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On serial HbA1c variability and CGM-derived indicators in cardiovascular risk assessment in diabetes mellitus Yi Wang1, Guoliang Wang2, Gaopeng Li1,3 1 Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan 030032, China. 2 Department of Tumor and Immunology, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China. 3 Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan 030032, China. Correspondence: Gaopeng Li, Email: malone2001@163.com Abstract This Letter comments on the recent opinion review by Goyal et al on glycated hemoglobin (HbA1c) and cardiovascular risk in diabetes mellitus. The review draws attention to the interpretation of HbA1c beyond average glycemic exposure and places it within a broader cardiometabolic context. From the perspective of a medical reader, two points may merit further clarification. First, serial HbA1c variability requires a more explicit operational definition, as recent studies have quantified it using indices such as average successive variability, standard deviation, and HbA1c variability score. Second, the clinical roles of HbA1c, serial HbA1c variability, and continuous glucose monitoring-derived indicators may be better explained through a layered framework. Such clarification may help translate the concept of “beyond glycemic control” into more practical cardiovascular risk assessment in diabetes mellitus. Core Tip This Letter discusses the interpretation of HbA1c-related indicators in cardiovascular risk assessment in diabetes mellitus. Mean HbA1c, serial HbA1c variability, and continuous glucose monitoring-derived indicators reflect different dimensions of glycemic exposure. A clearer operational definition of serial HbA1c variability and a layered clinical framework for using these indicators may improve the practical value of the review by Goyal et al. To the Editor, We read with interest the recent opinion review by Goyal et al[1] entitled “Glycated hemoglobin and cardiovascular risk in diabetes mellitus: Evolving evidence beyond glycemic control.” The review highlights the evolving interpretation of glycated hemoglobin (HbA1c) in diabetes care, particularly its potential relevance to cardiovascular risk assessment beyond the estimation of average glycemic exposure. By summarizing clinical trial evidence, mechanistic considerations, and emerging glucose-monitoring indicators, the article provides a relevant perspective for considering HbA1c within broader cardiometabolic risk management. From the perspective of a medical reader, two aspects may benefit from further clarification. Operational definition of serial HbA1c variability A more explicit distinction between mean HbA1c and serial HbA1c variability may make the cardiovascular interpretation of HbA1c more precise. In this context, serial HbA1c variability refers to fluctuation in repeated HbA1c measurements within the same individual over time, rather than the HbA1c value measured at a single clinical visit. Recent studies have operationalized this concept using several quantitative indices. Sheng et al [2] assessed glycemic variability in the ACCORD cohort using average successive variability, defined as the average absolute difference between consecutive HbA1c values during follow-up. Pei et al [3] measured HbA1c variability using both standard deviation and HbA1c variability score; the latter represents the proportion of HbA1c changes exceeding 0.5% among all available HbA1c measurements for an individual. This distinction is clinically relevant. Patients with similar mean HbA1c levels may show different glycemic fluctuation profiles, including unstable treatment responses, intermittent hypoglycemia, postprandial hyperglycemia, or repeated shifts in metabolic control. Such differences may contribute to heterogeneous cardiovascular outcomes among patients who appear comparable when assessed only by average glycemic exposure. Sheng et al [2] reported that glycemic variability assessed by HbA1c, rather than fasting plasma glucose, was associated with major adverse cardiovascular events in patients with type 2 diabetes. Similarly, Pei et al [3] suggested that HbA1c variability may modify the relationship among mean HbA1c, intensive glycemic control, cardiovascular events, and mortality. These findings indicate that serial HbA1c variability may represent a clinically meaningful dimension of cardiovascular risk stratification. The discussion would be more informative if it specified how HbA1c variability is defined, how it differs from mean HbA1c, and whether it provides incremental prognostic value beyond conventional cardiovascular risk factors. Clinical positioning of HbA1c and CGM-derived indicators A more practical clinical positioning of HbA1c, serial HbA1c variability, and continuous glucose monitoring (CGM)-derived indicators may also strengthen the discussion. The original review has recognized the complementary value of CGM-related metrics. However, these markers may be better interpreted as indicators of different temporal and clinical dimensions of glycemic exposure, rather than as parallel alternatives. HbA1c mainly reflects medium-term average glycemia; serial HbA1c variability reflects longer-term glycemic stability across clinical visits; CGM-derived indicators provide higher-resolution information on daily glucose distribution, including hypoglycemic exposure, postprandial excursions, and the proportion of glucose values maintained within predefined target ranges. This layered interpretation may help clarify when each marker is most informative. HbA1c may remain appropriate for routine monitoring in clinically stable patients with concordant glucose profiles. Serial HbA1c variability may be more informative when repeated HbA1c values fluctuate, when treatment changes are frequent, or when cardiovascular risk appears disproportionate to mean HbA1c. CGM-derived indicators may add value when hypoglycemia, postprandial excursions, or more precise glycemic pattern assessment is clinically relevant. Cai et al [4] reported that a smaller proportion of CGM-recorded glucose values within the 3.9-7.8 mmol/L range was associated with higher all-cause and cardiovascular mortality in patients with type 2 diabetes, even after adjustment for HbA1c. This finding supports a layered framework in which HbA1c serves as a baseline marker, serial HbA1c variability reflects longitudinal glycemic stability, and CGM-derived indicators help identify short-term glucose patterns that may carry additional prognostic information. Taken together, the review by Goyal et al [1] draws attention to the cardiovascular implications of HbA1c beyond average glycemic exposure. Its discussion would be further strengthened by a more concrete definition of serial HbA1c variability and a clearer explanation of how HbA1c, longitudinal glycemic stability, and CGM-derived indicators can be used together in cardiovascular risk assessment. Such clarification may help readers move from a general concept of “beyond glycemic control” toward a more practical framework for individualized diabetes management. Funding None. Conflict of Interest The authors declare no conflicts of interest. References [1] Goyal MK, Hatwal J, Desai R, Sehgal T, Batta A. Glycated hemoglobin and cardiovascular risk in diabetes mellitus: Evolving evidence beyond glycemic control. World J Diabetes. 2026; 17(6): 115820 [DOI: 10.4239/wjd.115820]. [2] Sheng L, Yang G, Chai X, Zhou Y, Sun X, Xing Z. Glycemic variability evaluated by HbA1c rather than fasting plasma glucose is associated with adverse cardiovascular events. Front Endocrinol (Lausanne). 2024; 15: 1323571 [PMID: 38419951 DOI: 10.3389/fendo.2024.1323571]. [3] Pei J, Wang X, Pei Z, Hu X. Glycemic control, HbA1c variability, and major cardiovascular adverse outcomes in type 2 diabetes patients with elevated cardiovascular risk: Insights from the ACCORD study. Cardiovasc Diabetol. 2023; 22: 287 [PMID: 37891565 DOI: 10.1186/s12933-023-02026-9]. [4] Cai J, Liu J, Lu J, Ni J, Wang C, Chen L, et al. Impact of time in tight range on all-cause and cardiovascular mortality in type 2 diabetes: A prospective cohort study. Diabetes ObesMetab. 2025; 27: 2154-2162 [PMID: 39868655 DOI: 10.1111/dom.16212].