Episode 190 - Pharmacological Treatments for Obesity with Dr Matthew Peverelle
Australians who are either overweight or obese are increasingly turning to pharmacological approaches, coupled with dietary measures, to achieve their weight loss goals before considering bariatric surgery.
These therapies are typically considered for adults whose BMIs are equal to or above 30 kg/m², or above 27 kg/m² with associated comorbidities, and include the following:
Incretin-based therapies, including dual incretin agonists (most effective)
Appetite suppressants – central acting drugs
Dopaminergic/opioid pathway modulation therapies
Nutrient absorption inhibition therapies
1. The most effective pharmacologic treatments available in clinical use are synthetic incretins.
Natural incretins are gut-derived hormones released after eating that enhance pancreatic insulin secretion in a glucose-dependent manner. The so-called incretin effect, whereby more insulin is released from the pancreas by ingestion of oral glucose than by intravenous glucose at the same blood levels, is now understood, as it is mediated predominantly by these hormones.
There are two physiologically important incretins, including GLP-1, which stands for glucagon-like peptide 1, first discovered 50 years ago. This hormone shares the same ancestry as glucagon, being derived from the same precursor molecule, proglucagon, yet has completely opposite hormonal effects.
GLP-1 is secreted predominantly by L cells in the distal ileum and colon, with smaller amounts from pancreatic alpha cells and the brainstem. Its release is initially triggered by neural signals while eating and then, in a more sustained way after 30–60 minutes, by carbohydrates, fats, proteins, and fibre (via their metabolism to short-chain fatty acids) making contact with the L cells.
GLP-1 is insulinotropic, stimulating the pancreas to release more insulin when blood sugar levels are high. It also increases satiety, slowing gastric emptying by reducing stomach muscle contractions (antral motility) and increasing the tightness of the pyloric sphincter (pyloric tone). This effect is primarily mediated through the vagus nerve and brain centres like the dorsal motor nucleus.
Additionally, GLP-1 acts on the hypothalamus in several key areas, primarily the Arcuate Nucleus (ARC) and the Paraventricular Nucleus (PVN), activating neurons that release anorectic peptides (like proopiomelanocortin - POMC) and inhibiting those releasing the appetite-stimulating orexigenic peptides (like NPY/AgRP), reducing cravings and regulating hunger.
GLP-1 has a very short half-life and is degraded by enzymes, including the widespread DPP-4 (Dipeptidyl Peptidase-4), within 1–2 minutes. Synthetic GLP-1 receptor agonists mimic the GLP-1 hormone, resist rapid breakdown, and last for a prolonged period.
Examples in clinical use include Exenatide (Byetta, a synthetic version of a peptide found in the saliva of the Gila monster lizard), Semaglutide (Ozempic – approved for type 2 diabetes; Wegovy – approved for weight loss, with dosing up to 2.4 mg per week), and Liraglutide (Saxenda, with daily dosing). Another well-known GLP-1 is Dulaglutide (Trulicity).
When applied for weight loss, Semaglutide and Liraglutide lead to 10–15% body weight reduction. For many people living with obesity, this level of weight loss is not just cosmetic; it reduces the risk of heart disease, joint pain, improves mobility, and boosts quality of life. Benefits beyond diabetes and weight loss include a 30% reduction in the risk of heart attacks and strokes. These drugs also show promise in treating conditions such as fatty liver disease, obstructive sleep apnoea, and kidney disease.
Side effects include nausea, vomiting, diarrhoea, gallstones, and pancreatitis (0.2–0.3% in most studies). They are contraindicated in patients with medullary thyroid cancer.
Another incretin in clinical practice is Gastric Inhibitory Polypeptide (GIP), also known as Glucose-Dependent Insulinotropic Polypeptide. Like the GLP-1 incretin, GIP also stimulates insulin release in a glucose-dependent way, though it was first named for its weaker ability to inhibit stomach acid.
GIP is primarily produced and secreted by K cells located in the mucosa of the duodenum and jejunum.
Its secretion into the bloodstream is also rapidly triggered by the presence and absorption of nutrients, particularly glucose and fats, after a meal. The highest concentration of GIP-producing K cells is found in the most proximal part of the small intestine, consistent with its role as an early response signal to food intake.
Some studies have also detected minor GIP expression in other tissues, including pancreatic alpha cells, the brain, and the stomach. This hormone has no effect on gastric emptying but, like the GLP-1 agonists, also inhibits appetite through actions mediated in the hypothalamus.
The synthetic GIP receptor agonist in clinical use today is called Tirzepatide. When combined with GLP-1 receptor agonists (like semaglutide), the combination greatly increases weight loss and improves glucose control. This combination is known as "twincretin" therapy and, in clinical use for obesity, is marketed as Mounjaro. Clinical trials demonstrate it producing 20–22% weight loss for patients.
Large trials (SURPASS-CVOT) show Mounjaro also significantly reduces the risk of major cardiovascular events (MACE) and all-cause mortality.
Discontinuation rates for patients using incretin therapies for weight loss are quoted between 50–75% in one year, with factors including expense and side effects influencing this statistic. Recent data also points to significant weight regain over a two-year period after medication withdrawal.
2. The centrally acting appetite suppressants include Phentermine, which is a sympathomimetic noradrenergic agent used short-term over weeks to months and increases noradrenaline and dopamine in the hypothalamus to reduce appetite.
It is often combined with Topiramate (private script) for added satiety enhancement, as Topiramate affects GABA/glutamate signalling. These therapies can expect an 8–12% weight loss. Adverse effects include tachycardia, hypertension, insomnia, and teratogenic concerns.
3. Naltrexone combined with Bupropion acts on the POMC neurons, reducing appetite and food cravings. Nausea, seizure activity, and hypertension are side effects for a quoted 5–9% weight loss.
4. Orlistat is a gastrointestinal fat absorption inhibitor, inhibiting pancreatic lipase and decreasing fat absorption by about 30%. Steatorrhoea and loss of fat-soluble vitamins are side effects for only 3–5% weight loss.
The future may see triple therapy combining GLP-1, GIP, and glucagon. Their development is eagerly awaited.
To discuss the application of these therapies in more depth, we are joined by gastroenterologist Dr Matthew Peverelle. Matthew completed his advanced training in gastroenterology at Monash Health and Austin Health, including the Victorian Liver Transplant Unit. He then continued his studies abroad, completing a hepatology fellowship at the prestigious King's College Hospital in London. Subsequently, he has developed a strong interest in both hepatology, luminal gastroenterology, and endobariatrics.
Thank you for joining us as he brings his expertise to the next two podcast episodes.
References:
Australian Family Physician, Pharmacotherapy for Obesity, Lee & Dixon, Vol 46, No. 7, July 2017
Obesity Evidence Hub, 31/07/2025