Therapeutic potential of GLP-1 receptor agonists and SGLT2 inhibitors in diabetic neuropathy: a critical appraisal

The management of type 2 diabetes (T2D) has recently witnessed a paradigm shift extending beyond blood glucose regulation towards cardiovascular and renal health targeted by cardiovascular outcome trials (CVOTs) of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i). Preclinical studies suggest a potential role for GLP-1RAs and SGLT2i in the treatment of diabetic neuropathy and neuropathic pain. However, to date largely only small-size phase II shorter-term randomized controlled trials (RCTs) of heterogeneous designs and quality have been performed, without clear evidence of favorable effect of both GLP-1RAs and SGLT2i on clinical and neurophysiological neuropathic outcomes. Moreover, responses to GLP1-RA and SGLT2i treatments in real‑world clinical practice appear heterogeneous, with relatively high rates of non-responders and discontinuation. Several possible risks associated with GLP-1RAs and SGLT2i treatment in real-world practice have been identified requiring increased attention by physicians, their professional societies, and patients alike. Unfortunately, the opportunity has been missed to use simple tools for the detection and monitoring of diabetic sensorimotor polyneuropathy (DSPN) and cardiovascular autonomic neuropathy (CAN) in the multiple published large-scale pivotal CVOTs. Diabetic neuropathy is linked to considerable patient burden and mortality, and there remains an unmet need for the disease modifying effects of novel pharmacotherapies derived from the pathogenetic concepts of diabetic neuropathy. In the future, when designing and conducting RCTs more emphasis should be placed on considering neuropathy as a serious and potentially life-threatening complication.