tibial arteries using doppler ultrasound. If the participant had a contraindication to blood pressure measurement using the right arm, the systolic blood pressure at the left brachial artery was used instead. PAD was defined as a right or left ABI < 0.90 [29]. We also examined PN and PAD as separate outcomes.
Covariate Definitions
All information on covariates was obtained by trained study personnel using standardized procedures per NHANES protocols [28]. Age, sex, race/ethnicity, education, and smoking status were self-reported by participants. Diabetes was defined as self-reported doctor diagnosed diabetes. Body mass index (BMI) was calculated as measured weight (kilograms) divided by measured height squared (meters2). Hypertension was defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or taking blood pressure control medication. Hypercholesterolemia was defined as total cholesterol ≥ 240 mg/dL or taking cholesterol control medication. Prevalent cardiovascular disease was defined as self-reported doctor diagnosed coronary heart disease, heart attack or stroke. Chronic kidney disease was defined as eGFR < 60 mL/min/1.73m2 or urine albumin to creatinine ratio ≥ 30 mg/g [28].
Statistical Analyses
We conducted analyses overall and stratified by diabetes status. We divided participants into categories based on clinical cutpoints of HbA1c [17]: <7.0%, 7.0–8.9%, and >8.9% in adults with diagnosed diabetes; and <5.7%, 5.7–<6.5%, and ≥6.5% in adults without diagnosed diabetes. We divided participants into glycated albumin categories using percentiles equivalent to diagnostic categories of HbA1c [23]: <82nd percentile, 82nd –<97th percentile, ≥97th percentile for adults with diagnosed diabetes; and <46th percentile, 46th –<83rd percentile, ≥83rd percentile for adults without diagnosed diabetes. We examined the characteristics of the overall study population and according to categories of HbA1c and glycated albumin. We also compared participants with and without lower extremity disease using survey-weighted chi-square tests for categorical variables and weighted ANOVA for continuous variables.
We used multivariable logistic regression models to evaluate the associations of glycated albumin and HbA1c with the lower extremity disease outcome. Model 1 included age, sex, and race/ethnicity. Model 2 adjusted for all variables in Model 1 as well as education, BMI, smoking status, hypertension, hypercholesterolemia, prevalent cardiovascular disease, and chronic kidney disease. In analyses of persons with diabetes, we also adjusted for duration of diabetes (Model 2a). To characterize the shape of the continuous associations of HbA1c and glycated albumin with lower extremity disease, we modeled the biomarkers using restricted cubic splines with 4 knots placed at the 5th, 35th, 65th, and 95th percentiles. We compared the strength of the observed associations for HbA1c and glycated albumin using seemingly unrelated regression.
Due to concerns that ABI is a less accurate measurement of PAD in adults with diabetes (due to potential medial arterial calcification and stiffening), we conducted a sensitivity analysis of PAD excluding participants with non-compressible vessels (i.e., ABI ≥1.4).
All analyses incorporated sampling weights to obtain unbiased estimates from the complex NHANES design. Results for this study are nationally representative of the US civilian non-institutionalized population aged 40 years or older. Analyses were performed using Stata, version 16.1 (StataCorp) with a P-value less than 0.05 indicating statistical significance.
Results
The prevalence (±standard error) of lower extremity disease was 17.4±0.6% (15.9±0.7% in adults without diabetes and 33.2±2.9% in adults with diabetes). The prevalence of PAD was 5.1±0.3% (4.5±0.3% in adults without diabetes and 11.5±2.0% in adults with diabetes). The prevalence of PN was 11.8±0.5% (10.7±0.5% in adults without diabetes and 23.5±1.7% in adults with diabetes). Prior foot ulcer or amputation was uncommon in this general population, affecting only 2.2±0.2% of adults overall (1.7±0.2% in adults without diabetes and 7.0±1.2% in adults with diabetes).
Baseline characteristics of adults according to diabetes-specific glycated albumin categories are summarized in Table 1. Baseline characteristics according to diabetes-specific HbA1c categories are summarized in Supplementary Table I. The prevalence of lower extremity disease, and particularly PN, were higher at higher glycated albumin and HbA1c levels among adults both with and without diabetes.
Table 1.
