With the number of patients in India living with diabetes crossing 7 crore and soon projected to reach 14 crore, diabetic peripheral neuropathy (DPN) is a common microvascular complication of immense public health concern with a significant drain on the healthcare system and patient resources. It’s estimated that up to 50% of the patients with diabetes eventually develop neuropathy and of these 50% develop chronic neuropathic pain with 15% developing chronic foot ulcers. Moderate-to-severe unremitting pain is present in over 70% of patients with DPNP resulting in insomnia, poor quality of life, mood disorders and 5-times more health-care costs compared with diabetes alone . In our rough estimate, the population at risk of these debilitating consequences in India alone stands at 3.5 crore at this point in time.

While excellent glycaemic control and controlling other risk factors are the surest way to prevent neuropathy, a large proportion of patients in India will still be at risk of developing neuropathy, due to problems such as treatment non-adherence and overall poor risk factor control. Therefore, for patients who develop neuropathy, apart from good risk factor control, an effective disease modifying agent will be an important addition to the treatment armamentarium of the clinician . Such disease modifying agents must ideally target one or more of any 4 key patho-physiologic mechanisms – (i) disturbances in the fatty acid and acetyl-CoA metabolic pathways, (ii) microcirculation and endothelial dysfunction, (iii) oxidative stress from metabolites and free radicals and (iv) mitochondrial dysfunction, ATP overload and endoplasmic reticulum (ER) stress .

Till date, alpha-lipoic acid (free radical scavenger) and the aldose reductase inhibitor, epalrestat are the only disease modifying medication classes with weak and conflicting evidence of disease modifying efficacy , are not recommended by treatment guidelines or currently a part of standard clinical care. Few trials have evaluated other drug classes. Nebivolol, a highly selective beta-receptor antagonist with Nitric Oxide generating properties through endothelial nitric oxide synthase (e-NOS) induction (6) is a drug that pre-clinical studies have demonstrated, can have an alleviatory effect on pathophysiologic mechanisms. Studies have demonstrated that nebivolol, (i) inhibits ER stress markers (GRP78 and CHOP), increasing endothelial expression of the insulin receptor substrate-1 (IRS-1), thus alleviating endothelial insulin resistance , (ii) the combination of the alleviation of endothelial vascular insulin resistance and enhanced nitric oxide production through eNOS induction has beneficial effects on the vascular microcirculation (8,9). (iii) Inhibition of mitochondrial complex-1 and ATP synthase activity that alleviates mitochondrial toxicity and (iv) it’s anti-oxidant and free radical scavenging effects. Since nebivolol is widely and safely prescribed in chronic heart failure, it’s safety profile is well known, with most patients tolerating the drug well in the long term, up to the recommended 10 mg/ day. Thus, nebivolol appears to be a promising candidate drug that may modify the pathogenetic processes in diabetic neuropathy.