HbA_1c for diagnosis of type 2 diabetes. Is there an optimal cut point to assess high risk of diabetes complications, and how well does the 6.5% cutoff perform?

Figures & data

Table 1 Studies on the identification of HbA_1c thresholds for prevalent or incident retinopathy

Study	Study population characteristics	Definition of retinopathy	Method/criterion of determining cutoff	Cutoff	AROC	Sensitivity	Specificity	Cases of retinopathy above/below cutoff
McCance et al^Citation15	Cross-sectional; 960 Pima Indians; age ≥25 years; exclusion of subjects receiving insulin or oral hypoglycemic treatment at the last examination	At least one microaneurysm or hemorrhage or proliferative retinopathy	Crossing point of the two components of a bimodal HbA1c distribution	7.8%	–	65.6	87.6	15.6%/1.3%
			Equivalent to 2hPG cutoff of 11.1 mmol/L	6.1%	–	81.3	76.8	NR
			Maximum of Youden index	7.0%	NR	78.1	84.7	NR
McCance et al^Citation15	Longitudinal; 960 Pima Indians; age ≥25 years; subjects receiving insulin or oral hypoglycemic treatment at baseline were excluded; assessment of incidence of retinopathy after 5 years	At least one microaneurysm or hemorrhage or proliferative retinopathy	Crossing point of the two components of a bimodal HbA1c distribution	7.8%a	–	–	–	Incident cases above/below cutoff: 22.9%/1.1%
Engelgau et al^Citation23	Cross-sectional; 1,018 Egyptians; age ≥20 years; subjects with diabetes not excluded	Bilateral retinal fundus photography	Increase between 7th and 8th decile (entire population)	6.9%	–	78%	78%	28%/5%
			Increase between 9th and 10th decile (excluding subjects with antihyperglycemic medication)	7.5%		NR	NR	18%/5.6%
Expert committee; NHANES III^Citation24	Cross-sectional; n=2,821; age 40–74 years	Fundus photography	Increase between 9th and 10th decile	6.2%	–	NR	NR	NR
Ito et al^Citation43	Cross-sectional; 12,208 Japanese exposed to atomic bomb radiation in 1945; age 16–99 years; no exclusion of subjects with known diabetes	Bilateral fundus photography	Test of significant changes in prevalence of retinopathy between subsequent deciles	7.3%	–	NR	NR	4.2%/1.0%b
van Leiden et al; Hoorn study^Citation25	Longitudinal; follow-up 7.9–11.0 years; n=233; age 50–74 years; analyses in total study group and in subjects without diabetes	Presence of at least one microaneurysm, hemorrhage, or hard exudate	Logistic model with categories of HbA1c (adjusted for age, sex, hypertension, glucose metabolism category)	Increase in incidence of retinopathy for HbA1c in the range of 5.8%–13.1% compared to HbA1c 4.3%–5.2%; no threshold reported
Miyazaki et al; Hisayama study^Citation44	Cross-sectional; 1,637 Japanese; age 40–79 years; no exclusion of subjects with known diabetes	Fundus examination with grading by Airlie House classification	Maximum of Youden index	5.7%	0.945	86.5	90.1	20%/2%
Tapp et al; AusDiab study^Citation27	Cross-sectional; n=2,182; age ≥25 years; no exclusion of subjects with known diabetes	Presence of at least one definite retinal hemorrhage and/or microaneurysm	Visual (total population) Visual (exclusion of subjects on hypoglycemic medication)	6.1% No threshold found	–	NR	NR	21.3%/6.6%
			Change-point model without adjustment	5.2%	–	NR	NR	NR
			Change-point model adjusted for age, sex, blood pressure	5.6%	–	NR	NR	NR
			Change-point model with further adjustment for diabetes duration	6.0%	–	NR	NR	NR
Sabanayagam et al^Citation20	Cross-sectional; 3,190 Malay people; age 40–80 years; subjects with diabetes not excluded	Two digital fundus photographs; retinopathy was defined by ETDRS scores (any ≥15; mild ≥20; moderate >43)	Maximization of Youden index for any retinopathy	7.0%	0.754	55.6	85.0	35.4%/7.2%
			Maximization of Youden index for mild retinopathy	6.6%	0.899	87.0	77.1	NR
			Maximization of Youden index for moderate retinopathy	7.0%	0.904	82.9	82.3	15.8%/0.8%
			Change-point model for any retinopathy	No threshold observed
			Change-point model for mild retinopathy	No threshold observed
			Change-point model for moderate retinopathy	No threshold observed
Cheng et al; NHANES study^Citation45	Cross-sectional; 1,066 Americans; age ≥40 years	Two 45° nonmydriatic photographs; retinopathy was defined as a score ≥14 by ETDRS severity scale	Joinpoint regression: deciles	5.5%	0.71	80	37	12.7% increase in prevalence of retinopathy above cutoff/0.7% increase below cutoff per 1% increment of HbA1c
			Joinpoint regression: Pima cutpoints	5.5%