Characteristics of US adults aged >40 years by diabetes and glycated albumin (GA) category a, NHANES 1999–2004
| No Diabetes | Diabetes | |||||
|---|---|---|---|---|---|---|
| GA <14.5% | GA 14.5–18.2% | GA≥18.3% | GA<17.9% | GA 17.9–24.3% | GA≥24.4% | |
| Unweighted N | 3888 | 1070 | 134 | 347 | 232 | 114 |
| Mean age, years | 54.4 (0.2) | 59.8 (0.6) | 59.9 (1.3) | 60.4 (0.6) | 61.3 (1.0) | 55.9 (1.5) |
| Male, % | 48.8 (0.8) | 43.3 (1.8) | 61.6 (5.0) | 53.5 (2.3) | 54.8 (4.4) | 58.7 (7.0) |
| Race, % | ||||||
| White | 82.4 (1.4) | 74.3 (2.4) | 68.5 (7.1) | 71.2 (3.9) | 68.1 (4.0) | 54.3 (6.5) |
| Black | 6.5 (0.6) | 12.3 (1.5) | 12.5 (3.3) | 8.8 (1.5) | 12.4 (2.7) | 19.2 (3.8) |
| Other | 11.1 (1.3) | 13.4 (2.3) | 19.1 (5.6) | 20.0 (3.4) | 19.5 (3.8) | 26.5 (5.8) |
| Education, % | ||||||
| College and above | 56.5 (1.4) | 54.8 (2.4) | 41.3 (5.2) | 48.7 (3.1) | 41.0 (4.4) | 45.2 (6.2) |
| High school or equivalent | 26.9 (1.0) | 24.3 (1.5) | 23.9 (5.1) | 26.5 (3.1) | 24.5 (3.5) | 30.5 (6.5) |
| Less than high school | 16.6 (0.9) | 21.0 (2.0) | 34.8 (5.2) | 24.8 (3.2) | 34.4 (4.1) | 24.2 (6.0) |
| Smoking status, % | ||||||
| Never | 44.8 (1.1) | 53.4 (2.0) | 42.8 (6.0) | 43.3 (3.2) | 47.1 (5.4) | 46.1 (7.2) |
| Former | 32.9 (1.1) | 33.7 (1.8) | 38.7 (6.3) | 33.2 (3.3) | 37.8 (5.1) | 29.0 (5.8) |
| Current | 22.3 (1.0) | 12.9 (1.6) | 18.5 (4.5) | 23.5 (3.1) | 15.0 (3.0) | 25.0 (5.3) |
| BMI category, % | ||||||
| <25 kg/m2 | 28.6 (1.2) | 41.5 (2.8) | 21.4 (4.3) | 13.9 (2.4) | 17.0 (3.6) | 32.8 (5.8) |
| 25–<30 kg/m2 | 39.5 (1.0) | 38.0 (2.3) | 41.9 (5.9) | 30.9 (4.0) | 28.2 (3.5) | 38.2 (6.5) |
| ≥30 kg/m2 | 31.9 (1.0) | 20.5 (1.9) | 36.8 (5.8) | 55.3 (3.7) | 54.8 (4.0) | 29.0 (6.5) |
| Cardiovascular disease, % | 8.2 (0.5) | 10.0 (1.1) | 15.0 (3.6) | 23.5 (2.9) | 25.7 (4.4) | 10.1 (2.6) |
| Hypertension, % | 38.1 (1.2) | 44.8 (2.4) | 41.0 (5.7) | 65.7 (2.9) | 64.0 (3.7) | 53.3 (6.8) |
| Hypercholesterolemia, % | 33.7 (1.0) | 29.4 (1.8) | 35.6 (5.6) | 47.5 (3.0) | 50.5 (3.5) | 41.8 (8.1) |
| Chronic kidney disease, % | 12.6 (0.8) | 22.7 (1.8) | 33.6 (5.2) | 37.5 (3.8) | 39.1 (4.3) | 44.3 (5.4) |
| Lower extremity disease, % | 14.6 (0.7) | 20.9 (1.7) | 24.2 (5.0) | 28.6 (2.8) | 36.6 (5.0) | 41.6 (5.5) |
| Peripheral neuropathy, % | 9.8 (0.6) | 14.1 (1.4) | 15.6 (4.3) | 19.9 (2.3) | 23.5 (3.1) | 35.7 (5.6) |
| Peripheral artery disease, % | 3.9 (0.3) | 7.3 (1.0) | 6.4 (2.7) | 9.3 (1.9) | 16.2 (4.6) | 8.7 (3.4) |
| HbA1c, median (p25, p75), % | 5.4 (5.2, 5.6) | 5.6 (5.3, 5.9) | 6.6 (5.5, 8.3) | 6.2 (5.8, 6.7) | 7.7 (7.2, 8.5) | 10.1 (9.0, 11.3) |
Categories correspond to <80.6th percentile, 80.6–98.1th percentile, and ≥98.1th percentile for adults without diabetes; and <52.1th, 52.1–85.0th, and ≥85.0th percentile in adults with diabetes
All p-values comparing percentages across the six categories were < 0.0001.
Clinical categories of HbA1c and percentile-equivalent categories of glycated albumin were both associated with lower extremity disease in adults with diabetes in demographically-adjusted models (Table 2). Associations in persons with diabetes were somewhat attenuated but persisted after adjusting for vascular risk factors and duration of diabetes (Model 2a). The patterns of association were similar for HbA1c and glycated albumin (P for seemingly unrelated regression = 0.60). Associations of HbA1c and glycated albumin with lower extremity disease in adults without diabetes were not statistically significant (Table 2).
Table 2.
