GLP-1 agonists in obesity – A backgrounder

Currently, the drug semaglutide is receiving a lot of press – some celebrities openly discuss their off-label use of this drug to lose weight. As demand surges for it and similar drugs, the supply has not been able to keep up, resulting in shortages across the United States.

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. These medications were originally developed for the management of type 2 diabetes by regulating blood sugar levels. GLP-1 and GIP (gastric inhibitory peptide) are hormones known as incretins. These increase the amount of insulin released after a meal, causing decreases in blood glucose. These hormones are rapidly degraded by dipeptidyl peptidase-4 (DPP4). As targets for type 2 diabetes, one could inhibit DPP-4 (as in drugs such as sitagliptin and saxagliptin) and thus increase the actions of endogenous GLP-1, or one could target the receptor directly (as in drugs such as semaglutide, dulaglutide, and liraglutide). Furthermore, there is a GLP-1/GIP dual analogue available on the market – tirzepatide.

In obesity, GLP-1 agonists are thought to produce their anti-obesity effects by decreasing gastric emptying and decreasing gastrointestinal motility, meaning that food will spend more time in the stomach. This can make it easier to physically feel full from eating. These agonists can also affect the brain directly, causing decreased appetite, increased satiety, and decreased reward associated with food. It is also suggested that GLP-1 agonists may increase energy expenditure, which combined with decreased caloric intake, may result in weight loss.

The hormonal changes that occur during weight loss can make it very difficult to sustain weight loss (see this link for more details!). Reducing caloric intake results in decreased energy expenditure and increased appetite, and the sustained physiological changes can result in weight regain that occurs for some time afterwards. GLP-1 agonists may act as an external stimulus that helps prevent those decreases in energy expenditure and increases in appetite. However, once they are stopped, many patients regain some portion of their weight, with one study finding that participants regained two-thirds of their lost weight in a year.

Although GLP-1 agonists are a promising therapy to help manage a chronic condition that affects 40% of Americans and 30% of Canadians, we must recognize that there are other factors that lead to obesity, including a change towards a more sedentary lifestyle and lower quality diets. We must acknowledge that obesity is not simply a result of low willpower or laziness, and that complex physiological and social factors have contributed to what may be one of the greatest public health crises we face today.

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