			Joinpoint regression: 0.1 increments of HbA1c	5.5%
			Joinpoint regression after exclusion of subjects on hypoglycemic medication	5.5%	–	–	–	10.5% increase in prevalence of retinopathy above cutoff/0.8% increase below cutoff per 1% increment of HbA1c
Massin et al; DESIR study^Citation21	Longitudinal; 10 year follow-up; n=700; one group of 235 subjects with diabetes, and two age, sex, and study center matched groups (n=227 and n=238, respectively), with FPG level 110–125 mg/dL, and FPG <110 mg/dL, respectively; age 30–65 years	Subjects with microaneurysms, hemorrhages, exudates, cotton-wool spots, intramicrovascular abnormalities, venous bleeding, or new vessels	Increase in positive predictive valuec	6.0%	0.64	19%	92%	NR
Selvin et al; ARIC study^Citation19	Cross-sectional; 10,584 subjects without known diabetes	Nonmydriatic 45° retinal photograph; retinopathy was defined by ETDRS scores (none <14, mild 14–20, moderate to severe ≥35)	Cubic-spline models with maximization of likelihood ratio with respect to location of threshold	No evidence for presence of a threshold (AROC for any retinopathy: 0.561 AROC for mild retinopathy: 0.543 AROC for moderate to severe retinopathy: 0.658)
Colagiuri et al; DETECT-2 collaboration^Citation22	Cross-sectional; pooled analysis of nine studies from five countries; n=44,623; age 20–79 years; subjects with known diabetes (13.8%) not excluded	Use of gradable retinal photographs; different methods of classifying and assessing retinopathy between studies	Maximum of Youden index	6.4%	–	84.5	87.0	–
			Logistic regression adjusted for study center (applied to continuous distribution)	6.5%–6.9%	–	80.1d	89.7d	–
			Logistic regression adjusted for study center (applied to vigintile distribution)	6.3%–6.7%	–	82.8d	88.1d	–
Xin et al^Citation30	Cross-sectional; 2,551 Chinese; age 18–79 years; FPG ≥5.6 mmol/L; no exclusion of subjects with known diabetes	Bilateral retinal fundus photography	Maximization of Youden index (total sample)	6.8%	0.864	85.1	88.0	NR
			Maximization of Youden index (exclusion of subjects receiving antihyperglycemic medication)	6.9%	0.725	60.7	93.6
			Joinpoint regression (total sample)	6.4%	–	85.1	82.1	NR
			Joinpoint regression (exclusion of subjects receiving antihyperglycemic medication)	6.7%	–	60.7	91.6
Tsugawa et al^Citation36	Cross-sectional; 2,804 White and 1,008 Black Americans; analysis of whole study group and of subjects not treated for diabetes only; age ≥40 years	One or more microaneurysms or more severe forms of retinopathy; Airlie House classification	Visual inspection of cubic-spline models	Cutoff “near 5.5%” in Blacks, “at higher HbA1c levels” in Whites
Tsugawa et al^Citation26	Cross-sectional; 20,433 Japanese subjects; age ≥21 years; subjects with known diabetes not excluded	Presence of hard exudates, cotton wool spots, retinal hemorrhage, or more severe forms of retinopathy; Fukuda standard A2 or higher	Test for nonlinearity in multivariate logistic regression models with restricted cubic spline	No threshold found for prevalence of retinopathy (test for nonlinearity: P=0.08)
Tsugawa et al^Citation26	Longitudinal; 3 years follow-up; 19,987 Japanese subjects; age ≥21 years; subjects with known diabetes not excluded	Presence of hard exudates, cotton wool spots, retinal hemorrhage, or more severe forms of retinopathy; Fukuda standard A2 or higher	Test for nonlinearity in multivariate logistic regression models with restricted cubic spline	“Possible threshold at HbA1c levels between 6.0 and 7.0” (test for nonlinearity: P=0.001)
			Multivariate logistic regression with categories of HbA1c as independent variable	6.5%–6.9%	–	–	–	–
Cho et al^Citation29	Cross-sectional; 3,403 participants from South Korea; age 40–69 years; 24% of the subjects had diabetes by ADA criteria	Single-field nonmydriatic fundus photography	Maximization of Youden index: any retinopathy	6.6%	0.83	76.2	84.2	8.4%/0.5%
			Maximization of Youden index: moderate/severe retinopathy	6.9%	0.84	77.1	88.7	6.6%/0.3%
			Logistic regression (unadjusted): any retinopathy	6.9%	–	68.3	89.0	10.5%/0.7%
			Logistic regression (unadjusted): moderate/severe retinopathy	6.9%	–	77.1	88.7	6.6%/0.3%
			Logistic regression (multivariable adjustment): any retinopathy	6.9%	–	68.3	89.0	10.5%/0.7%
			Logistic regression (multivariable adjustment): moderate/severe retinopathy	6.9%	–	77.1	88.7	6.6%/0.3%