Associations (OR, 95% CI) of HbA1c and glycated albumin categories with lower extremity disease, overall and by diabetes status, NHANES adults aged >40 years, 1999–2004
| Overall | No Diabetes | Diabetes | ||||
|---|---|---|---|---|---|---|
| Model 1 | Model 2 | Model 1 | Model 2 | Model 1 | Model 2a | |
| HbA1c category | ||||||
| No diabetes, <5.7% | 1 (Ref) | 1 (Ref) | 1 (Ref) | 1 (ref) | -- | -- |
| No diabetes, 5.7–6.4% | 1.24 (1.05, 1.46) | 1.09 (0.92, 1.29) | 1.23 (1.05, 1.45) | 1.09 (0.93, 1.29) | -- | -- |
| No diabetes, ≥6.5% | 1.28 (0.71, 2.32) | 1.02 (0.56, 1.86) | 1.28 (0.71, 2.31) | 1.05 (0.58, 1.90) | -- | -- |
| Diabetes, <7% | 1.81 (1.24, 2.66) | 1.44 (0.98, 2.11) | -- | -- | 1 (Ref) | 1 (Ref) |
| Diabetes, 7–8.9% | 2.47 (1.61, 3.79) | 1.86 (1.24, 2.79) | -- | -- | 1.36 (0.79, 2.34) | 1.08 (0.62, 1.88) |
| Diabetes, ≥9% | 3.96 (2.11, 7.42) | 3.16 (1.71, 5.86) | -- | -- | 2.24 (1.24, 4.06) | 2.07 (1.11, 3.84) |
| Glycated albumin category a | ||||||
| No diabetes, <14.5% | 1 (Ref) | 1 (Ref) | 1 (Ref) | 1 (Ref) | -- | -- |
| No diabetes, 14.5–18.2% | 1.11 (0.88, 1.41) | 1.20 (0.94, 1.53) | 1.10 (0.86, 1.39) | 1.19 (0.93, 1.52) | -- | -- |
| No diabetes, ≥18.3% | 1.23 (0.69, 2.19) | 1.09 (0.60, 1.95) | 1.22 (0.68, 2.18) | 1.11 (0.61, 2.00) | -- | -- |
| Diabetes, <17.9% | 1.71 (1.23, 2.38) | 1.37 (0.99, 1.90) | -- | -- | 1 (Ref) | 1 (Ref) |
| Diabetes, 17.9–24.3% | 2.36 (1.49, 3.74) | 1.91 (1.23, 2.96) | -- | -- | 1.38 (0.81, 2.34) | 1.26 (0.74, 2.17) |
| Diabetes, ≥24.4% | 3.96 (2.18, 7.19) | 3.74 (2.11, 6.62) | -- | -- | 2.26 (1.24, 4.09) | 2.59 (1.43, 4.72) |
Categories correspond to <80.6th percentile, 80.6–98.1th percentile, and ≥98.1th percentile for adults without diabetes; and <52.1th, 52.1–85.0th, and ≥85.0th percentile in adults with diabetes
Model 1: age, sex and race/ethnicity
Model 2: all variables in Model 1 plus education, smoking status, BMI, prevalent cardiovascular disease, hypertension, hypercholesterolemia and chronic kidney disease
Model 2a: all variables in Model 1 plus duration of diabetes
In persons with diabetes, HbA1c and glycated albumin were both associated with PAD and PN (Table 3). The patterns of association observed were similar for HbA1c and glycated albumin (P for seemingly unrelated regression = 0.13). The observed associations of HbA1c and glycated albumin with PAD were similar for adults with diabetes when participants with ABI >1.4 were excluded (Supplementary Table II).
Table 3.
