The Impact of Glycemic Control and Variability (HbA1c) on the Rate of Glomerular Filtration Rate Decline in Diabetes Mellitus: A Systematic Review
Keywords:
Diabetic Kidney Disease, Glycated Hemoglobin A1c, HbA1c Variability, Glomerular Filtration Rate, Renal Function Decline, Systematic ReviewAbstract
Introduction: Diabetic Kidney Disease (DKD) is a leading cause of end-stage renal disease (ESRD) globally. While mean glycated hemoglobin (HbA1c) is an established risk factor for DKD progression, the impact of long-term glycemic variability remains less clearly synthesized. This review systematically evaluates the association of both mean HbA1c and HbA1c variability with the rate of glomerular filtration rate (GFR) decline in individuals with type 1 (T1DM) and type 2 diabetes (T2DM).
Methods: A systematic search of PubMed, Embase, Web of Science, and the Cochrane Library was conducted for longitudinal cohort studies published up to March 2024. Studies were included if they reported on mean HbA1c or long-term HbA1c variability (measured by standard deviation, coefficient of variation [CV], or variability score) and the primary outcome of GFR decline. The methodological quality of included studies was assessed using the Cochrane ROBINS-I tool for non-randomized studies.
Results: A total of 16 longitudinal studies met the inclusion criteria. The findings consistently demonstrated that both higher mean HbA1c and greater HbA1c variability were significantly and independently associated with a more rapid decline in GFR. A "moderate-increasing" HbA1c trajectory was associated with a more than twofold increased risk of CKD progression (Hazard Ratio 2.23) (Critchley et al., 2019). High HbA1c variability, as measured by the highest versus lowest quartiles, was associated with an HR for renal function decline ranging from 1.26 to 1.47 across different metrics (Wang et al., 2024). Notably, this association persisted even in patients with well-controlled mean glycemia (HbA1c < 7.0%), where high variability still predicted a faster GFR decline (Tsai et al., 2020).
Discussion: The evidence supports a "dual threat" model where both the absolute level and the instability of glycemia contribute to nephropathy progression. The independent role of HbA1c variability suggests that glycemic fluctuations may induce renal damage through distinct pathways, such as heightened oxidative stress and inflammation, beyond that of sustained hyperglycemia (Gorst et al., 2015). These findings underscore the need to look beyond a single HbA1c value and consider the entire glycemic trajectory in clinical risk assessment.
Conclusion: Glycemic stability, in addition to achieving mean HbA1c targets, is a crucial therapeutic goal in diabetes management to preserve long-term renal function. Monitoring HbA1c variability may identify high-risk individuals who would otherwise be missed by conventional glycemic metrics.
References
American Diabetes Association Professional Practice Committee. (2022). 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2022. Diabetes Care, 45(Supplement_1), S17–S38.
Biesen, T., Gnudi, L., Licht-Assal, O., et al. (2014). Risk factors for severe decline in kidney function in patients with type 2 diabetes. BMJ Open, 3(12), e004029.
Ceriello, A. (2020). The emerging challenge in diabetes: The “double threat” of hyperglycemia and glycemic variability. Diabetes Research and Clinical Practice, 166, 108316.
Ceriello, A., De Cosmo, S., & Prattichizzo, F. (2023). The "dual threat" of hyperglycemia and glycemic variability in the development of diabetic complications. Endocrine, 80(2), 267–276.
Chen, Z., Li, L., Liu, J., et al. (2022). Glycated Haemoglobin A1c Variability Score Elicits Kidney Function Decline in Chinese People Living with Type 2 Diabetes. Journal of Clinical Medicine, 11(22), 6692.
Chinese Society of Endocrinology. (2021). Expert consensus on clinical application of continuous glucose monitoring (2021 Edition). Chinese Journal of Endocrinology and Metabolism, 37(10), 845-857.
Critchley, J.A., Carey, I.M., Harris, T., DeWilde, S., & Cook, D.G. (2019). Variability in Glycated Hemoglobin and Risk of Poor Outcomes Among People with Type 2 Diabetes in a Large Primary Care Cohort Study. Diabetes Care, 42(12), 2237-2246.
DCCT Research Group. (1987). Diabetes Control and Complications Trial (DCCT): results of feasibility study. Diabetes Care, 10(1), 1-19.
DCCT Research Group. (1993). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The New England Journal of Medicine, 329(14), 977-986.
DCCT/EDIC Research Group. (2003). Effect of intensive diabetes therapy on the development and progression of nephropathy in the Diabetes Control and Complications Trial. Kidney International, 63(1), 225-232.
DCCT/EDIC Research Group. (2005). Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. The New England Journal of Medicine, 353(25), 2643-2653.
DCCT/EDIC Research Group. (2016). Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes. The New England Journal of Medicine, 374(1), 13-22.
de Boer, I.H., Sun, W., Cleary, P.A., et al. (2010). The effect of intensive diabetes treatment on albumin excretion in type 1 diabetes: long-term follow-up of the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications study. The Lancet, 376(9758), 2089-2097.
