Chapter 42
Obesity and Diabetes — 1
One of the most life-changing medicines in history—based on the discovery of glucagon-like peptides or GLP-1s—sat under our noses for over twenty years before it began making a transformative difference to human health span. Glucagon and GLP-1s are naturally occurring hormones that arise from our gut and serve a critical role for managing the body’s metabolism. The new GLP-1 medications mimic the structure of the natural hormones and can achieve far greater levels of these hormones in the blood. The first GLP-1 drug, exenatide, was approved in 2005. It took nearly a decade before a GLP-1 drug was available as a once-weekly injection instead of twice a day. Now these longer-acting drugs, such as Ozempic, Wegovy, Mounjaro, and Zepbound, are the rage and cannot be manufactured fast enough to keep up with the demand. The discovery of a venom in the saliva of the Gila monster, containing a long-acting GLP-1, accelerated the hunt for a synthetic activator with a long half-life (requiring less than daily injections). Once we had such a long-acting peptide in hand, we needed to figure out how to use it. Ten years later, this remarkable class of peptides won the 2023 Breakthrough of the Year Award from the journal Science for its anti-obesity impact.
THE STORY OF A DRUG
It started with the problem we have with sugar. Drug companies hoped these drugs would enable people with diabetes to get their hemoglobin A1c test results, the accepted metric for glucose control, down. If that were possible, then the adverse end-organ sequelae from diabetes, such as heart disease, could perhaps be prevented or at least delayed. Beginning in 2016, more than nine thousand people with type 2 diabetes were given the GLP-1 molecule liraglutide or a placebo. This drug trial resulted in fewer cardiovascular deaths, heart attacks, and strokes, even though it was associated with only five pounds of weight loss. One unsolved puzzle is that weight loss resulting from the drug in people with diabetes is substantially less than in those who are simply obese.
It took until 2021 for another GLP-1 (specifically the semaglutide peptide) to be tested on people with obesity, but not diabetes. That trial found a dramatic effect—an average loss of 15 percent of body weight, or thirty-four pounds. What was different in that experiment was the dose escalation to 2.4 milligrams of semaglutide, more than double the dose used in previous Ozempic trials. Novo Nordisk changed the name of the drug from Ozempic to Wegovy even though the semaglutide molecule was the same, just delivered at a higher dose. Then the new synthetic molecule tirzepatide, tested in a similar clinical trial, exceeded the weight loss achieved by semaglutide, inducing more than 20 percent body weight loss at higher doses. The manufacturer of tirzepatide, Eli Lilly, followed suit and changed the name of its diabetes drug from Mounjaro to Zepbound for obesity, even though, again, the only difference was the dose.
The naturally occurring GLP-1s and related gut hormones have receptors in the body that are activated by these peptides. The semaglutide peptide activates only the GLP-1 receptor peptide already in the body, whereas tirzepatide is a dual-receptor peptide, activating both the GLP-1 receptor and another gut hormone receptor called gastric inhibitory polypeptide (GIP). Now there are even triple-receptor activators such as retatrutide, which adds glucagon. By forty-eight weeks in a pivotal clinical trial, this agent, at doses of 8 or 12 milligrams, reduced weight by 24 percent, and there was no sign of plateauing. That means the weight loss may continue over time without established limits known to date. These levels of body weight loss equate to or exceed what is typically observed with gastric-bypass surgery.