Associations (OR, 95% CI) of HbA1c and glycated albumin categories with peripheral neuropathy and peripheral artery disease, overall and by diabetes status, NHANES adults aged >40 years, 1999–2004
| Overall | No Diabetes | Diabetes | ||||
|---|---|---|---|---|---|---|
| Model 1 | Model 2 | Model 1 | Model 2 | Model 1 | Model 2a | |
| Peripheral neuropathy | ||||||
| HbA1c category | ||||||
| No diabetes, <5.7% | 1 (Ref) | 1 (Ref) | 1 (Ref) | 1 (Ref) | -- | -- |
| No diabetes, 5.7–6.4% | 1.18 (0.96, 1.44) | 1.07 (0.88, 1.30) | 1.16 (0.95, 1.43) | 1.07 (0.88, 1.30) | -- | -- |
| No diabetes, ≥6.5% | 1.41 (0.71, 2.80) | 1.16 (0.57, 2.35) | 1.38 (0.70, 2.75) | 1.17 (0.58, 2.40) | -- | -- |
| Diabetes, <7% | 1.68 (1.14, 2.46) | 1.46 (1.01, 2.11) | -- | -- | 1 (Ref) | 1 (Ref) |
| Diabetes, 7–8.9% | 2.25 (1.46, 3.46) | 1.85 (1.23, 2.79) | -- | -- | 1.40 (0.74, 2.67) | 1.07 (0.57, 2.00) |
| Diabetes, ≥9% | 4.74 (2.47, 9.09) | 4.25 (2.24, 8.06) | -- | -- | 3.06 (1.55, 6.03) | 2.93 (1.58, 5.44) |
| Glycated albumin category a | ||||||
| No diabetes, <14.5% | 1 (Ref) | 1 (Ref) | 1 (Ref) | 1 (Ref) | -- | -- |
| No diabetes, 14.5–18.2% | 1.17 (0.88, 1.56) | 1.24 (0.94, 1.66) | 1.15 (0.87, 1.54) | 1.23 (0.92, 1.64) | -- | -- |
| No diabetes, ≥18.3% | 1.15 (0.58, 2.27) | 1.04 (0.52, 2.06) | 1.12 (0.57, 2.22) | 1.05 (0.53, 2.09) | -- | -- |
| Diabetes, <17.9% | 1.71 (1.21, 2.41) | 1.51 (1.09, 2.09) | -- | -- | 1 (Ref) | 1 (Ref) |
| Diabetes, 17.9–24.3% | 2.01 (1.37, 2.95) | 1.73 (1.18, 2.53) | -- | -- | 1.19 (0.68, 2.08) | 1.02 (0.60, 1.74) |
| Diabetes, ≥24.4% | 4.81 (2.69, 8.58) | 4.91 (2.80, 8.62) | -- | -- | 2.91 (1.50, 5.65) | 3.36 (1.82, 6.17) |
| Peripheral artery disease | ||||||
| HbA1c category | ||||||
| No diabetes, <5.7% | 1 (Ref) | 1 (Ref) | 1 (Ref) | 1 (Ref) | -- | -- |
| No diabetes, 5.7–6.4% | 1.37 (1.01, 1.86) | 1.19 (0.87, 1.63) | 1.37 (1.01, 1.86) | 1.18 (0.87, 1.61) | -- | -- |
| No diabetes, ≥6.5% | 0.88 (0.44, 1.76) | 0.73 (0.36, 1.48) | 0.89 (0.45, 1.77) | 0.74 (0.36, 1.53) | -- | -- |
| Diabetes, <7% | 2.19 (1.13, 4.26) | 1.57 (0.78, 3.17) | -- | -- | 1 (Ref) | 1 (Ref) |
| Diabetes, 7–8.9% | 2.42 (1.28, 4.57) | 1.67 (0.88, 3.17) | -- | -- | 1.09 (0.53, 2.23) | 0.93 (0.42, 2.04) |
| Diabetes, ≥9% | 3.09 (1.20, 7.93) | 1.89 (0.71, 5.03) | -- | -- | 1.51 (0.44, 5.16) | 1.25 (0.38, 4.15) |
| Glycated albumin category a | ||||||
| No diabetes, <14.5% | 1 (Ref) | 1 (Ref) | 1 (Ref) | 1 (Ref) | -- | -- |
| No diabetes, 14.5–18.2% | 1.08 (0.79, 1.47) | 1.14 (0.82, 1.60) | 1.06 (0.78, 1.44) | 1.15 (0.82, 1.61) | -- | -- |
| No diabetes, ≥18.3% | 0.88 (0.33, 2.32) | 0.81 (0.31, 2.12) | 0.87 (0.33, 2.30) | 0.83 (0.31, 2.21) | -- | -- |
| Diabetes, <17.9% | 1.63 (0.93, 2.88) | 1.17 (0.64, 2.13) | -- | -- | 1 (ref) | 1 (ref) |
| Diabetes, 17.9–24.3% | 3.05 (1.38, 6.72) | 2.34 (1.06, 5.18) | -- | -- | 1.81 (0.86, 3.81) | 1.95 (0.89, 4.28) |
| Diabetes, ≥24.4% | 2.00 (0.70, 5.77) | 1.53 (0.50, 4.67) | -- | -- | 1.23 (0.39, 3.86) | 1.26 (0.41, 3.87) |
Categories correspond to <80.6th percentile, 80.6–98.1th percentile, and ≥98.1th percentile for adults without diabetes; and <52.1th, 52.1–85.0th, and ≥85.0th percentile in adults with diabetes
Model 1: age, sex and race
Model 2: all variables in Model 1 plus education, smoking status, BMI, prevalent cardiovascular disease, hypertension, hypercholesterolemia and chronic kidney disease
Model 2a: all variables in Model 1 plus duration of diabetes
Consistent results were observed when we modeled HbA1c and glycated albumin as splines, with strong linear associations observed at high (diabetic) levels of HbA1c and glycated albumin. Associations of HbA1c and glycated albumin with PN were particularly robust (Figure 1).
Figure 1. Cross-sectional associations of HbA1c and glycated albumin with lower extremity disease.