El-ghormli, L., & TODAY Study Group. (2018). Worsening of Insulin Sensitivity and Worsening of β-Cell Function Are Associated With an Increase in Albuminuria in the TODAY Study. Diabetes Care, 41(4), 819-826.
Gnudi, L., Thomas, S. M., & Viberti, G. (2016). Diabetic nephropathy: landmark clinical trials and tribulations. Nephrology Dialysis Transplantation, 31(3), 359–368.
Gorst, C., Kwok, C. S., Aslam, S., et al. (2015). Long-term glycemic variability and risk of adverse outcomes: a systematic review and meta-analysis. Diabetes Care, 38(12), 2354–2369.
Heerspink, H. J. L., Cherney, D. Z. I., Postmus, D., et al. (2021). A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on kidney function and cardiovascular outcomes in patients with and without type 2 diabetes. Kidney International, 100(1), 215–225.
Heerspink, H. J. L., Stefánsson, B. V., Correa-Rotter, R., et al. (2023). Dapagliflozin in Patients with Chronic Kidney Disease. The New England Journal of Medicine, 388(2), 117-127.
Higgins, J. P. T., Sterne, J. A. C., Reeves, B. C., et al. (2024). A Cochrane Risk Of Bias Assessment Tool: for Non-Randomized Studies of Interventions (ROBINS-I). Cochrane Methods.
Kalim, S., Shafi, T., Hawley, C.E., et al. (2023). The Impact of Carbamylation and Anemia on HbA1c's Association With Renal Outcomes in Patients With Diabetes and Chronic Kidney Disease. Diabetes Care, 46(1), 130-137.
Lee, M.Y., Hsiao, P.J., Lin, H.W., et al. (2022). Hemoglobin glycation index predicts renal function deterioration in patients with type 2 diabetes and a low risk of chronic kidney disease. Diabetes Research and Clinical Practice, 186, 109834.
Lim, C.S., Lee, S.W., Lee, S.Y., et al. (2017). Effect of long-term glycemic variability on estimated glomerular filtration rate decline among patients with type 2 diabetes mellitus: Insights from the Diabetic Nephropathy Cohort in Singapore. Journal of Diabetes and its Complications, 31(3), 565-570.
Mann, J. F. E., Baigent, C., Haynes, R., et al. (2022). Empagliflozin in Patients with Chronic Kidney Disease. The New England Journal of Medicine, 387(12), 1079-1088.
Marcovecchio, M.L., Dalton, R.N., Daneman, D., et al. (2016). A1c variability and the risk of microvascular complications in adolescents with type 1 diabetes. Diabetes Care, 39(6), 964-971.
Mok, Y., Ballew, S.H., Bash, L.D., et al. (2022). Glycaemic variability and progression of chronic kidney disease in people with diabetes and comorbid kidney disease: Retrospective cohort study. Diabetes Research and Clinical Practice, 193, 110117.
Moradi, M., Ebrahimi, H., & Saeedi, M. (2022). A disease progression model of estimated glomerular filtration rate in Malaysian patients with type 2 diabetes mellitus. Journal of Diabetes & Metabolic Disorders, 21(1), 585-594.
Paka, P., Cherney, D.Z.I., Goldenberg, R., et al. (2024). Estimated glomerular filtration rate trajectories in adults with type 1 diabetes. Canadian Journal of Diabetes, S1499-2671(24)00155-2.
Pavkov, M.E., Bjornstad, P., Cherney, D.Z., et al. (2016). The time-varying association of baseline glomerular filtration rate with renal function decline in type 1 diabetes. Diabetologia, 59(4), 790-798.
Penno, G., Solini, A., Zoppini, G., et al. (2014). Rate and determinants of association between advanced glycation end products and renal function in patients with type 1 diabetes. Diabetes, 63(10), 3466-3477.
Perkins, B. A., Bebu, I., de Boer, I. H., et al. (2020). Risk Factors for Kidney Disease in Type 1 Diabetes. Diabetes Care, 43(3), 663–670.
Sterne, J. A. C., Hernán, M. A., Reeves, B. C., et al. (2016). ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ, 355, i4919.
Thomas, H. Y., & Ford Versypt, A. N. (2022). Pathophysiology of mesangial expansion in diabetic nephropathy: mesangial structure, glomerular biomechanics, and biochemical signaling and regulation. Journal of biological engineering, 16(1), 1.
Tsai, Y.W., Wu, H.Y., Lu, C.L., et al. (2020). The variability of glycated hemoglobin is associated with renal function decline in patients with type 2 diabetes. International Journal of Medical Sciences, 17(4), 527-534.
Wang, S., Song, S., Gao, J., et al. (2024). Glycated haemoglobin variability and risk of renal function decline in type 2 diabetes mellitus: An updated systematic review and meta-analysis. Diabetes, Obesity and Metabolism, 26(11), 5167-5182.
Yuan, Y., Zhang, R., Li, L., et al. (2019). Family history of diabetes is an independent risk factor for a rapid decline in eGFR in patients with type 2 diabetes and biopsy-proven diabetic kidney disease. Frontiers in Endocrinology, 10, 855.
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