All About Incretins
Once an obscure group of hormones, incretins are now a fixture in American culture. Polysyllabic nonsense words like Ozempic, Wegovy, and Mounjaro have forced their way into English vernacular. For the uninitiated, each bizarre name can be explained away with a hand wave: it’s one of those GLP-1s.
In little over three years, these GLP-1s have radically altered the landscape of treating obesity and diabetes, if not the whole of society. Market analysts once downgraded Krispy Kreme’s stock given the anticipated impact of weight-loss drugs on donut sales. (The stock later rebounded, to the relief of portfolio managers everywhere.)
Incretins comprise only two hormones: GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide, which may one day feature in the Scripps National Spelling Bee).
Following a meal, these humble hormones are normally dispatched from the intestine and seek out receptors in the pancreas, brain, heart, kidneys, GI tract, fat cells, and immune cells. In tandem with insulin, incretins promote satiety and reduce appetite.
Semaglutide, the medication found in Ozempic, Wegovy, and Rybelsus, only activates receptors for GLP-1. Tirzepatide, the medication found in Mounjaro and Zepbound, acts on receptors for both GLP-1 and GIP, demonstrating greater effects on weight loss compared to semaglutide. Together, these medications form a class known as incretin mimetics (IMs).
Whereas endogenous incretins are degraded within a few minutes of their release, modern IMs have a half-life of seven days, permitting their weekly dosing schedule.
Historically, type two diabetes was the only indication for IM therapy. As high-quality evidence accumulated, stand-alone indications for weight loss, obstructive sleep apnea, heart failure, and chronic kidney disease were approved in the U.S.
As further trials wrap up, approved uses may soon expand to metabolic dysfunction-associated steatohepatitis (MASH), once known as “fatty-liver disease,” prediabetes, knee osteoarthritis, and prevention of cardiovascular death. Separately, incretin mimetics show mildly beneficial effects on cholesterol and blood pressure.
Limited evidence also suggests that incretins reduce consumption of alcohol, cocaine, and tobacco and curb other compulsive behaviors like online shopping and hair-pulling.
Incretin and insulin signaling are also considered novel therapeutic targets for Alzheimer disease and Parkinson disease as well as some autoimmune diseases and cancers. These are areas that Eli Lilly will soon begin investigating in their quest to become the first pharma company with a trillion-dollar market cap.
Lilly has two more tongue-twisters in the pipeline called retatrutide and orforglipron, both of which Microsoft Word jaggedly underlines in deep crimson.
In addition to GLP-1 and GIP receptors, retatrutide activates receptors for glucagon, a non-incretin hormone that promotes satiety and energy expenditure. Phase 2 trial data suggest retatrutide is more effective at promoting weight loss compared to placebo than Mounjaro. Additional evidence for retatrutide is expected later this year.
Orforglipron—apparently not a Scandinavian fishing village—is a novel oral GLP-1 receptor agonist (i.e., it’s an Ozempic pill). Initial results show orforglipron has similar efficacy in weight loss compared to injectable IMs, with further data anticipated for release in late 2025.
Orforglipron would be only the second incretin mimetic pill on the market behind Rybelsus, an oral, albeit less effective, form of semaglutide. All other options are administered via injection. Excluding cost, some work finds that the need for a daily or weekly poke is the top reason for discontinuing incretin mimetic therapy, followed in short order by GI side effects like nausea, vomiting, and diarrhea.
These side effects tend to decrease with time and gradual dose escalation, but nearly 50% of all patients nonetheless experience nausea when initiating an incretin mimetic.
Then come the aesthetic issues. Ozempic face made waves after patients expressed concern that losing facial fat aged their skin practically overnight. To regain the veneer of youth, some turned to another type of injection: dermal fillers.
Other patients prescribed IMs for reasons other than weight management might not actually want to be lighter (an issue raised by some of my patients), or their romantic partners may take issue.
Clinicians, on the other hand, are likely most concerned with the loss of fat-free mass (FFM) in patients on incretin mimetics. FFM includes skeletal muscle, bone density, and organ mass.
One’s goal in losing weight is virtually always to lose fat, mainly around the waistline and thighs. Rarely, if ever, is the aim to decrease muscle mass. (And certainly no one thinks of shedding pounds by reducing the density of bones or major organs.)