Adjusted odds ratios and 95% CIs for the continuous associations of HbA1c (top row) and glycated albumin (bottom row) with prevalent lower extremity disease, peripheral neuropathy, and peripheral artery disease in US adults aged 40 and older. Model was adjusted for age, sex, race, education, smoking status, body mass index, prevalent cardiovascular disease, hypertension, hypercholesterolemia and chronic kidney disease. HbA1c and glycated albumin were modeled using restricted cubic splines with knots at the 5th, 35th, 65th, and 95th percentiles. The models were centered at the 50th percentile, and the displays of graph were truncated at the 1st and 99th percentile. The light gray bars denote the distribution of adults without diabetes, and the dark gray bars denote the distribution of adults with diabetes
Discussion
Lower extremity diseases, such as PN and PAD, are important complications of diabetes. Few studies have examined these complications in the general population. We evaluated and compared associations of HbA1c and glycated albumin with lower extremity disease in the a nationally representative sample of US adults. We found robust (and similar) associations of both biomarkers with lower extremity disease in adults with diabetes. We did not observe significant associations of HbA1c or glycated albumin with lower extremity disease in adults without diabetes.
Our results highlight the important role of hyperglycemia in the development of lower extremity disease. HbA1c is associated with diabetic foot ulcers [5] and major amputations in adults with diabetes [30, 31]. We have previously shown strong associations of HbA1c with PAD and PN in a community-based population [6–8]. Other cohort studies have shown similar associations of HbA1c and long-standing hyperglycemia with lower extremity disease in adults with diabetes [9–14]. The association of HbA1c with lower extremity complications is well recognized; in fact, HbA1c has been proposed as a biomarker for lower extremity disease in adults with diabetes [32].
Few studies have examined the link between glycated albumin and lower extremity disease. Ours is the first study to conduct a head-to-head comparison of glycated albumin and HbA1C with lower extremity disease in the general US adult population. Small, cross-sectional studies have suggested an association of glycated albumin with PN in adults with type 1 diabetes [15], and with cardiac autonomic neuropathy in adults with type 2 diabetes [33]. We recently demonstrated that glycated albumin was associated with PN in older adults with diabetes in the community-based Atherosclerosis Risk in Communities (ARIC) Study [8]. In the present study, we demonstrated strong associations of glycated albumin with lower extremity disease, particularly PN, in adults with diabetes, confirming our prior results. The magnitude and shape of the observed association for glycated albumin was similar to that for HbA1c. Glycated albumin is a short-term marker of glycemic control and is not affected by conditions that shorten the life span of erythrocytes or by hemoglobin variants [18], but may be affected by conditions that affect albumin metabolism. Our results extend prior work and suggest the construct validity of using glycated albumin as a measure of glycemic control which may serve as a complementary or substitute test of hyperglycemia when HbA1c testing is problematic.
We have previously shown a positive graded association of HbA1c with risk of incident PAD in the ARIC Study [7]. In the present study, associations of glycated albumin and HbA1c with PAD (when defined according to a binary ABI cut-point) were more non-linear. The association of HbA1c with PAD has been shown to be stronger for participants with symptomatic PAD than for PAD defined by low ABI alone [7], and for advanced PAD (critical limb ischemia) than for PAD without critical limb ischemia [6]. Here, we defined PAD based solely on ABI. It is well established that ABI is a less accurate measure of PAD in adults with diabetes [34]. Diabetes is associated with calcific atherosclerotic disease that can result in abnormally elevated or normal ABIs due to medial calcification, and thus reduced sensitivity for PAD [35]. We did not find a difference in the strength of our associations when adults with ABI >1.4 were excluded from the analysis, but the sensitivity of ABI for detecting PAD is only 53% in adults with both diabetes and PN [35]. Future studies assessing the association of HbA1c and glycated albumin with PAD in adults with diabetes may benefit from the use of toe-brachial index measurements, which are less affected by arterial calcification than ABI and thus more accurate for diagnosing PAD in adults with diabetes [36], but were not available in NHANES.
Diabetes exists along a spectrum, which is why we were also interested to see if the observed associations of HbA1c and glycated albumin extended to persons without a history of diagnosed diabetes. In adults without diabetes, we did not find robust associations of HbA1c or glycated albumin with lower extremity disease, PN, or PAD. This lack of association may partly reflect the cross-sectional design of our study. There are data to support a link between HbA1c and future development of PAD among adults both with and without diabetes [6, 7]. Randomized controlled trials suggest that intensive glycemic control is important in the long-term prevention of macrovascular disease [37–39], as damage from hyperglycemia may take many years to accumulate term. Our results suggest that cross-sectional measures of HbA1c and glycated albumin in adults without diabetes may not be associated with lower extremity disease.
