Diagnosing type 2 diabetes using Hemoglobin A1c: a systematic review and meta-analysis of the diagnostic cutpoint based on microvascular complications

Abstract

Aims Diabetic microvascular complications of retinopathy, nephropathy and neuropathy may occur at hemoglobin A1c levels (HbA1c) below the 6.5% (48 mmol/mol) diagnostic threshold. Our objective was to assess the validity of the HbA1c diagnostic cutpoint of 6.5% based upon published evidence of the prevalence of retinopathy, nephropathy and neuropathy as markers of diabetes. Methods Data Sources PubMed, Embase, Cochrane, Scopus and CINAHL from 1990-March 2019, grey literature sources. Study Selection All studies reported after 1990 (to ensure standardized HbA1c values) where HbA1c levels were presented in relation to prevalence of retinopathy, nephropathy or neuropathy in subjects not known to have diabetes. Data Extraction Studies were screened independently, data abstracted, and risk of bias appraised. Data Synthesis Data were synthesized using HbA1c categories of < 6.0% (< 42 mmol/mol), 6.0–6.4% (42–47 mmol/mol) and ≥ 6.5% (≥ 48 mmol/mol). Random-effects meta-analyses were conducted for retinopathy, nephropathy and neuropathy prevalence stratified by HbA1c categories. Random-effects multivariable meta-regression was conducted to identify predictors of retinopathy prevalence and sources of between-study heterogeneity. Results Pooled mean prevalence was: 4.0%(95% CI: 3.2–5.0%) for retinopathy, 10.5% (95% CI: 4.0–19.5%) for nephropathy, 2.5% (95% CI: 1.1–4.3%) for neuropathy. Mean prevalence when stratified for HbA1c < 6.0%, 6.0–6.4% and ≥ 6.5% was: retinopathy: 3.4% (95% CI: 1.8–5.4%), 2.3% (95% CI: 1.6–3.2%) and 7.8%(95% CI: 5.7–10.3%); nephropathy: 7.1% (95% CI: 1.7–15.9%), 9.6% (95% CI: 0.8–26.4%) and 17.1% (95% CI: 1.0–46.9%); neuropathy: 2.1% (95% CI: 0.0–6.8%), 3.4% (95% CI: 0.0–11.6%) and 2.8% (95% CI: 0.0–12.8%). Multivariable meta-regression showed HbA1c ≥ 6.5% (OR: 4.05; 95% CI: 1.92–8.57%), age > 55 (OR: 3.23; 95% CI 1.81–5.77), and African-American race (OR: 10.73; 95% CI: 4.34–26.55), to be associated with higher retinopathy prevalence. Marked heterogeneity in prevalence estimates was found across all meta-analyses (Cochran’s Q-statistic p < 0.0001). Conclusions The prevalence of nephropathy and moderate retinopathy was increased in subjects with HbA1c values ≥ 6.5% confirming the high specificity of this value for diagnosing T2DM; however, at HbA1c < 6.5% retinopathy increased at age > 55 years and, most strikingly, in African-Americans, suggesting there may be excess microvascular complication prevalence (particularly nephropathy) in individuals below the diabetes diagnostic threshold.

The retinopathy‐derived HbA1c threshold of 6.5% for type 2 diabetes also captures the risk of diabetic nephropathy in NHANES

“…As the HbA1c threshold was moved to lower levels, the percentage of subjects with a high UACR that were added to the high HbA1c group decreased, reducing the OR. The significant ORs only at higher HbA1c are in accord with a meta‐analysis that suggested there was an increase in nephropathy defined by the UACR above an HbA1c of 6.5%, 14 although only four studies were available for meta‐analysis 14 . From the category analysis of NHANES, non‐significant ORs were similar for elevated UACRs for the 6.0%‐6.4% and 6.5%‐6.9% HbA1c categories versus the less than 5.0% HbA1c category (ORs of 1.4 and 1.3), and were similar to the meta‐analysis non‐significant prevalence ratio of 1.35 (9.6%/7.1%) 14 for HbA1c of 6.0%‐6.4% versus less than 6.0%.…”

“…The significant ORs only at higher HbA1c are in accord with a meta‐analysis that suggested there was an increase in nephropathy defined by the UACR above an HbA1c of 6.5%, 14 although only four studies were available for meta‐analysis 14 . From the category analysis of NHANES, non‐significant ORs were similar for elevated UACRs for the 6.0%‐6.4% and 6.5%‐6.9% HbA1c categories versus the less than 5.0% HbA1c category (ORs of 1.4 and 1.3), and were similar to the meta‐analysis non‐significant prevalence ratio of 1.35 (9.6%/7.1%) 14 for HbA1c of 6.0%‐6.4% versus less than 6.0%. These results suggest that some nephropathy is beginning to appear at the prediabetic HbA1c levels and may predict progression to diabetes, 20 but the prevalence is not yet significantly higher than at HbA1c levels of less than 5%.…”

“…Ethnic differences in nitric oxide capacity and UACR have been noted, which may in part account for these differences 19 . These data agree with those for retinopathy, where the African American population had a notably higher prevalence of retinopathy at every level of HbA1c 14 …”

“…19 These data agree with those for retinopathy, where the African American population had a notably higher prevalence of retinopathy at every level of HbA1c. 14 A threshold analysis also does not show a specific HbA1c threshold for elevated UACR to predict a diagnostic HbA1c value for diabetes, in accord with a recent meta-analysis, 14 even though there was an apparent linear progressive trend of increasing prevalence of elevated UACR as HbA1c increased in the population. The UACR OR showed a progressive increase up to an HbA1c of 7% and became significantly greater than 1.0 at an HbA1c greater than 5.6%.…”

“…However, even at the time, experts voiced concern that an HbA1c threshold of 6.5% (48 mmol/mol) might be too high because diagnosis of diabetes using blood glucose criteria identified more individuals. 12 Subsequent studies have focused upon better delineating the optimal HbA1c threshold based upon all three microvascular diabetic complications 13,14 and indicate that the current threshold of 6.5% may indeed be too high.…”