Notes:

a The value “9.4%” indicated in Table 2 of the paper by McCance et al (1994) is obviously a mistake.

b Prevalence of retinopathy below threshold was calculated by the authors.

c Visual inspection of the frequency of retinopathy according to baseline HbA_1c would lead to a much larger cutoff but was not assessed by the authors.

d Values were calculated for the middle of the range.

Abbreviations: 2hPG, 2-hour plasma glucose; ADA, American Diabetes Association; ARIC, Atherosclerosis Risk in Communities; AROC, area under the receiver operating characteristic curve; AusDiab, Australian Diabetes Obesity and Lifestyle study; DESIR, Data from an Epidemiological Study on the Insulin Resistance Syndrome; DETECT-2, Evaluation of Screening and Early Detection Strategies for Type 2 Diabetes and Impaired Glucose Tolerance; ETDRS: Early Treatment Diabetic Retinopathy Study; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; NHANES, National Health and Nutrition Examination Survey; NR, not reported.

Table 2 Studies on the identification of HbA_1c thresholds for prevalence or incidence of microvascular complications (except retinopathy)

Study	Study characteristics	Microvascular complication	Method of determining cutoff	Cutoff	Sensitivity	Specificity	Cases above/below cutoff	AROC
McCance et al^Citation15	Cross-sectional; 960 Pima Indians; age ≥25 years; exclusion of subjects receiving insulin or oral hypoglycemic treatment at the last examination	Nephropathy	Crossing point of the two components of a bimodal HbA1c distribution	7.8%	40.0	86.6	7.5%/1.8%	–
	Longitudinal; 960 Pima Indians; age ≥25 years; subjects receiving insulin or oral hypoglycemic treatment at baseline were excluded; assessment of incidence of retinopathy after 5 years	Nephropathy	Crossing point of the two components of a bimodal HbA1c distribution	7.8%a	–	–	3.8%/1.4%	–
Tapp et al; AusDiab^Citation27	Cross-sectional; n=2,389; age ≥25 years; no exclusion of subjects with known diabetes	Microalbuminuria	Visual inspection Change-point model	6.1% No significant threshold	NR	NR	29.8%/11.2%	–
Sabanayagam et al^Citation20	Cross-sectional; 3,190 Malay people; age 40–80 years; subjects with diabetes not excluded	Chronic kidney disease	Maximum of Youden index	6.6%	37.9	76.6	–	0.615
		Microalbuminuria or macroalbuminuria	Maximum of Youden index	7.0%	31.8	90.6	–	0.673
		Peripheral neuropathy	Maximum of Youden index	6.6%	66.5	41.5	–	0.573
		Chronic kidney disease	Change-point model	No threshold observed			–	–
		Microalbuminuria or macroalbuminuria	Change-point model	No threshold observed			–	–
		Peripheral neuropathy	Change-point model	No threshold observed			–	–
