Limitations of glycated hemoglobin and emerging biomarkers for diabetes care after bariatric surgery

Abstract

Bariatric surgery significantly improves glycemic control and can lead to type 2 diabetes remission. However, the reliability of glycated hemoglobin (HbA1c) as a type 2 diabetes biomarker post-surgery can be confounded by conditions such as anemia and gastrointestinal complications. Hence, we explored the use of alternative biomarkers such as glycated albumin (GA), 1,5-anhydroglucitol (1,5-AG), and insulin-like growth factor binding protein-1 (IGFBP-1) to monitor glycemic control more effectively in post-bariatric surgery patients. Measuring GA and 1,5-AG levels can detect glycemic variability more sensitively than HbA1c, especially under non-fasting conditions. GA shows promise for short-term monitoring post-surgery while 1,5-AG could be useful for real-time glucose monitoring. IGFBP-1 can be used to monitor metabolic improvement and to predict HbA1c normalization. However, challenges in assay standardization and cost remain significant barriers to their clinical adoption. Although these biomarkers could offer a more personalized approach to glucose monitoring (thereby addressing the limitations of utilizing HbA1c in this endeavor in post-bariatric surgery patients), this would require overcoming technical, logistical, and cost-related challenges. While using GA, 1,5-AG, and IGFBP-1 shows promise for glycemic monitoring, further research and validation are crucial for their routine clinical implementation, especially in the context of diabetes management post-bariatric surgery.

Key Words: Bariatric surgery; Obesity management; Diabetes mellitus; Glycemic control; Biological markers; Glycated hemoglobin; Glycated albumin; 1,5-anhydroglucitol; Diabetes remission

Core Tip: Alternative biomarkers to glycated hemoglobin (HbA1c), such as glycated albumin (GA) and 1,5-anhydroglucitol (1,5-AG), can provide better monitoring of glycemic control post-bariatric surgery by overcoming some of the limitations of using HbA1c in this respect. Although GA and 1,5-AG offer significant advantages for short-term and real-time glycemic monitoring, challenges such as assay standardization and lack of consensus on optimal protocols must be addressed before these biomarkers can be routinely implemented in clinical practice. Further validation is needed for their effective use in post-bariatric surgery diabetes management.

TO THE EDITOR

Advancements in obesity management have significantly progressed with the introduction of bariatric surgery (also known as weight loss surgery), which not only aids in weight reduction but also improves or even resolves many obesity-related conditions. Notably, bariatric surgery enhances long-term blood glucose control and can lead to the remission of type 2 diabetes[1,2]. Effective glycemic control is essential for preventing long-term complications such as retinopathy, nephropathy, and neuropathy caused by untreated hyperglycemia[3]. A recent NIH-supported study reports the effectiveness of bariatric surgery in achieving better long-term blood glucose control compared to medical management and lifestyle interventions[1]. At 12 years post-surgery, 54% of patients who had undergone bariatric surgery achieved a glycated hemoglobin (HbA1c) level of less than 7% compared to just 27% in the medical/lifestyle group[1]. Furthermore, more participants in the bariatric surgery group went into remission and were able to discontinue diabetes medications, thereby highlighting the profound impact of bariatric surgery on diabetes management.

Despite these improvements, the reliability of using HbA1c as a biomarker for glycemic control is questionable during the recovery period post-bariatric surgery as it fails to capture real-time fluctuations and individual variability in glucose levels[4]. Previous studies have shown that it is unreliable for detecting dysglycemia, particularly in obese patients post-bariatric surgery[5,6].

Although significant reductions in HbA1c (3.0% ± 1.3% P < 0.01) have been observed in participants with diabetes and elevated HbA1c prior to bariatric intervention, glycemic variability measures such as 1-hour plasma glucose during an oral glucose tolerance test (OGTT) and the mean amplitude of glycemic excursion remained elevated[5]. Furthermore, the oral disposition index (indicative of pancreatic β-cell function) remained impaired in the diabetes group compared to the non-diabetic group. These findings suggest that alternative metrics may provide a more accurate assessment of glycemic control following bariatric surgery, particularly in individuals with persistently abnormal glycemic patterns despite improved HbA1c levels[5]. Moreover, HbA1c's reliability is further compromised for post-bariatric surgery glycemic monitoring in instances of iron deficiency anemia and altered red blood cell turnover[5,7]. Iron deficiency, in particular (commonly observed in patients post-bariatric surgery) can significantly distort HbA1c values by shortening the erythrocyte lifespan, which in turn lowers the HbA1c level independently of the actual glycemic status[5]. Since HbA1c reflects the average blood glucose over the life of the red blood cells, this accelerated turnover introduces a bias that can mask any underlying hyperglycemia.