The strong link between glycemic control biomarkers with PN in adults with diabetes suggests the importance of targeted interventions to prevent lower extremity disease and reduce amputation risk among patients with poor glycemic control. Adults with diabetes and PN have a high risk of diabetic foot ulcer, which can progress to major amputation [40]. The vast majority (~83%) of non-traumatic amputation cases in the US are attributed to diabetes US [41]. Early detection and risk factor management are critical components of amputation prevention in persons with diabetes. Annual diabetic foot exams are an important aspect of routine diabetes care and should include a full foot exam as well as vibration testing and monofilament testing for PN [42]. However, only 70% of US adults with diabetes report having received a foot exam in the past 12 months by their doctor [43]. It is critical to identify adults with diabetes who are at high risk for foot ulceration and amputation before these conditions occur. Our data suggest that adults with diabetes who have poor glycemic control have a high burden of lower extremity disease, and that prevalence increases in a linear fashion with biomarkers of hyperglycemia.
The limitations of our study include the cross-sectional design; we cannot establish the temporality of the observed associations. Future cohort studies assessing the association of HbA1c and glycated albumin with incident lower extremity disease are needed. As noted above, ABI is associated with measurement error, particularly in adults with diabetes. In addition, monofilament testing is not the gold standard examination for PN; nerve conduction tests or monofilament testing combined with ankle reflexes and vibration sensation testing are more sensitive for diagnosing PN [44]. PN as diagnosed by monofilament testing represents loss of protective sensation, which is a more severe form of PN. As a result, the prevalence of PN that we report may be underestimated. We also cannot rule out the possibility of residual confounding. Strengths of our study include the large sample size, the availability of both HbA1c and glycated albumin measurements in a nationally representative sample of the US general population, rigorous measurement of traditional risk factors for lower extremity disease by trained technicians using standardized protocol including standardized monofilament testing for PN and ABI assessment for PAD.
In conclusion, there were robust and similar associations of HbA1c and glycated albumin with prevalent lower extremity disease in adults with diabetes. We did not observe a strong signal for these measures of hyperglycemia with lower extremity disease in adults without diabetes. Our findings suggest the utility of glycated albumin as a biomarker of hyperglycemia in adults with diabetes and reemphasize the critically important role of hyperglycemia in the development of lower extremity outcomes.
Supplementary Material
Highlights.
There were robust and similar associations of HbA1c and glycated albumin with prevalent lower extremity disease in adults with diabetes.
We did not observe associations of HbA1c and glycated albumin with prevalent lower extremity disease in adults without diabetes.
Our findings suggest the utility of glycated albumin as a biomarker of hyperglycemia and reemphasize the critically important role of hyperglycemia in the development of lower extremity outcomes.
Acknowledgements
Reagents for the glycated albumin assay were donated by the Asahi Kasei Pharma Corporation.
Sources of Funding
This work was funded by a grant from the Foundation for the National Institutes of Health Biomarkers Consortium to the Johns Hopkins Bloomberg School of Public Health (PI: Elizabeth Selvin). The Foundation for the National Institutes of Health received support for this project from Abbott Laboratories, AstraZeneca, Johnson & Johnson, the National Dairy Council, Ortho Clinical Diagnostics, Roche Diagnostics, and Siemens Healthcare Diagnostics. Dr. Selvin was also supported by NIH/NHLBI grant K24 HL152440. Dr. Matsushita was supported by R21HL133694. Dr. Hicks was supported by K23DK124515.
Footnotes
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Conflict of interest
The authors declare no conflict of interest.
References
- 1.Hicks CW, Wang D, Matsushita K, Windham BG, Selvin E. Peripheral Neuropathy and All-Cause and Cardiovascular Mortality in U.S. Adults : A Prospective Cohort Study. Ann Intern Med 2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Adler AI, Boyko EJ, Ahroni JH, Smith DG. Lower-extremity amputation in diabetes. The independent effects of peripheral vascular disease, sensory neuropathy, and foot ulcers. Diabetes Care 1999; 22:1029–1035. [DOI] [PubMed] [Google Scholar]
