Sodium Glucose Cotransporter-2 Inhibitor Protects Against Diabetic Neuropathy and Nephropathy in Modestly Controlled Type 2 Diabetes: Follow-Up Study

Abstract

Aims: This three-year follow-up study aimed to elucidate whether sodium-glucose cotransporter-2 inhibitors (SGLT2is) have any protection against diabetic neuropathy and nephropathy in patients with type 2 diabetes via reducing variability in glycemia and extraglycemic factors or their averages.

Methods: Two type 2 diabetic cohorts of 40 and 73 patients treated with or without SGLT2i along with 60 control subjects were recruited. Two diabetic cohorts matched for HbA1c levels and oral hypoglycemic agents other than SGLT2is underwent glycemic control with or without SGLT2is more than two years. The urinary albumin to creatinine ratio (ACR), estimated glomerular filtration rate (eGFR) every 3 months and neuropathy outcome measures and mean Z-score of 8 neurophysiological tests were determined at the baseline and endpoint. Glycemic variability, evaluated by the coefficient of variation of monthly measured HbA1c levels and casual postprandial plasma glucose (CPPG), and coefficient of variation and average of extraglycemic parameters in diabetic cohorts were determined.

Results: The glycemic variability and variability of some extraglycemic factors in SGLT2i cohort were smaller than those in non-SGLT2i cohort. However, only smaller coefficient of variation of HbA1c improved some neuropathy outcome measures, and ameliorated eGFR decline. SGLT2i improved the Z-score of neurophysiological tests. The optimized changes in the blood pressure, HDL-cholesterol and uric acid by SGLT2i led to neurological and renal protection. SGLT2i decreased the prevalence of nephropathy significantly and the prevalence of neuropathy insignificantly.

Conclusion: Over 3 years period, SGLT2i significantly improved some neuropathy outcome measures, mean Z-score of 8 neurophysiological tests, and attenuated nephropathy in modestly controlled type 2 diabetes by reducing glycemic variability and mean nonglycemic factors of diabetic microvascular complication.

Keywords: SGLT2i; diabetic microvascular complication; extraglycemic factors; glycemic variability; modest glycemic control; protection against neuropathy and nephropathy; type 2 diabetes.

Figure 1

Sequential changes in estimated glomerular filtration rate (A) and albumin to creatinine ratio (B) in patients treated by SGLT2i (solid circle) and treated without SGLT2i (open circle). Values were mean ± standard error of the mean. The trend of decrease was assessed by Jonckheere-Terpstra test, and p value presents the significance of trend. (C) Comparison of mean Z-score of 8 neurophysiological tests (median motor nerve conduction velocity and amplitude, sural sensory nerve conduction velocity and amplitude, vibration perception threshold, coefficient of variation of R-R interval, warm perception threshold, and cold perception threshold) among patients treated with or without SGLT2i at the baseline and endpoint and healthy control subjects at the baseline. Open column; at the baseline, solid column; at the endpoint. Values were mean ± standard error of the mean. *p < 0.001 compared with control subjects, ^†p < 0.001 compared with baseline, ^‡p < 0.05 compared with baseline, ^§p < 0.05 compared with patients without SGLT2i.