Given the high prevalence of anemia, micronutrient malabsorption, and gastrointestinal complications in post-bariatric surgery patients[1,7], HbA1c may not serve as a reliable predictor of glycemic status or be a suitable tool for perioperative monitoring. For these reasons, alternative monitoring strategies are required to complement or replace HbA1c in this patient group, with the goal of providing a more accurate reflection of post-surgical glycemic patterns and to help mitigate inaccuracies associated with anemia-related changes in red blood cell dynamics.

THE NEED FOR ALTERNATIVE GLYCEMIC BIOMARKERS

Biomarkers are measurable biological indicators used to assess physiological and pathological processes. An ideal biomarker suitable for glucose monitoring is chosen for specificity, sensitivity, prognostic value (correlates with disease severity), and persistence (remains detectable for a period). Currently, five key biomarkers are used to diagnose and monitor diabetes [blood glucose, HbA1c, glycated albumin (GA), fructosamine, and 1,5-anhydroglucitol (1,5-AG)][8]. Blood glucose and HbA1c are two conventional biomarkers used to assess short-term and long-term glycemic control, respectively. Glucose monitoring by either measuring fasting plasma glucose (FPG) or using the OGTT provides valuable information on glycemic control. However, the results of these tests can be influenced by external factors such as the blood collection and storage processes.

HbA1c (belonging to a group of advanced glycation end-products) is produced by a non-enzymatic reaction between the hemoglobin in red blood cells and glucose in the blood (glycation)[9]. It is recognized as being the most clinically significant marker for diagnosing diabetes mellitus because it measures the percentage of HbA1c in circulating red blood cells that reflects the average blood glucose levels over 2 to 3 months[10]. Baseline HbA1c ≤ 7.0% is a strong predictor for diabetes remission and reduced relapse risk[11]. Compared to direct glucose measurements, HbA1c provides a more realistic indication of long-term glucose control as it is less affected by short-term fluctuations. However, studies have shown that individuals with iron deficiency (whether diabetic or non-diabetic) often exhibit increased HbA1c values; this has been observed in various populations, including those with chronic kidney disease and pregnant women with diabetes[12,13]. HbA1c reliability is compromised in conditions affecting erythrocyte turnover, such as anemia, iron or nutritional deficiency, and hemoglobinopathies, all of which are common in post-bariatric surgery patients[14].

The clinical utility of GA and 1,5-AG as supplementary biomarkers for diagnosing and predicting diabetes, especially for use in non-fasting settings, has recently been highlighted[15]. During an assessment of an obese Chinese cohort consisting of 462 individuals, both GA and 1,5-AG measurements provided predictive values comparable to those using FPG and HbA1c measurements for detecting incident diabetes. The area under the curve (AUC) values for GA [AUC (95%CI): 0.680 (0.622-0.738)] and 1,5-AG [AUC (95%CI): 0.664 (0.604-0.723)] were similar to HbA1c [AUC of 0.635 (95%CI: 0.574-0.697)] and FPG [AUC of 0.650 (95%CI: 0.589-0.710)][15].

GA has been strongly associated with HbAIc and fasting blood glucose levels are approximately three times higher than HbA1c. GA has a half-life of 12-21 days, meaning it can provide a measure of glycemic control over 2 to 3 weeks, and this is not influenced by erythrocyte turnover, making it a promising marker for post-bariatric patients[16]. GA demonstrated a 42.9% reduction at 1 month post-surgery, compared to only a 13.1% reduction in HbA1c[15]. Moreover, combining GA with HbA1c improved diabetes detection by about 8% compared to using FPG alone, based on Ku et al’s findings[15]. For classifying prediabetes and diabetes, a higher Cohen’s kappa (κ) value for GA and HbA1c levels (0.529) indicates better agreement between them than between GA and FPG (κ = 0.389). Moreover, specifically for diabetes classification, GA showed substantial agreement with both FPG (κ = 0.623) and HbA1c (κ = 0.735). This indicates that GA’s higher specificity and a stronger correlation with FPG make it a more valuable tool for detecting glycemic variability than using HbA1c[15].