- 3.Barnes JA, Eid MA, Creager MA, Goodney PP. Epidemiology and Risk of Amputation in Patients With Diabetes Mellitus and Peripheral Artery Disease. Arterioscler Thromb Vasc Biol 2020; 40:1808–1817. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Gregg EW, Sorlie P, Paulose-Ram R, Gu Q, Eberhardt MS, Wolz M, et al. Prevalence of lower-extremity disease in the US adult population >=40 years of age with and without diabetes: 1999–2000 national health and nutrition examination survey. Diabetes Care 2004; 27:1591–1597. [DOI] [PubMed] [Google Scholar]
- 5.Hamilton EJ, Davis WA, Siru R, Baba M, Norman PE, Davis TME. Temporal Trends in Incident Hospitalization for Diabetes-Related Foot Ulcer in Type 2 Diabetes: The Fremantle Diabetes Study. Diabetes Care 2021; 44:722–730. [DOI] [PubMed] [Google Scholar]
- 6.Ding N, Kwak L, Ballew SH, Jaar B, Hoogeveen RC, Ballantyne CM, et al. Traditional and nontraditional glycemic markers and risk of peripheral artery disease: The Atherosclerosis Risk in Communities (ARIC) study. Atherosclerosis 2018; 274:86–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Selvin E, Wattanakit K, Steffes MW, Coresh J, Sharrett AR. HbA1c and peripheral arterial disease in diabetes: the Atherosclerosis Risk in Communities study. Diabetes Care 2006; 29:877–882. [DOI] [PubMed] [Google Scholar]
- 8.Hicks CW, Wang D, Daya NR, Windham BG, Ballantyne CM, Matsushita K, et al. Associations of Cardiac, Kidney, and Diabetes Biomarkers With Peripheral Neuropathy among Older Adults in the Atherosclerosis Risk in Communities (ARIC) Study. Clin Chem 2020; 66:686–696. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Adler AI, Stevens RJ, Neil A, Stratton IM, Boulton AJ, Holman RR. UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes. Diabetes Care 2002; 25:894–899. [DOI] [PubMed] [Google Scholar]
- 10.Al-Delaimy WK, Merchant AT, Rimm EB, Willett WC, Stampfer MJ, Hu FB. Effect of type 2 diabetes and its duration on the risk of peripheral arterial disease among men. Am J Med 2004; 116:236–240. [DOI] [PubMed] [Google Scholar]
- 11.Khan N, Ahmad I, Noohu MM. Association of disease duration and sensorimotor function in type 2 diabetes mellitus: beyond diabetic peripheral neuropathy. Somatosens Mot Res 2020; 37:326–333. [DOI] [PubMed] [Google Scholar]
- 12.Peterson M, Pingel R, Lagali N, Dahlin LB, Rolandsson O. Association between HbA1c and peripheral neuropathy in a 10-year follow-up study of people with normal glucose tolerance, impaired glucose tolerance and Type 2 diabetes. Diabet Med 2017; 34:1756–1764. [DOI] [PubMed] [Google Scholar]
- 13.Su JB, Zhao LH, Zhang XL, Cai HL, Huang HY, Xu F, et al. HbA1c variability and diabetic peripheral neuropathy in type 2 diabetic patients. Cardiovasc Diabetol 2018; 17:47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Valensi P, Giroux C, Seeboth-Ghalayini B, Attali JR. Diabetic peripheral neuropathy: effects of age, duration of diabetes, glycemic control, and vascular factors. J Diabetes Complications 1997; 11:27–34. [DOI] [PubMed] [Google Scholar]
- 15.Wang N, Guo C, Han P, Li T. Glycated albumin indicates peripheral diabetic neuropathy. Acta Diabetol 2016; 53:973–979. [DOI] [PubMed] [Google Scholar]
- 16.Gregg EW, Gu Q, Williams D, de Rekeneire N, Cheng YJ, Geiss L, et al. Prevalence of lower extremity diseases associated with normal glucose levels, impaired fasting glucose, and diabetes among U.S. adults aged 40 or older. Diabetes Res Clin Pract 2007; 77:485–488. [DOI] [PubMed] [Google Scholar]
- 17.American Diabetes Association. Standards of medical care in diabetes--2010. Diabetes Care 2010; 33 Suppl 1:S11–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Jeffcoate SL. Diabetes control and complications: the role of glycated haemoglobin, 25 years on. Diabet Med 2004; 21:657–665. [DOI] [PubMed] [Google Scholar]
- 19.Takahashi S, Uchino H, Shimizu T, Kanazawa A, Tamura Y, Sakai K, et al. Comparison of glycated albumin (GA) and glycated hemoglobin (HbA1c) in type 2 diabetic patients: usefulness of GA for evaluation of short-term changes in glycemic control. Endocr J 2007; 54:139–144. [DOI] [PubMed] [Google Scholar]
- 20.Parrinello CM, Selvin E. Beyond HbA1c and glucose: the role of nontraditional glycemic markers in diabetes diagnosis, prognosis, and management. Curr Diab Rep 2014; 14:548. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Selvin E Hemoglobin A1c-Using Epidemiology to Guide Medical Practice: Kelly West Award Lecture 2020. Diabetes Care 2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Rooney MR, Tang O, Pankow JS, Selvin E. Glycaemic markers and all-cause mortality in older adults with and without diabetes: the Atherosclerosis Risk in Communities (ARIC) study. Diabetologia 2021; 64:339–348. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Selvin E, Rawlings AM, Grams M, Klein R, Sharrett AR, Steffes M, et al. Fructosamine and glycated albumin for risk stratification and prediction of incident diabetes and microvascular complications: a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study. Lancet Diabetes Endocrinol 2014; 2:279–288. