[Click here to read the previous part: Current issues]
Many pharmaceutical companies have now entered the space of GLP-1 agonists and related therapies for obesity, attempting to increase effectiveness and also finding oral alternatives to the injections currently used.
Let’s dive back into the hormones involved. In part 1, we discussed how GLP-1 and GIP increase release of the pancreatic hormone insulin following a meal, which decreases blood sugar. Amylin is also produced along with insulin in beta cells, helping to delay gastric emptying and decrease food intake. Amylin and GLP-1 both suppress the production of the pancreatic hormone glucagon, whose function is to raise blood sugar and prevent it from going too low. When eating, peptide YY (PYY) is also released, which also acts to slow gastric emptying and decrease appetite.
Currently, several peptide drugs are available in the form of GLP-1 agonists (semaglutide, liraglutide) and GLP-1/GIP dual agonists (tirzepatide). However, more medications with different mechanisms are currently being investigated for weight management. There is a GLP-1/glucagon dual agonist currently under development – mazdutide. Although glucagon functions to raise blood sugar, it also has the ability to increase energy expenditure, which theoretically could increase weight loss. There is also a GLP-1/GIP/glucagon triple agonist, retatrutide, that is currently being trialled, which may have superior efficacy.
Drugs currently being developed that target other mechanisms include cagrilintide, a long-lasting analogue of amylin, which is currently being studied in conjunction with semaglutide. PYY analogues are also in the early stages of being tested along with semaglutide. Further drugs are also being developed to target different combinations of these pathways, aiming to reduce side effects and to improve efficacy.
However, all of the drugs mentioned above are peptides – they must be injected subcutaneously, as oral administration would degrade and inactivate the drug. There is an oral formulation of semaglutide available, but it must be taken in certain conditions (in the morning, with a certain amount of water, and a certain time before eating or taking other medications). To combat this, small molecule drugs are being developed – these drugs would bind to the same receptors, but they would be able to be taken orally. These include drugs such as orforglipron, lotiglipron, and danuglipron, which are all small molecule GLP-1 receptor agonists. The development of these therapies could open up this class of medications to those who prefer not to use injections, and could potentially allow for easier storage, compared to the current medications that must be kept refrigerated.
The world of obesity medicine is going through an exciting time now, with many new therapies being developed and many new mechanisms and combinations of mechanisms being explored. These medications may become more accessible to everyone, and could help reduce the risk of other chronic diseases, reducing the burden on our healthcare system in general. However, the long-term risks and benefits are still unknown, and we should still address the root causes of obesity in our society.