Obesity and Diabetes — 4

It’s fair to say that even though the GLP-1 family of drugs is having such pronounced effect on weight loss now, we don’t fully understand why. For semaglutide, the single GLP-1 receptor activator, the effect is less than tirzepatide, a dual-receptor—GLP-1 and GIP—agonist. It’s unclear as to what role the GIP activation has in increasing the magnitude of weight loss. This becomes more complicated when you consider that a molecule being pursued by Amgen, known as cafraglutide (MariTide), is a monoclonal antibody (man-made antibody) designed to bind to two gut hormone peptides, acting as an activator of GLP-1 but a blocker of GIP. In a trial with the drug given monthly (as compared to weekly for semaglutide and tirzepatide), it achieved substantial body weight loss, about 15 percent of body weight, at the highest doses, akin to semaglutide. The most potent GLP-1 family drug to date, retatrutide, one of the triple-receptor activators being developed, revs up the third, added glucagon receptor, which may reduce energy uptake or increase its expenditure, or both. There is one thing surprising about the drug class that is rarely seen: a dissociation between side effects and efficacy. Usually, they track together. A high proportion of people taking these drugs in early weeks experience gastrointestinal side effects that fade. But the weight loss and anti-inflammatory effects do not. The reason for this unusual dissociation may be tied to the discovery of a distinct brain neural circuit that mediates the gastrointestinal side effects of nausea and vomiting in response to GLP-1 drugs. That may lead to a way to prevent or reduce these side effects in the future.

Altogether, these results don’t add up to a simple explanation of how these gut hormones work. This is not so unusual in medicine. Many drugs, such as anesthetics routinely used during surgery, antidepressants, metformin for diabetes, aspirin, and lithium for bipolar disorder, are mysteries when it comes to the precise mechanisms that make them work.

But there are parts of the mechanism we do now understand. Before taking a bite of food, these drugs induce a sense of fullness, termed pre-ingestion satiation, mediated by neurons in the hypothalamus. We’re familiar with postmeal satiety, but the discovery of two neuronal “fullness” circuits in the same part of the brain, one for pre-ingestion and the other after eating, both activated by GLP-1 drugs, helps provide an explanation for how these drugs work. The GLP-1 drugs also lower body weight in part by slowing stomach emptying, providing a sense of fullness with stretching of the stomach, signaling vagus nerves on its surface to fire, and relaying that information to the brain. The drugs can induce nausea, sensed in the brain, which of course also reduces appetite. Although GLP-1 drugs can get across the blood-brain barrier to some extent, they also talk to the brainstem and hypothalamus via the gut-brain axis, activating neural circuits that regulate appetite and reward. This modulation of part of the brain’s limbic system dulls cravings and suppresses addiction to many things besides food: alcohol, tobacco, and gambling. There’s also a noted shift in the foods eaten by people who are taking GLP-1 drugs, from less candy and snack foods to more vegetables and fish. As the pancreas secretes more insulin, muscles, fat tissue, and the liver happily become less resistant to insulin. These effects improve glucose control, which helps to fend off the pernicious effects of metabolic syndrome.