Diagnosing type 2 diabetes using Hemoglobin A1c: a systematic review and meta-analysis of the diagnostic cutpoint
Alexandra E Butler1, Emma English2, Eric S Kilpatrick3
1Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar. aeb91011@gmail.com.
Insights
Diabetic microvascular complications like retinopathy and nephropathy can occur below the 6.5% hemoglobin A1c (HbA1c) threshold. This study found increased prevalence of these complications in individuals with HbA1c below 6.5%, especially in older adults and African Americans.
Area of Science:
- Endocrinology
- Diabetology
- Public Health
Background:
- Diabetic microvascular complications, including retinopathy, nephropathy, and neuropathy, are significant health concerns.
- The diagnostic threshold for diabetes, hemoglobin A1c (HbA1c) of 6.5% (48 mmol/mol), may not capture all individuals at risk for these complications.
Purpose of the Study:
- To evaluate the validity of the HbA1c diagnostic cutpoint of 6.5% for identifying individuals with diabetic microvascular complications.
- To assess the prevalence of retinopathy, nephropathy, and neuropathy at HbA1c levels below the 6.5% threshold.
Main Methods:
- A systematic review and meta-analysis of studies published from 1990 to March 2019.
- Inclusion of studies reporting HbA1c levels in relation to retinopathy, nephropathy, or neuropathy prevalence in non-diabetic individuals.
- Data synthesis using HbA1c categories (<6.0%, 6.0-6.4%, and ≥6.5%) with random-effects meta-analyses and meta-regression.
Main Results:
- Pooled prevalence rates for retinopathy, nephropathy, and neuropathy were 4.0%, 10.5%, and 2.5%, respectively.
- Prevalence of retinopathy and nephropathy increased with higher HbA1c categories.
- HbA1c ≥6.5%, age >55 years, and African-American race were associated with higher retinopathy prevalence.
Conclusions:
- The HbA1c of 6.5% confirms high specificity for diagnosing type 2 diabetes (T2DM) due to increased nephropathy and retinopathy.
- However, a notable prevalence of microvascular complications, particularly nephropathy, exists in individuals with HbA1c <6.5%, especially older adults and African Americans.
- This suggests that the current diagnostic threshold may underestimate the burden of microvascular complications in certain populations.
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.
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