High Glycemic Variability as a Risk Factor for CKD Progression in Type 2 Diabetes with Mild-to-Moderate Kidney Dysfunction

Abstract

Aims

This study retrospectively evaluates the risk of chronic kidney disease (CKD) progression in patients with type 2 diabetes and mild-to-moderate reduction in the estimated glomerular filtration rate (eGFR).

Methods

Sixty-six patients with type 2 diabetes and an eGFR between 45 and 60 mL/min/1.73 m² were included, from April 1, 2014, to March 31, 2015, with an 8-year follow-up ending on March 31, 2023. Baseline clinical parameters, including the body mass index, blood pressure, and biochemical markers, were recorded. The HbA1c and eGFR levels were measured annually. The eGFR slope (mL/min/1.73 m²/year) was used to evaluate the CKD progression.

Results

Patients with a negative eGFR slope (n=40) exhibited significantly greater HbA1c fluctuations and a higher coefficient of variation (CV) compared with those with an eGFR decline (P=0.011 for both) and were also markedly older (P=0.049). Logistic regression analysis showed a significant association between each one standard deviation increase in the CV and eGFR decline (odds ratio, 1.99; P=0.041), whereas the HbA1c fluctuation showed a trend toward association.

Conclusions

Greater variability in glycemic control is linked to an increased risk for CKD progression in type 2 diabetes with mild-to-moderate kidney dysfunction.

