https://www.ahajournals.org/doi/10.1161/circoutcomes.110.957936
Abstract
Background—
Among individuals without diabetes, elevated hemoglobin A1c (HbA1c) has been associated with increased morbidity and mortality, but the literature is sparse regarding the prognostic importance of low HbA1c.
Methods and Results—
National Health and Nutrition Examination Survey III (NHANES III) participants, 20 years and older, were followed up to 12 years (median follow-up, 8.8 years) for all-cause mortality. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the association between HbA1c levels and all-cause mortality for 14 099 participants without diabetes. There were 1825 deaths during the follow-up period. Participants with a low HbA1c (<4.0%) had the highest levels of mean red blood cell volume, ferritin, and liver enzymes and the lowest levels of mean total cholesterol and diastolic blood pressure compared with their counterparts with HbA1c levels between 4.0% and 6.4%. An HbA1c <4.0% versus 5.0% to 5.4% was associated with an increased risk of all-cause mortality (HR, 3.73; 95% CI, 1.45 to 9.63) after adjustment for age, race-ethnicity, and sex. This association was attenuated but remained statistically significant after further multivariable adjustment for lifestyle, cardiovascular factors, metabolic factors, red blood cell indices, iron storage indices, and liver function indices (HR, 2.90; 95% CI, 1.25 to 6.76).
Conclusions—
In this nationally representative cohort, low HbA1c was associated with increased all-cause mortality among US adults without diabetes. Additional research is needed to confirm these results and identify potential mechanisms that may be underlying this association.
O3:
Paper: Carson AP et al. “Low Hemoglobin A1c and Risk of All‑Cause Mortality Among US Adults Without Diabetes.” Circ Cardiovasc Qual Outcomes 2010;3:661‑667. (utsouthwestern.elsevierpure.com, PubMed)
1) Summary (what they did & found)
- Question: Is low HbA1c (in people without diabetes) associated with higher mortality?
- Design: Prospective analysis of NHANES III adults ≥20 y without diabetes (n = 14 099), median follow‑up 8.8 years (max 12); 1 825 deaths. Cox models estimated HRs across HbA1c categories, with extensive adjustment (lifestyle, cardiovascular & metabolic factors, red‑cell indices, iron storage, liver function). (PubMed)
- Main result: HbA1c <4.0% vs 5.0–5.4% was linked to higher all‑cause mortality (HR 3.73, 95% CI 1.45–9.63; multivariable‑adjusted HR 2.90, 95% CI 1.25–6.76). Participants with HbA1c < 4.0% had higher MCV, ferritin, liver enzymes and lower total cholesterol & diastolic BP. A non‑linear (spline) relationship was shown. (PubMed)
- Conclusion: Very low HbA1c may be a risk marker for mortality in nondiabetic adults; mechanisms need clarification. (PubMed)
2) What was novel (in 2010)
- Shifted focus to the low end of HbA1c: Most prior work emphasized elevated HbA1c; this study highlighted potential harm at <4.0% in people without diabetes. (PubMed)
- Nationally representative sample (NHANES III) with broad covariate adjustment, including RBC indices, iron and liver markers, attempting to probe biological explanations (e.g., altered erythrocyte turnover, liver disease). (PubMed)
- Use of flexible splines to show non‑linearity rather than only categorical cut‑points. (PubMed)
3) Critique
Methods & data
- Rare exposure, wide CIs: HbA1c < 4.0% is uncommon; estimates are imprecise (note the wide 95% CIs), raising concern about statistical fragility. (PubMed)
- Single baseline HbA1c: No time‑updated measures → regression dilution and inability to see whether incident illness lowered HbA1c (reverse causation). (PubMed)
- Residual confounding / reverse causality: Despite extensive adjustment, occult liver disease, alcohol misuse, hemolytic states, malignancy, frailty, inflammation could still drive both low HbA1c and mortality. The higher ferritin/liver enzymes in the low‑HbA1c group hint at this. (PubMed)
- Cause‑specific mortality not examined: Limits mechanistic inference (e.g., is excess risk hepatic, cancer, infection?). (PubMed)
- Misclassification of diabetes status: Reliance on baseline data (before universal A1c‑based diagnosis was standard) risks undiagnosed diabetes or other glycemic disorders. (PubMed)
- Biological mechanism underdeveloped: The paper documents association but doesn’t dissect pathways (e.g., RBC lifespan variability, hemoglobinopathies, malnutrition, inflammation). (PubMed)
Interpretation
- The paper frames low HbA1c as a risk marker, but the causal language should remain cautious; the spline suggests nonlinearity/J‑shape, typical when a biomarker reflects underlying illness at low levels. (PubMed)
- Clinical translation unclear: No guidance on screening or work‑up for unexpectedly low HbA1c, nor thresholds that warrant evaluation. (PubMed)
4) How to build on it (then & now)
- Replicate with newer cohorts (post‑2010) using repeated HbA1c measures, glycated albumin/fructosamine, and RBC lifespan markers to parse biology vs artifact.
- Cause‑specific & competing‑risk analyses to pinpoint drivers of mortality signal.
- Mendelian randomization / negative‑control outcomes to probe causality vs confounding.
- Stratified analyses (anemia, liver disease, CKD, alcohol use, inflammatory markers, hemoglobinopathies) and sensitivity to excluding early deaths to mitigate reverse causation.
- Clinical algorithms: Define when very low HbA1c should trigger evaluations (e.g., liver function, hemolysis, nutrition, occult malignancy).
Bottom line
This influential 2010 analysis alerted clinicians that “too low” HbA1c in nondiabetic adults might signal excess risk, not health. Its strengths are national representativeness, extensive covariate adjustment, and explicit modeling of nonlinearity. Its weaknesses are the rarity of the exposure, residual confounding, lack of cause‑specific insights, and single‑timepoint measurement, making low HbA1c best viewed as a flag for underlying disease rather than a causal target. (PubMed, utsouthwestern.elsevierpure.com)