Effect of Tirzepatide on Diabetic Peripheral Sensorimotor Neuropathy: A Randomized, Open Label, Controlled Study

589 million adults (20-79 years) are living with diabetes worldwide - 1 in 9 and the total number of adults with diabetes is predicted to rise to 853 million by 2050 - 1 in 8. An estimated 43% of adults living with diabetes (252 million people) are undiagnosed. (1 ).

Diabetic peripheral neuropathy (DPN) is particularly prevalent, affecting anywhere from 18.8 to 61.9% of individuals with DM in India (2). The appropriate management of this disturbance is essential if late-stage complications, such as foot ulceration and amputations are to be avoided in these patients. [3] The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study evaluated the incidence of DPN in type1 DM and illustrated that the incidence of DPN is 33% (4). In Europe, a study found overall prevalence of DPN is 28% (the EURODIAB IDDM Complications Study) (5). The KORA F4/FF4 Study conducted in Germany reported a prevalence of DPN of 25% (6). The ADDITION Demark study reported that the prevalence of DPN was up to 34.8 (7). The pathogenesis of DN is multifactorial and remains poorly understood. DPN is characterized by progressive, nerve-length-dependent loss of peripheral nerve fibers, leading to impaired sensory and autonomic function, pain, numbness, and eventually, complete loss of sensation. (8)Hyperglycemia, dyslipidemia, and insulin resistance activate various metabolic pathways, resulting in oxidative stress, mitochondrial dysfunction, inflammation, and microvascular damage, culminating in neuronal injury, Schwann cell damage, and myelin sheath degeneration. (9,10,11) . Schwann cels serve as the myelinating cell of the PNS and support cells of peripheral neurons. A Schwann cell forms a myelin sheath by wrapping its plasma membrane concentrically around the inner axon. The plasma membrane of Schwanncells has an extremely high lipid content, and cholesterol is particularly important for assembling the myelin sheath. The compact myelin sheath insulates the axon segment, significantly reducing membrane capacitance and increasing conduction velocity .Schwann cells are critical in response to PNS axon damage and axon regeneration. Wallerian degeneration will occur distal to injury site. The distal axon segment dies and Schwann cells, followed by macrophages, clear the dead cell contents and promote axon regeneration.

Schwann cells undergo several phenotypic changes at this time ; they activate myelin breakdown, upregulate the expression of cytokines (including TNF_ alpha ) to recruit macrophages to the injury site, up-regulate neurotropic factors to stimulate axon regeneration and neuron survival, and organize a regeneration pathway along their basal lamina tube to guide axon growth. .Risk factors for diabetic neuropathy include age, duration of diabetes, glycosylated haemoglobin , age and DR while BMI, smoking , total triglycerides, and total cholesterol do not indicate risk of diabetic neuropathy. Despite extensive research, effective treatments capable of halting or reversing progression of diabetic neuropathy remain elusive. Current management strategies primarily focus on alleviating symptoms and controlling pain.(12)Antidepressants, anticonvulsants, and opioids have shown limited efficacy and are associated with various side effects, such as dizziness and nausea.(13,14) Furthermore, no novel therapies have received approval in recent years (12,15).

Novel pharmacological agents, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and have shown promising neuroprotective and pain management effects. (16). GLP1 1 and GIP receptors are expressed in both murine and human adipose tissue and schwann cells . (17) the differential pharmacodynamics property of incretin drugs should be explored further in treatment of peripheral neuropathy. (17) There are different methods to quantify neuropathy including clinical scores based on patients symptoms and neurological assessment electrophysiological tests,intraepithithelial nerve fibre density measurement and quantitative sensory testing each with variable sensitivity.though neurophysiology is consider the gold standard it is less sensitive to detect early diabetic peripheral neuropathy (18) The human cornea is the most densely innervated tissue of the body.. Corneal confocal microscopy (CCM) is a non-invasive imaging technique, which allows us to view the microscopic layers of the cornea. Examination of the cornea with this high-resolution method demonstrates an objective means to assess corneal nerve fibre density (CNFD), corneal nerve fibre length (CNFL), and corneal nerve branch density (CNBD) in persons with diabetes,with high sensitivity and good reproducibility . (19)

Corneal Confocal microsccopy (CCM) is a sensitive measure of early small nerve fibre regeneration. A recent 12-week cross-over trial of dapagliflozin and glimepiride showed no differences in measures of cardiac autonomic neuropathy (20) , while another study showed an improvement in multiple measures of diabetic autonomic neuropathy after 24 weeks oftreatment with dapagliflozin (21).