GLP-1 analogues for medical weight loss.

We commonly see patients who say that no matter what they do, they can’t lose weight. There could be several reasons for this. Sometimes there are obvious, or less obvious dietary changes that could be made. Just because foods are healthy doesn’t mean they can’t contribute to weight gain. Alcohol is an often unaccounted for calorie dense item of consumption. Sometimes it is the loss of muscle mass that has occurred with recurrent dietary restriction without adequate resistance exercises that has lowered basal metabolic rate. Sometimes there are unregistered self-sabotaging behaviours that a clinical psychologist skilled in the area of weight loss might help tease out.

These things notwithstanding, there are some people for whom weight loss is harder. Twin studies have shown us that about 60% of our weight is genetically pre-determined, with 40% due to lifestyle. We are only at the tip of the iceberg in understanding what these genetically determined drivers are. One area of current interest is gut hormones.

When we eat, we secrete several gut hormones that help control hunger and fullness. Glucagon-like peptide 1 (GLP-1) is one such hormone secreted from intestinal L-cells, originally discovered when it was noted that oral glucose resulted in the secretion of more insulin than the same glucose load administered intravenously. This “incretin effect” was found to be due to GLP-1 mediating improved insulin secretion in response to a meal. People with diabetes, and other insulin resistance syndromes such as PCOS and pre-diabetes, have lower levels of GLP-1, or are GLP-1 resistant. GLP-1 analogues were developed as treatments for diabetes, as glucose lowering agents, but then found to have several other beneficial side effects, such as weight loss, protection of our insulin-secreting B-cells (diabetes prevention) and cardioprotection.

We now have several GLP-1 analogues available including exenatide (twice daily), liraglutide (once daily), dulaglutide and semaglutide (the latter two once-weekly), administered as self-injections. In Australia, currently only liraglutide (Saxenda) is TGA approved for the indication of weight loss, however semaglutide (Ozempic) is FDA approved for weight loss elsewhere. Notably, semaglutide trials for weight loss used a 2.4mg SC weekly dose, which compares to the 1.0 mg SC weekly dose currently TGA approved in Australia for diabetes management. The weight loss mechanism of these medications is thought to be via GLP-1 receptors present in the hypothalamus, in areas that control satiety.

Weight loss achieved with these medications is very variable, with one study showing that over 12 months, 35% of people taking semaglutide, 6% of those taking liraglutide and 2% of people taking placebo lost 20% or more of body weight. Data for long term use (several years duration) is also available, which differentiates these medications from oral weight loss medications whose use should be limited to only several months. Side effects are commonly gastrointestinal upset (constipation or diarrhoea) and more likely to occur in those with renal impairment. There are reports of acute pancreatitis on these medications (rate 1 in 10000 patients). In animal studies, rats were found to have an increased risk of medullary thyroid cancer, in doses higher than those recommended for humans, and these medications are contraindicated in those with a history of medullary thyroid cancer.

The future for medical weight loss management is exciting, with an oral formulation of semaglutide now available overseas, and a combined GLP-1/GIP agonist in the pipeline that in early studies boasts weight loss similar to sleeve gastrectomy.

In summary, GLP-1 analogues improve satiety through central mechanisms, have longevity, and may be the first quill in our arsenal against any genetic predisposition to weight gain. They are welcome additions to diet and lifestyle measures, and may provide motivation to consolidate new lifestyle routines. They are unlikely to be as effective in those who are simply consuming too much calorie dense foods, who have unacknowledged stress or sleep deprivation, or who have secondary (pathologic) causes of obesity. It is important to stress that exercise should be undertaken concurrently to maintain muscle mass (and therefore basal metabolic rate) during the weight loss phase, as otherwise weight loss will result in concurrent muscle loss. Medical weight management is currently evolving in exciting directions.