Obesity in adults - Emerging treatments

Oral semaglutide

An oral formulation of semaglutide has entered early-stage clinical development for the treatment of obesity. There is a poorly documented but probably substantial off-label use of oral semaglutide for the treatment of obesity in the US. If approved, oral semaglutide may be a useful option for patients in whom administration of an injectable medication is prohibitive.[190] Both the oral and subcutaneous formulations of semaglutide are already indicated for the treatment of type 2 diabetes.

Amylin

Amylin is an anorexic peptide released by pancreatic beta-cells and functions as an adjunct to insulin in the control of blood glucose levels. It also decreases gastric emptying and may restore leptin sensitivity in obese patients. When used as an adjunct to dieting, exercise, and behavioural therapy, pramlintide (a synthetic analogue of amylin) increased 12-month weight loss in obese patients.[191][192] Cagrilintide (a long-acting amylin analogue) has been evaluated in combination with semaglutide for weight management in patients who are overweight or have obesity. Early clinical trials show an acceptable safety profile; however, further studies are needed to confirm the efficacy and safety of treatment.[193]

Endocannabinoid antagonists

Antagonism of the cannabinoid receptor CB1 is known to have an anorexic effect. Rimonabant, an inverse agonist of the CB1 receptor, reduced intra-abdominal fat and improved multiple cardiometabolic risk factors in a randomised controlled trial, but was withdrawn from the market due to increased risk of suicide.[194][195][196] Second-generation agents with lower brain penetrance are in clinical development.[197]

Ghrelin

Antagonism of this hunger hormone has shown promise in pre-clinical studies but not in human trials. Novel therapies such as ghrelin vaccines remain in early-stage development.[130]

Human growth hormone (hGH)

Exogenous hGH can inhibit lipoprotein lipase and decrease the adipocyte mass, but it can also cause hyperglycaemia. The domain of the hGH peptide that inhibits lipoprotein lipase has been isolated; however, and this fragment does not appear to be diabetogenic. A meta-analysis has suggested that treatment with recombinant hGH is associated with a decrease in visceral obesity without overall weight loss.[198] Other findings included positive effects on serum lipids and cholesterol in obese children.[199][200]

Thyroid hormone

Thyroid hormone therapy has been suggested for weight loss in obesity during caloric deprivation and to improve morbidity and mortality in adults with non-thyroidal illnesses. Data regarding the effectiveness of thyroid hormone therapy in treating obesity or non-thyroidal illnesses are inconclusive. Data does support that such therapy induces subclinical hyperthyroidism.[201]

Cetilistat

Cetilistat, a lipase inhibitor similar to orlistat, reduced body weight and serum lipid levels when administered in combination with a caloric deficit in obese patients with and without diabetes.[202][203] The most common adverse events associated with cetilistat were gastrointestinal in nature; however, fewer gastrointestinal events were observed with cetilistat than with orlistat. Cetilistat is approved in Japan for the treatment of obesity with complications.

Metformin

A meta-analysis of 21 randomised controlled trials indicated that treatment with metformin led to modest reductions in body mass index (BMI).[204] Larger trials are needed to confirm the effect of metformin on weight loss.

Tesofensine

Tesofensine, an inhibitor of the reuptake of noradrenaline, dopamine, and serotonin, demonstrated efficacy as an adjunct to dieting in a phase 2 trial.[205] A fixed-dose combination therapy of tesofensine and metoprolol, a beta-blocker, has been granted orphan-drug designation by the US Food and Drug Administration (FDA) for hypothalamic obesity and Prader-Willi syndrome.

Vagal nerve blockade

Reversible intermittent vagal blocking devices, such as the Maestro Rechargeable System, have been approved by the FDA for the treatment of obesity.[206] Vagal nerve blocking has been shown to induce satiety resulting in weight loss and glycaemic control.[207][208]

Duodenal-jejunal bypass liner

The duodenal-jejunal bypass liner is an impermeable sleeve that is inserted endoscopically into the proximal intestine to form a barrier between food and the intestinal wall. One randomised clinical trial has shown the duodenal-jejunal bypass liner plus diet to be effective in reducing weight compared with diet alone in patients with obesity and type 2 diabetes.[209] However, the clinical benefits of duodenal-jejunal bypass liners are not sustained 12 months after explantation.[210]

Endoscopic sleeve gastroplasty

Endoscopic sleeve gastroplasty is an experimental procedure with short-term results of 14.9% to 18.6% total body weight loss.[211] One systematic review and meta-analysis found that endoscopic sleeve gastroplasty was associated with fewer complications than laparoscopic sleeve gastrectomy.[212]