Drug Therapy in Obesity: A Review of Current and Emerging Treatments

Abstract

Whilst the prevalence of obesity continues to increase at an alarming rate worldwide, the personal and economic burden of obesity-related complications becomes ever more important. Whilst dietary and lifestyle measures remain the fundamental focus of the patient to counter obesity, more frequently pharmacological and/or surgical interventions are required. Nevertheless, these therapies are often limited by weight loss efficacy, side effects, surgical risks and frequently obesity relapse. Currently, only five drug therapies are approved for the specific treatment of obesity. However, our understanding of the pathophysiology of obesity and of gut hormones has developed precipitously over the last 20-30 years. As a result, there has been a recent movement to create and use analogues that manipulate these gut hormones to support weight loss. In this article we review the efficacy of the currently approved drug therapies and discuss future potential drug mechanisms and early clinical trial results exploring these budding avenues. We discuss the use of glucagon-like peptide-1 (GLP-1) analogues as monotherapy and unimolecular dual or triple agonists that exploit the GLP-1 receptor and/or the gastric inhibitory peptide (GIP) receptor and/or the glucagon receptor. We also explore the use of sodiumglucose co-transporter-2 (SGLT-2) inhibitors, amylin mimetics, leptin analogues, ghrelin antagonists and centrally acting agents to suppress appetite [neuropeptide Y (NPY) antagonists, melanocortin-4 receptor (MC4R) agonists and cannabinoid-1 receptor antagonists]. Whilst further evidence is required to support their clinical use, preclinical and early clinical trial results are encouraging. Key Summary PointsObesity is a complex metabolic disorder, with several licensed drug and surgical therapies currently available.Current therapies are often associated with inadequate efficacy or complications and side effects, limiting their use.Multiple pathophysiological mechanisms of obesity are recognized, though only few of these are manipulated using currently licensed therapies.Whilst most drug classes are in early stages of development and/or clinical trials, results are promising for multiple drug targets.

Pathophysiology of NAFLD and NASH in Experimental Models: The Role of Food Intake Regulating Peptides

“…It is likely that there will not be only one right approach for all patients with NAFLD, it will be necessary to adapt the diet individually, including the inclusion of n-3 fatty acids, foods with higher monounsaturated fatty acids, fruits, vegetables and reducing the intake of saturated fats or simple carbohydrates ( 6 , 7 ). Recently, it was proposed that food intake regulating peptides play a significant role in obesity regulation and may have the potential to be a drug for obesity treatment ( 8 – 11 ). Nevertheless, to elucidate the detailed pathophysiological mechanisms of NAFLD and NASH, appropriate experimental models need to be used.…”

Diabetes and Novel Coronavirus Infection: Implications for Treatment

“…Drugs within this class of medication inhibit the sodium-glucose cotransporter-2 (SGLT-2) protein in the proximal convoluted tubule, thereby preventing the reuptake of both sodium and glucose to promote their urinary excretion [48]. Use of these medications is associated with significant improvements in glycaemic control, body weight and reduced progression of renal disease [49,50]. Since their introduction in 2013, their prescribing usage has increased dramatically, and they are amongst the most commonly used drugs for treating T2D [51].…”

“…Glucagon-like peptide-1 is an endogenous peptide secreted by the distal small bowel in response to glucose ingestion to stimulate insulin release from the b-cells of the pancreas and is subsequently degraded by the DPP-4 enzyme. GLP-1 analogues act directly to stimulate pancreatic insulin secretion and are associated with improved glycaemic control, body weight and reduced progression of renal disease [49,50].…”

Advances and complications of regenerative medicine in diabetes therapy

“…This often leads to hyper-or hypoglycemia with corresponding complications increasing with the time. Hyperglycemia increases the development and progression of microvascular complications such as retinopathy, nephropathy, and neuropathy (Gibbons & Freeman, 2020;Williams, Nawaz & Evans, 2020). Furthermore, the most severe complications are those related to hypoglycemia in T1D patients, resulting in neurocognitive dysfunction (Kodl & Seaquist, 2008).…”