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The first glucagon-like peptide-1 (GLP-1)-based therapeutic was approved by Health Canada in 2011 for the treatment of hyperglycemia in patients with Type 2 diabetes. Little was it suspected at that time that this class of drugs would go on to become a global success not only for Type 2 diabetes but, now, also for people living with overweight/obesity. Since that time, numerous variants of GLP-1 have been developed, with at least 7 different forms in trials or available today. Given the pace of development and tremendous success of these drugs, one wonders if there is any room for improvement on either their actions and/or their disease targets. It turns out that the answer is a resounding YES. 

Recent advances in the area of drug development have led to the combination of GLP-1 receptor agonists with other novel bioactive peptides. For example, in one single molecule, tirzepatide, the sequences of both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) are intertwined in a so-called co-agonist. Although both GLP-1 and GIP stimulate insulin secretion, GLP-1 also reduces appetite while GIP has direct actions on fat cells. As a result, tirzepatide captures the metabolic benefits of both GLP-1 and GIP and has now been proven to be the most effective drug developed to date for both glucose lowering and weight loss. Other combinatorial therapeutics that are under investigation include a novel GLP-1/GIP/glucagon molecule, that additionally harnesses the biological actions of glucagon to increase energy expenditure, leading to even greater weight loss. Similarly, addition to GLP-1 of the hormone amylin, which delays gastric emptying and reduces appetite, results in superior effects on both glucose lowering and weight loss as compared to each drug alone.  

Current dosing regimens of GLP-1-based therapeutics range from twice-per day to once-weekly and require injection to prevent degradation by the gastric/intestinal juices. However, advances in drug delivery systems may improve the ease of administering these drugs. Indeed, a daily, orally-available preparation of GLP-1is now providing another option for those who do not wish to take injections. Furthermore, a recent report has shown that placement of GLP-1-based drugs into a novel hydrogel allows the drug to sit in a ‘slow-release depot’ that may require dosing only once every 4 months.  

Excitingly, researchers are now investigating the possible use of GLP-1 based therapeutics for diseases beyond Type 2 diabetes and obesity. For example, recent studies have shown that these drugs reduce the incidence of Major Adverse Cardiovascular Events (MACE, i.e., non-fatal stroke, non-fatal myocardial infarction, or cardiovascular death) in individuals with Type 2 diabetes; current trials are assessing whether these benefits are also found in those living with overweight or obesity. Similarly, studies have shown that GLP-1-based therapeutics can delay the progression of kidney disease in individuals with Type 2 diabetes, although the mechanisms are not well understood. Similar studies are ongoing in patients with metabolic liver diseases, such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), based on the known ability of GLP-1 to reduce fat levels in the liver. Even more interestingly, studies in rodents have shown that GLP-1 has beneficial actions in the brain, including neuroprotection, leading to clinical trials for the use of these drugs in patients with Alzheimer’s disease, Parkinson’s disease and even addiction. These findings add weight to the notion that individuals without either diabetes or overweight/obesity may benefit from treatment with GLP-1 receptor agonists. 

Despite all the hype about the benefits of GLP-1-based therapeutics, particularly for body weight reduction, a note of caution must be introduced. While these drugs have proven to be safe through their use in millions of individuals with Type 2 diabetes, the newer more-effective drugs as well as their applications in novel diseases will require long-term studies to provide safety data. Although some adverse events are common, and are stated in the product sheets, i.e., nausea and vomiting, recent reports have suggested that caution must be taken if drug dosing is not carefully monitored by a physician. Potential detrimental effects due to gastric stasis have also been reported in the setting of anesthesia. There has also been a suggestion of increased suicidal ideation. Without further study, it remains unclear as to whether these are, indeed, true side effects and, if so, how common they may be.  

To end on a less serious note, a final note of caution has been introduced in the press recently about the possible economic ‘cost’ of reducing disease burden through the use of GLP-1-based drugs, particularly for weight loss. Hence, in a world where appetite and the desire to eat are reduced, there is the potential for lost sales of fast foods, snacks and sugary drinks. Just as horseshoe sales were made largely obsolete by the invention of the car, manufacturers and vendors of diabesogenic foods should beware! 

@PatriciaBrubaker

Patricia Brubaker, Ph.D., F.R.S.C., F.C.A.H.S. is a Professor Emerita, Departments of Physiology and Medicine and a Banting & Best Distinguished Scholar at the University of Toronto, Toronto, ON, Canada. Dr. Brubaker completed both her undergrad and PhD at ¿´Æ¬ÊÓƵ