Selvin et al; ARIC study^Citation19	Longitudinal; median of follow-up 14 years; 10,584 subjects without diabetes at baseline	Chronic kidney disease	Maximum likelihood ratio method	No evidence for a threshold (P-values for presence of a threshold: P=0.54 (adjustment for age, sex and race; P=0.59 [multivariable adjustment])				0.562
Bongaerts et al; KORA F4 study^Citation46	Cross-sectional; n= 1,100; age 61–82 years; no exclusion of subjects with known diabetes	Distal sensorimotor polyneuropathy (DSPN)	Logistic regression with categories of HbA1c	No relationship between quartiles of HbA1c and DSPN
Hernandez et al^Citation47	Cross-sectional; n=2,270; age 18–80 years; no exclusion of subjects with known diabetes	Combined endpoint of chronic kidney disease or cardiovascular disease	Maximum of Youden index	5.5%	82	55	–	0.76

Note:

a The figure “9.4%” indicated in Table 2 of the paper by McCance (1994) is obviously a mistake.

Abbreviations: HbA_1c, glycated hemoglobin; ARIC, Atherosclerosis Risk in Communities; AROC, area under the receiver operating characteristic curve; AusDiab, Australian Diabetes Obesity and Lifestyle study; KORA, Cooperative Health Research in the Region of Augsburg; NR, not reported.

Table 3 Association of HbA_1c based diagnosis of type 2 diabetes (HbA_1c ≥6.5%) with prevalence or incidence of microvascular complications

Study	Study characteristics	Microvascular complication considered	Prevalence of microvascular complications
			HbA1c ≥6.5%	HbA1c <6.5%
Sabanayagam et al^Citation20	Cross-sectional study in Malay people; age 40–80 years; subjects with diabetes not excluded; n=3,190 (chronic kidney disease) n=930 (microalbuminuria and macroalbuminuria) n=855 (peripheral neuropathy)	Prevalence of any retinopathy	28.6%	6.4%
		Prevalence of mild retinopathy	17.2%	0.8%
		Prevalence of moderate retinopathy	12.2%	0.4%
		Prevalence of chronic kidney disease	29.9%	17.8%
		Prevalence of microalbuminuria and macroalbuminuria	58.9%	29.6%
		Prevalence of peripheral neuropathy	23.9%	16.7%
Tsugawa et al^Citation36	Cross-sectional; 2,527 White and 805 Black Americans; age ≥40 years	Prevalence of retinopathy (subjects not treated for T2DM, Whites only)	12.3% (95% CI 4.5–20.1)	4.1%a
		Prevalence of retinopathy (subjects not treated for T2DM, Blacks only)	17.1% (95% CI 6.9–27.2)	6.7%a
Gunnslaugsdottir; Reykjavik study (AGES-R)^Citation35	Cross-sectional; n=4,994; age ≥67 years	Prevalence of any retinopathy	27.0% (95% CI 23.2–31.0)	10.7% (95% CI 9.8–11.6)
		Prevalence of mild retinopathy	23.4% (95% CI 19.8–27.4)	10.6% (95% CI 9.7–11.5)
		Prevalence of moderate retinopathy	2.5% (95% CI 1.4–4.3)	0.1% (95% CI 0.0–0.2)
		Prevalence of proliferative diabetic retinopathy	1.0% (95% CI 0.3–2.3)	0

Note:

a Prevalence of retinopathy below threshold was calculated by the authors.

