The Therapeutic Potential of Sodium-Glucose Cotransporter-2 Inhibitors in Diabetic Neuropathy

Abstract

Diabetic neuropathy is a serious complication of diabetes mellitus (DM). Its commonest manifestation is diabetic peripheral neuropathy (DPN). Diabetic neuropathy may also affect the autonomic nervous system, cardiac autonomic neuropathy (CAN) being its most widely studied manifestation. Treatment of DPN and CAN relies on glycaemic control and symptom alleviation, emphasizing the need for improvement. To this purpose, the novel antidiabetic oral agents sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have been studied. Beyond their favourable effects on metabolic control and cardiovascular and renal outcomes, these agents appear to harbour some beneficial actions in DPN and CAN as well. The underlying mechanisms are not entirely clear, but appear to involve the 5' adenosine monophosphate-activated protein kinase (AMPK)-pathway. So far, clinical experience has been limited. Significant improvement in electrophysiological parameters and thermal perception has been observed among subjects with type 2 diabetes mellitus (T2DM) in small studies. However, contradictory findings have also been reported. The same ambiguous effect of SGLT-2is has been observed in CAN. Thus, future large studies are required to delineate the utility of SGLT-2is in DPN and/or CAN.

Keywords

diabetic peripheral neuropathy - cardiac autonomic neuropathy - sodium glucose cotransporter 2 inhibitors - diabetes mellitus - treatment