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Selvin E, Rawlings AM, Lutsey PL, Maruthur N, Pankow JS, Steffes M, et al. Fructosamine and Glycated Albumin and the Risk of Cardiovascular Outcomes and Death. Circulation 2015; 132:269–277. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Giglio RV, Lo Sasso B, Agnello L, Bivona G, Maniscalco R, Ligi D, et al. Recent Updates and Advances in the Use of Glycated Albumin for the Diagnosis and Monitoring of Diabetes and Renal, Cerebro- and Cardio-Metabolic Diseases. J Clin Med 2020; 9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Selvin E, Warren B, He X, Sacks DB, Saenger AK. Establishment of Community-Based Reference Intervals for Fructosamine, Glycated Albumin, and 1,5-Anhydroglucitol. Clin Chem 2018; 64:843–850. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Daya NR, Rooney MR, Tang O, Coresh J, Christenson RH, Selvin E. Glycated Albumin in Pristine and Non-Pristine Stored Samples in the National Health and Nutrition Examination Survey (NHANES) 1999–2004. J Appl Lab Med 2022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Centers for Disease Control and Preventions. About the National Health and Nutrition Examination Survey. 2017. Accessed 08/03/2021. https://www.cdc.gov/nchs/nhanes/about_nhanes.htm
- 29.Centers for Medicare and Medicaid Services. National Health and Nutrition Examination Survey 1999–2000 Data Documentation, Codebook, and Frequencies: Lower Extremity Disease - Peripheral Neuropathy (LEXPN). 2002. https://wwwn.cdc.gov/nchs/nhanes/1999-2000/LEXPN.htm
- 30.Lane KL, Abusamaan MS, Voss BF, Thurber EG, Al-Hajri N, Gopakumar S, et al. Glycemic control and diabetic foot ulcer outcomes: A systematic review and meta-analysis of observational studies. J Diabetes Complications 2020; 34:107638. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Zhou ZY, Liu YK, Chen HL, Yang HL, Liu F. HbA1c and Lower Extremity Amputation Risk in Patients With Diabetes: A Meta-Analysis. Int J Low Extrem Wounds 2015; 14:168–177. [DOI] [PubMed] [Google Scholar]
- 32.Casadei G, Filippini M, Brognara L. Glycated Hemoglobin (HbA1c) as a Biomarker for Diabetic Foot Peripheral Neuropathy. Diseases 2021; 9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Jun JE, Lee SE, Lee YB, Ahn JY, Kim G, Jin SM, et al. Glycated albumin and its variability as an indicator of cardiovascular autonomic neuropathy development in type 2 diabetic patients. Cardiovasc Diabetol 2017; 16:127. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Potier L, Abi Khalil C, Mohammedi K, Roussel R. Use and utility of ankle brachial index in patients with diabetes. Eur J Vasc Endovasc Surg 2011; 41:110–116. [DOI] [PubMed] [Google Scholar]
- 35.Williams DT, Harding KG, Price P. An evaluation of the efficacy of methods used in screening for lower-limb arterial disease in diabetes. Diabetes Care 2005; 28:2206–2210. [DOI] [PubMed] [Google Scholar]
- 36.Herraiz-Adillo A, Cavero-Redondo I, Alvarez-Bueno C, Pozuelo-Carrascosa DP, Solera-Martinez M. The accuracy of toe brachial index and ankle brachial index in the diagnosis of lower limb peripheral arterial disease: A systematic review and meta-analysis. Atherosclerosis 2020; 315:81–92. [DOI] [PubMed] [Google Scholar]
- 37.Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359:1577–1589. [DOI] [PubMed] [Google Scholar]
- 38.Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 2000; 23 Suppl 2:B21–29. [PubMed] [Google Scholar]
- 39.Stettler C, Allemann S, Juni P, Cull CA, Holman RR, Egger M, et al. Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: Meta-analysis of randomized trials. Am Heart J 2006; 152:27–38. [DOI] [PubMed] [Google Scholar]
- 40.Hicks CW, Selvin E. Epidemiology of Peripheral Neuropathy and Lower Extremity Disease in Diabetes. Curr Diab Rep 2019; 19:86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Hicks CW, Selvarajah S, Mathioudakis N, Sherman RE, Hines KF, Black JH 3rd, et al. Burden of Infected Diabetic Foot Ulcers on Hospital Admissions and Costs. Ann Vasc Surg 2016; 33:149–158. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Boulton AJ, Armstrong DG, Albert SF, Frykberg RG, Hellman R, Kirkman MS, et al. Comprehensive foot examination and risk assessment: a report of the task force of the foot care interest group of the American Diabetes Association, with endorsement by the American Association of Clinical Endocrinologists. Diabetes Care 2008; 31:1679–1685. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Shin JI, Wang D, Fernandes G, Daya N, Grams ME, Golden SH, et al. Trends in Receipt of American Diabetes Association Guideline-Recommended Care Among U.S. Adults With Diabetes: NHANES 2005–2018. Diabetes Care 2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Al-Geffari M Comparison of different screening tests for diagnosis of diabetic peripheral neuropathy in Primary Health Care setting. Int J Health Sci (Qassim) 2012; 6:127–134. [DOI] [PMC free article] [PubMed] [Google Scholar]
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