Abbreviations: HbA1c, glycated hemoglobin; AGES-R, the Age, Gene/Environment Susceptibility – Reyjkavik Study; CI, confidence interval; T2DM, type 2 diabetes mellitus.

Table 4 Association of HbA_1c based diagnosis of type 2 diabetes and prediabetes (HbA_1c ≥6.5%, and HbA_1c 5.7% to <6.5%, respectively) with prevalence or incidence of microvascular complications

Study	Study characteristics	Microcomplication considered	Adjusted ORs (95% CI) and HRs (95% CI), respectively
			HbA1c <5.7%	HbA1c 5.7 to <6.5%	HbA1c ≥6.5%
Selvin et al; ARIC study^Citation19	Cross-sectional; 10,584 subjects without known diabetes	Prevalence of any retinopathy (adjusted for age, sex, and race)	OR =1	0.98 (0.73–1.33)	1.25 (0.75–2.07)
		Prevalence of any retinopathy (multivariable adjustment)	OR =1	0.84 (0.61–1.14)	0.91 (0.54–1.54)
		Prevalence of mild retinopathy (adjusted for age, sex, and race)	OR =1	0.88 (0.62–1.23)	0.85 (0.45–1.60)
		Prevalence of mild retinopathy (multivariable adjustment)	OR =1	0.77 (0.54–1.08)	0.65 (0.34–1.23)
		Prevalence of moderate/severe retinopathy (adjusted for age, sex, and race)	OR =1	1.76 (0.87–3.57)	4.35 (1.83–10.31)
		Prevalence of moderate/severe retinopathy (multivariable adjustment)	OR =1	1.42 (0.69–2.92)	2.91 (1.19–7.11)
	Longitudinal; median of follow-up 14 years; 10,584 subjects without diabetes at baseline	Incidence of chronic kidney disease (adjusted for age, sex, and race)	HR =1	1.31 (1.10–1.55)	1.84 (1.39–2.43)
		Incidence of chronic kidney disease (multivariable adjustment)	HR =1	1.12 (0.94–1.34)	1.39 (1.04–1.85)
		Incidence of ESRD (adjusted for age, sex, and race)	HR =1	2.00 (1.10–3.61)	3.04 (1.31–7.09)
		Incidence of ESRD (multivariable adjustment)	HR =1	1.51 (0.82–2.76)	1.98 (0.83–4.73)
Bower et al; NHANES^Citation41	Cross-sectional; 2,612 non-Hispanic	Prevalence of retinopathy (adjusted for age and sex)	OR =1	1.30 (0.89–1.90)	1.22 (0.47–3.16)
	Whites without history of diabetes	Prevalence of retinopathy (multivariable adjustment)	OR =1	1.23 (0.84–1.80)	1.16 (0.40–3.32)
	Cross-sectional; 805 non-Hispanic	Prevalence of retinopathy (adjusted for age and sex)	OR =1	1.45 (0.78–2.73)	2.71 (1.06–6.93)
	Blacks without history of diabetes	Prevalence of retinopathy (multivariable adjustment)	OR =1	1.45 (0.77–2.74)	2.88 (1.13–7.43)
	Cross-sectional; 996 Hispanic Americans without history of diabetes	Prevalence of retinopathy (adjusted for age and sex)	OR =1	1.23 (0.64–2.36)	3.32 (1.61–6.86)
		Prevalence of retinopathy (multivariable adjustment)	OR =1	1.34 (0.68–2.62)	3.58 (1.70–7.53)

Abbreviations: HbA1c, glycated hemoglobin; ARIC, Atherosclerosis Risk in Communities; CI, confidence interval; ESRD, end-stage renal disease; HR, hazard ratio; NHANES, National Health and Nutrition Examination Survey; OR, odds ratio.

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