Publication History

Received: 03 May 2025

Accepted after revision: 20 June 2025

Accepted Manuscript online:
20 June 2025

Article published online:
14 July 2025

• References

• 1 American Diabetes Association Professional Practice Committee. Retinopathy, neuropathy, and foot care: Standards of care in diabetes-2025. Diabetes Care 2025; 48: S252-S265
• 2 Savelieff MG, Elafros MA, Viswanathan V. et al. The global and regional burden of diabetic peripheral neuropathy. Nat Rev Neurol 2025; 21: 17-31
• 3 Pop-Busui R, Boulton AJ, Feldman EL. et al. Diabetic neuropathy: A position statement by the American Diabetes Association. Diabetes Care 2017; 40: 136-154
• 4 Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus: Rationale and clinical prospects. Nat Rev Endocrinol 2012; 8: 495-502
• 5 Khunti K. SGLT2 inhibitors in people with and without T2DM. Nat Rev Endocrinol 2021; 17: 75-76
• 6 Wanner C, Marx N. SGLT2 inhibitors: The future for treatment of type 2 diabetes mellitus and other chronic diseases. Diabetologia 2018; 61: 2134-2139
• 7 Takakura S, Toyoshi T, Hayashizaki Y. et al. Effect of ipragliflozin, an SGLT2 inhibitor, on progression of diabetic microvascular complications in spontaneously diabetic Torii fatty rats. Life Sci 2016; 147: 125-131
• 8 Sandhu HS, Butt AN, Powrie J, Swaminathan R. Measurement of circulating neuron-specific enolase mRNA in diabetes mellitus. Ann N Y Acad Sci 2008; 1137: 258-263
• 9 El Boghdady NA, Badr GA. Evaluation of oxidative stress markers and vascular risk factors in patients with diabetic peripheral neuropathy. Cell Biochem Funct 2012; 30: 328-334
• 10 Eid SA, O'Brien PD, Hinder LM. et al. Differential effects of empagliflozin on microvascular complications in murine models of type 1 and type 2 diabetes. Biology (Basel) 2020; 9: 347
• 11 Abdelkader NF, Elbaset MA, Moustafa PE. et al. Empagliflozin mitigates type 2 diabetes-associated peripheral neuropathy: A glucose-independent effect through AMPK signaling. Arch Pharm Res 2022; 45: 475-493
• 12 Sato A, Yasukochi S, Iwanaka N. et al. Dosing time-dependent difference in the suppressive effect of empagliflozin on the development of mechanical pain hypersensitivity in diabetic mice. J Pharmacol Exp Ther 2024; 390: 177-185
• 13 Kaur P, Singh T, Jena L. et al. Dapagliflozin ameliorate type-2 diabetes associated neuropathy via regulation of IGF-1R signaling. J Neuroimmune Pharmacol 2025; 20: 32
• 14 Deuis JR, Dvorakova LS, Vetter I. Methods used to evaluate pain behaviors in rodents. Front Mol Neurosci 2017; 10: 284
• 15 Guo D, Mizukami H, Osonoi S. et al. Beneficial effects of combination therapy of canagliflozin and teneligliptin on diabetic polyneuropathy and β-cell volume density in spontaneously type 2 diabetic Goto-Kakizaki rats. Metabolism 2020; 107: 154232
• 16 Ishibashi F, Kosaka A, Tavakoli M. Sodium glucose cotransporter-2 inhibitor protects against diabetic neuropathy and nephropathy in modestly controlled type 2 diabetes: Follow-up study. Front Endocrinol (Lausanne) 2022; 13: 864332
• 17 Young MJ, Boulton AJ, MacLeod AF. et al. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia 1993; 36: 150-154
• 18 Papanas N, Ziegler D. Corneal confocal microscopy: Recent progress in the evaluation of diabetic neuropathy. J Diabetes Investig 2015; 6: 381-389
• 19 Tesfaye S, Boulton AJ, Dyck PJ. et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 2010; 33: 2285-2293
• 20 Adhikari U, Gad H, Chatterjee D. et al. Dapagliflozin for small nerve fibre regeneration in diabetic peripheral neuropathy: A randomised controlled study (DINE). J Peripher Nerv Syst 2025; 30: e70011
• 21 Feldman EL, Stevens MJ, Thomas PK. et al. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 1994; 17: 1281-1289
• 22 Liao J, Kang A, Xia C. et al. The impact of canagliflozin on the risk of neuropathy events: A post-hoc exploratory analysis of the CREDENCE trial. Diabetes Metab 2022; 48: 101331
• 23 Jardine MJ, Mahaffey KW, Neal B. et al. The canagliflozin and renal endpoints in diabetes with established nephropathy clinical evaluation (CREDENCE) study rationale, design, and baseline characteristics. Am J Nephrol 2017; 46: 462-472
• 24 Perkovic V, Jardine MJ, Neal B. et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380: 2295-2306
• 25 El-Haggar SM, Hafez YM, El Sharkawy AM. et al. Effect of empagliflozin in peripheral diabetic neuropathy of patients with type 2 diabetes mellitus. Med Clin (Barc) 2024; 163: 53-61
• 26 Zelman DC, Gore M, Dukes E. et al. Validation of a modified version of the brief pain inventory for painful diabetic peripheral neuropathy. J Pain Symptom Manage 2005; 29: 401-410
• 27 Li J, Zhang H, Xie M. et al. NSE, a potential biomarker, is closely connected to diabetic peripheral neuropathy. Diabetes Care 2013; 36: 3405-3410
• 28 Sandhu HS, Butt AN, Powrie J, Swaminathan R. Measurement of circulating neuron-specific enolase mRNA in diabetes mellitus. Ann N Y Acad Sci 2008; 1137: 258-263
• 29 El Boghdady NA, Badr GA. Evaluation of oxidative stress markers and vascular risk factors in patients with diabetic peripheral neuropathy. Cell Biochem Funct 2012; 30: 328-334
• 30 Klabuzai Á, Bekő V, Sütő Z. et al. The impact of SGLT-2 inhibitors on hydroxyl radical markers and diabetic neuropathy: A short-term clinical study. Antioxidants (Basel) 2025; 14: 289
• 31 Sardu C, Massimo Massetti M, Rambaldi P. et al. SGLT2-inhibitors reduce the cardiac autonomic neuropathy dysfunction and vaso-vagal syncope recurrence in patients with type 2 diabetes mellitus: The SCAN study. Metabolism 2022; 137: 155243
• 32 Ang L, Kidwell KM, Dillon B. et al. Dapagliflozin and measures of cardiovascular autonomic function in patients with type 2 diabetes (T2D). J Diabetes Complications 2021; 35: 107949
• 33 Balcıoğlu AS, Çelik E, Şahin M. et al. Dapagliflozin improves cardiac autonomic function measures in type 2 diabetic patients with cardiac autonomic neuropathy. Anatol J Cardiol 2022; 26: 832-840
• 34 Balcıoğlu AS, Çelik E, Aksu E. et al. Impact of sodium-glucose cotransporter-2 inhibitors on sympathetic nervous system activity detected by sympathetic activity index and LF/HF Ratio in patients with type 2 diabetes mellitus. Turk Kardiyol Dern Ars 2022; 50: 415-421
• 35 Kandeel M. The outcomes of sodium-glucose co-transporter 2 inhibitors (SGLT2I) on diabetes-associated neuropathy: A systematic review and meta-analysis. Front Pharmacol 2022; 13: 926717
• 36 Patoulias D, Katsimardou A, Fragakis N. et al. Effect of SGLT-2 inhibitors on cardiac autonomic function in type 2 diabetes mellitus: A meta-analysis of randomized controlled trials. Acta Diabetol 2023; 60: 1-8
• 37 Laursen JC, Rotbain CV, Kroonen MYAM. et al. Effects of baricitinib, empagliflozin, linagliptin and telmisartan on cardiovascular autonomic neuropathy in type 1 diabetes: An exploratory, randomized, open-label, crossover trial. Diabetes Obes Metab 2023; 25: 3064-3067
• 38 Waibel M, Wentworth JM, So M. et al. Baricitinib and β-Cell function in patients with new-onset type 1 diabetes. N Engl J Med 2023; 389: 2140-2150
• 39 O'Brien PD, Sakowski SA, Feldman EL. Mouse models of diabetic neuropathy. ILAR J 2014; 54: 259-272
• 40 Jolivalt CG, Frizzi KE, Guernsey L. et al. Peripheral neuropathy in mouse models of diabetes. Curr Protoc Mouse Biol 2016; 6: 223-255
• 41 Entezari M, Hashemi D, Taheriazam A. et al. AMPK signaling in diabetes mellitus, insulin resistance and diabetic complications: A pre-clinical and clinical investigation. Biomed Pharmacother 2022; 146: 112563
• 42 Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev 2011; 91: 733-794
• 43 Poppe R, Karbach U, Gambaryan S. et al. Expression of the Na+-D-glucose cotransporter SGLT1 in neurons. J Neurochem 1997; 69: 84-94
• 44 Abdelsameea AA, Kabil SL. Mitigation of cisplatin-induced peripheral neuropathy by canagliflozin in rats. Naunyn Schmiedebergs Arch Pharmacol 2018; 391: 945-952
• 45 Victor-Sami S, Kamali-Roosta A, Shamsaldeen YA. Methylglyoxal induces death in human brain neuronal cells (SH-SY5Y), prevented by metformin and dapagliflozin. J Diabetes Complications 2024; 38: 108832
• 46 El-Safty H, Ismail A, Abdelsalam RM. et al. Dapagliflozin diminishes memory and cognition impairment in streptozotocin induced diabetes through its effect on Wnt/β-Catenin and CREB pathway. Brain Res Bull 2022; 181: 109-120
• 47 Cignarella A, Peterson CD. Mechanistic chronopharmacology: Preclinical modeling of an SGLT2 inhibitor in preventing painful diabetic neuropathy. J Pharmacol Exp Ther 2024; 390: 174-176