Keywords

chronic kidney disease - glycemic variability - eGFR slope - type 2 diabetes

Publication History

Received: 15 July 2025

Accepted after revision: 30 October 2025

Article published online:
09 December 2025

• References

• 1 Japanese Society of Nephrology. Essential points from evidence-based clinical practice guideline for chronic kidney disease 2023. Clin Exp Nephrol 2024; 28: 473-495
• 2 Penno G, Solini A, Orsi E. et al. Non-albuminuric renal impairment is a strong predictor of mortality in individuals with type 2 diabetes: The Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicentre study. Diabetologia 2018; 61: 2277-2289
• 3 Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney disease: Improving global outcomes (KDIGO) CKD work group. KDIGO 2024 clinical practice guideline for the Evaluation and management of chronic kidney disease. Kidney Int 2024; 105: S117-S314
• 4 Minami K, Sakuma Y, Ogawa K. et al. Risk factors for chronic kidney disease progression over 20 years for primary prevention in Japanese individuals at a preventive medicine research center: Focus on the influence of plasma glucose levels. J Diabetes Investig 2024; 15: 1434-1443
• 5 Matsuo S, Imai E, Horio M. et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009; 53: 982-992
• 6 Penno G, Solini A, Bonora E. et al. HbA1c variability as an independent correlate of nephropathy, but not retinopathy, in patients with type 2 diabetes: The Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicenter study. Diabetes Care 2013; 36: 2301-2310
• 7 Cardoso CRL, Leite NC, Moram CBM. et al. Long-term visit-to-visit glycemic variability as predictor of micro- and macrovascular complications in patients with type 2 diabetes: The Rio de Janeiro type 2 diabetes cohort study. Cardiovasc Diabetol 2018; 17: 33
• 8 Low S, Lim SC, Yeoh LY. et al. 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. J Diabetes 2017; 9: 908-919
• 9 Gaede P, Vedel P, Larsen N. et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348: 383-393
• 10 Ueki K, Sasako T, Okazaki Y. et al. Effect of an intensified multifactorial intervention on cardiovascular outcomes and mortality in type 2 diabetes (J-DOIT3): An open-label, randomised controlled trial. Lancet Diabetes Endocrinol 2017; 5: 951-964
• 11 American Diabetes Association Professional Practice Committee. 11. Chronic kidney disease and risk management: standards of care in diabetes-2025. Diabetes Care 2025; 48: S239-S251
• 12 Narres M, Claessen H, Droste S. et al. The incidence of end-stage renal disease in the diabetic (compared to the non-diabetic) population: A systematic review. PLoS One 2016; 11: e0147329
• 13 Hanafusa N, Abe M, Joki N. et al. Annual dialysis data report 2019, JSDT renal data registry. Ren Replace Ther 2023; 9: 47
• 14 Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: Variations with increasing levels of HbA(1c). Diabetes Care 2003; 26: 881-885
• 15 Watanabe K, Oba K, Suzuki T. et al. Oral glucose loading attenuates endothelial function in normal individual. Eur J Clin Investig 2011; 41: 465-473
• 16 Watanabe K, Suzuki T, Ouchi M. et al. Relationship between postprandial glucose level and carotid artery stiffness in patients without diabetes or cardiovascular disease. BMC Cardiovasc Disord 2013; 13: 11
• 17 Torimoto K, Okada Y, Mori H. et al. Relationship between fluctuations in glucose levels measured by continuous glucose monitoring and vascular endothelial dysfunction in type 2 diabetes mellitus. Cardiovasc Diabetol 2013; 2: 1
• 18 Ohara M, Fukui T, Ouchi M. et al. Relationship between daily and day-to-day glycemic variability and increased oxidative stress in type 2 diabetes. Diabetes Res Clin Pract 2016; 22: 62-70
• 19 Daenen K, Andries A, Mekahli D. et al. Oxidative stress in chronic kidney disease. Pediatr Nephrol 2019; 34: 975-991
• 20 Rossing K, Christensen PK, Hovind P. et al. Progression of nephropathy in type 2 diabetic patients. Kidney Int 2004; 66: 1596-1605
• 21 Shih CJ, Wu YL, Lo YH. et al. Association of hypoglycemia with incident chronic kidney disease in patients with type 2 diabetes: A nationwide population-based study. Medicine (Baltimore) 2015; 94: e771
• 22 Ushiogi Y, Kanehara H, Kato T. Frequency of hypoglycemia assessed by continuous glucose monitoring in advanced CKD. Clin J Am Soc Nephrol 2023; 18: 475-484
• 23 Nichols GA, Rosales AG, Kimes TM. et al. The change in HbA1c associated with initial adherence and subsequent change in adherence among diabetes patients newly initiating metformin therapy. J Diabetes Res 2016; 2016: 9687815
• 24 Farmer AJ, Rodgers LR, Lonergan M. et al. Adherence to oral glucose-lowering therapies and associations with 1-year HbA1c: A retrospective cohort analysis in a large primary care database. Diabetes Care 2016; 39: 258-263
• 25 Cedillo-Couvert EA, Ricardo AC, Chen J. et al. Self-reported medication adherence and CKD Progression. Kidney Int Rep 2018; 3: 645-651
• 26 Ridderstråle M, Gudbjörnsdottir S, Eliasson B. et al. Obesity and cardiovascular risk factors in type 2 diabetes: Results from the Swedish National diabetes register. J Intern Med 2006; 259: 314-322
• 27 Singer R, Huang HC. Weight change in chronic kidney disease: association with mortality and kidney function. Obes Sci Pract 2023; 10: e723
• 28 Liu P, Quinn RR, Lam NN. et al. Progression and regression of chronic kidney disease by age among adults in a population-based cohort in Alberta, Canada. JAMA Netw Open 2021; 4: e2112828
• 29 Oshima M, Jun M, Ohkuma T. et al. The relationship between eGFR slope and subsequent risk of vascular outcomes and all-cause mortality in type 2 diabetes: The ADVANCE-ON study. Diabetologia 2019; 62: 1988-1997
• 30 Sherwani SI, Khan HA, Ekhzaimy A. et al. Significance of HbA1c test in diagnosis and prognosis of diabetic patients. Biomark Insights 2016; 11: 95-104
• 31 Koga M. Glycated albumin; clinical usefulness. Clin Chim Acta 2014; 433: 96-104
• 32 Peabody J, Paculdo D, Acelajado MC. et al. Finding the clinical utility of 1,5-anhydroglucitol among primary care practitioners. J Clin Transl Endocrinol 2020; 20: 100224