Unfortunately, this is not how our physiology works.
Weight loss fundamentally occurs through an energy deficit—the total energy used by the body is greater than total energy intake. Energy deficits can be achieved through increasing total energy expenditure (i.e., burning more calories), decreasing energy intake (i.e., eating fewer calories), or a combination of both.
Incretin mimetics largely work by decreasing energy intake. In the stomach, incretins slow emptying into the small intestine, promoting the feeling of fullness, or “satiety,” from fewer calories. Activating incretin receptors in certain brain regions also helps to strengthen satiation and may help to curb compulsive food consumption by dampening reward pathways, which may explain the observed effects on substance use.
Emerging data suggest incretins may also increase energy expenditure by metabolizing brown fat, which is broken down to produce heat and increase body temperature. (When we think of “fat,” we usually picture white adipose tissue, which stores excess calories as triglycerides that are metabolized during energy deficits.) The jury’s still out on whether incretin mimetics consistently produce this effect.
By reducing caloric intake, incretin mimetics reliably produce an energy deficit.
To meet basic metabolic needs during an energy deficit, the body liberates stored energy. Fat cells are among the first to answer the call, but tragically fat-free mass quickly follows suit.
Over 72 weeks of treatment with incretin mimetics, patients with obesity may lose more than 10% of their overall skeletal muscle, roughly equivalent to twenty years of muscle loss related to aging.
Diminished skeletal muscle mass may in turn limit physical function and activity while reductions in organ mass are likely to slow resting metabolism. Together, these changes contribute to lower rates of energy expenditure, which may eventually match energy intake without further intervention. In other words, after a certain point continued weight loss will not be observed.
Indeed, the longest study of semaglutide to date, the SELECT trial, found that weight loss plateaued around week 65 of treatment. Importantly, this weight loss was maintained through the conclusion of the study at week 208 (four years). While these durable effects are striking, another concern lingers—what happens if these patients stop using an incretin mimetic?
Another study, the STEP 1 trial, found that patients may regain as much as 66% of their weight loss in the first year after discontinuing semaglutide.
To be sure, these phenomena are not unique to IMs. Whether through medication or diet and exercise, about 25% of observable weight loss tends to come from FFM in the form of intracellular fluid, glycogen, and protein shed from muscles and organs.
When lost weight is regained (a very common phenomenon), the pounds come back almost exclusively as adipose tissue.
There are a few key strategies that might help to preserve fat-free mass during an energy deficit:
Regular resistance training paired with daily protein intake between 1.2-1.5g/kg of body weight (source).
Other work suggests protein intake as high as 2.4g/kg of body weight might be even more effective at preserving FFM.
Limiting daily energy deficits to 500 calories
Limiting weekly weight loss to about 1.4% of body weight
Not one to fall behind, Big Pharma is concocting its own solutions. Combining amylin, another non-incretin hormone that promotes satiety, with semaglutide may help to preserve muscle mass during weight loss, for instance. Other firms are working on compounds that mimic testosterone and other androgens to maintain skeletal muscle while using an incretin mimetic.
By the early 2030s, the use of injections or pills to facilitate weight loss might even be deemed antiquated.
Focused ultrasound stimulation in certain brain regions and peripheral nerves near the liver are the newest frontier in weight management. Patients undergoing vagal nerve stimulation for treatment of epilepsy and depression, for instance, incidentally had significant weight loss, although these results are inconsistent.
More effective options would certainly be welcomed, as incretin mimetics are a non-starter for some patients.
A history of gallbladder disease or thyroid cancer is almost always a contraindication for their use, given the rare risk of pancreatitis and thyroid cancer, respectively. Some work also suggests that these medications could worsen diabetic retinopathy, which could stem from the rapid correction in hyperglycemia achieved by IMs.
Although a certain newly-installed Secretary of Health and Human Services has bloviated against the pharmaceutical industry, incretin mimetics are firmly here to stay.
Each passing month may carry new, high-quality evidence for their use. Given the mounting list of indications, adverts for Ozempic could soon carry a jingle reminiscent of Pepto Bismol. Instead of “nausea, heartburn, indigestion,” commercials will chant “snoring, weight loss, diabetes …”
Another very interesting and informative article -bringing me added and needed clarity to the complex GLP/weight-loss subject matter
The added humor made details more palatable & understandable