ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 63 S30.2 | DOI: 10.1530/endoabs.63.S30.2

New avenues for novel drugs to treat obesity

John Wilding

Obesity is a chronic disease with significant adverse implications for health. Guidelines recommend first line treatment with lifestyle interventions that include restriction of energy intake, increased physical activity and behavioural modification, but these only reduce body weight by 3–5% initial over 12 months, and weight regain is common. Bariatric surgery is effective, but most suitable for people with more severe obesity or with significant complications such as diabetes. Pharmacotherapy is an adjunct to lifestyle intervention and may help bridge the efficacy gap between lifestyle and surgery. The anti-obesity drugs currently available in Europe are the peripherally-acting intestinal lipase inhibitor, orlistat, a combination of the mu opioid antagonist naltrexone with bupropion, and the GLP-1 receptor analogue liraglutide. In the USA phentermine as monotherapy, or in combination with topiramate, and the 5HT2c receptor agonist lorcaserin are also approved. These drugs provide approximately 3–6% greater weight loss than lifestyle intervention alone over 12 months or more treatment duration. Adverse effects depend on the mode of action, and regulators have focussed on cardiac and neuropsychiatric safety given previous problems with older (now withdrawn) medicines for weight loss such as sibutramine and rimonabant. Lorcaserin was recently shown to be safe from a cardiovascular perspective, and data with the lower dose of liraglutide in people with diabetes suggests cardioprotection in those at high risk. The recently reported results of a phase 2 trial with the GLP1 agonist semaglutide are promising and suggest even greater weight loss is possible with potent long-acting GLP-1 analogues with central effects. Future developments will likely target multiple gut hormone pathways such as GLP1 together with glucagon, amylin or PYY in an attempt to optimise efficacy and approach the weight loss seen with surgical approaches. Drugs for specific monogenic forms of obesity such as metreleptin for leptin deficiency and the melanocortin 4 receptor agonist setmelanotide for patients with POMC mutations will also be discussed.

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