Similarly, 1,5-AG (a glucose analog) can serve as a sensitive marker for detecting periods of hyperglycemia. Under normal physiological conditions, 1,5-AG is filtered by the kidneys and almost completely reabsorbed in the renal tubules, maintaining stable serum levels through a balance of intake and excretion[17]. However, when blood glucose levels exceed the renal threshold of approximately 180 mg/dL, glucose competitively inhibits the renal reabsorption of 1,5-AG, leading to a decrease in its circulating concentration. This mechanism makes 1,5-AG particularly useful for real-time glucose monitoring, as its serum levels inversely correlate with hyperglycemia, underpinning its clinical relevance in detecting acute fluctuations in blood glucose levels. Consistent with this, 1,5-AG levels progressively decreasing with worsening glycemic status show moderate negative correlations with both FPG (r = –0.51) and HbA1c (r = –0.58) levels[15]. Despite its diagnostic potential, 1,5-AG has not yet been widely adopted in routine clinical practice due to a lack of standardization and broader clinical validation. Nevertheless, its real-time responsiveness positions it as a potentially valuable tool for glycemic monitoring in bariatric surgery patients and other populations where traditional markers may fall short.

Ku et al[15] developed a novel prediction model incorporating body mass index, HbA1c, GA, and 1,5-AG, which demonstrated comparable or even better predictive power than conventional clinical models, achieving an AUC of 0.793. Thus, the proposed model offers a simple, convenient, and effective tool for diabetes risk prediction.

Beyond these markers, insulin-like growth factor binding protein-1 (IGFBP-1) has emerged as a novel predictor of HbA1c normalization post-surgery[18,19]. IGFBP-1 levels are linked to hepatic insulin sensitivity, with higher postoperative levels correlating with improved β-cell function and enhanced glucose homeostasis. Unlike HbA1c, IGFBP-1 provides mechanistic insights into the metabolic improvements following bariatric surgery, thus making it a valuable prognostic biomarker. However, like other emerging biomarkers, its integration into routine clinical practice faces several significant challenges, especially a lack of consensus guidelines and standardization for clinical use.

CLINICAL IMPLEMENTATION CHALLENGES AND FUTURE DIRECTIONS FOR UTILIZING ALTERNATIVE GLYCEMIC BIOMARKERS

The clinical adoption of alternative glycemic biomarkers faces several significant challenges. First, there are significant gaps in standardization. The lack of homogeneity for GA and 1,5-AG assays increases the risk of inter-laboratory variability[15,20]. Furthermore, IGFBP-1 assays are not routinely available in the clinical setting, and no consensus exists regarding optimal measurement protocols. Moreover, existing data are largely limited to patients undergoing Roux-en-Y gastric bypass, with limited information on the applicability of IGFBP-1 to other types of bariatric surgery.

Genetic factors such as variants of the SLC5A10 gene, as well as physiological factors, can influence the renal reabsorption of 1,5-AG and impair measurement accuracy[20]. Detection variability also presents a challenge, with enzymatic kits showing variability between manufacturers and mass spectrometry methods being costly and technically demanding. The cost of enzymatic 1,5-AG kits ($15–$30 each) and the specialized equipment required for GA testing may limit their adoption for glycemic monitoring, particularly in resource-limited settings. Moreover, there are no established guidelines on the best combination of biomarkers (e.g., GA + HbA1c vs 1,5-AG + FPG) to maximize diagnostic accuracy and sensitivity.

Future priorities should include assay standardization, cost reduction, and the development of point-of-care platforms for rapid, low-cost testing. Combining multiple biomarkers may enhance predictive accuracy for diabetes remission and long-term glycemic control. Large, longitudinal studies tracking post-bariatric patients over 5–10 years are critical to validate clinical utility. Addressing these gaps will be essential for transitioning alternative biomarkers from investigational tools to routine clinical practice.

CONCLUSION

Given the limitations of measuring HbA1c levels in post-bariatric surgery patients, alternative biomarkers such as GA, 1,5-AG, and IGFBP-1 offer enhanced sensitivity in detecting glycemic variability and provide a more dynamic and individualized approach to glucose monitoring. While GA and 1,5-AG offer advantages over HbA1c for short-term glycemic monitoring, their clinical adoption hinges on addressing standardization and prohibitive cost issues. Moreover, the use of IGFBP-1 is under investigation but requires broader validation. Further research and clinical validation of these biomarkers are essential for integrating them into routine practice and ensuring that they are effectively utilized to benefit patients.