This past Monday [NOTE: March 18], Oprah Winfrey offered up an hour-long prime-time TV special devoted to “releasing the stigma and the shame and the judgment” around the new generation of weight-loss drugs. She told America she was taking one of those drugs. My judgment? It’s about time. Roughly 10-15% of my patients are taking one of the “incretin” drugs, some for the past two years or so. The results have been nothing less than extraordinary – weight-loss in the neighborhood of 15% of total body weight. Yet, despite that clinical success, some patients do struggle with the shame that Oprah addressed on television. These are people who, as a group, are very health-conscious, they tried their best for years to follow responsible diet and exercise guidelines and yet their hunger remained out of sync with their bodies’ energy requirements. When they lost weight on a stringent diet, they couldn’t keep it off, not surprising given the myriad ways that evolution has wired our bodies and brains to protect against famine and starvation. I tell them they wouldn’t feel guilty taking blood pressure meds; this shouldn’t be so different.
At least part of their ambivalence stems from the mystery that surrounds how these drugs work and why they work so well. Frankly, even the researchers who developed them don’t yet have all the answers. Here’s what we do know:
Drugs like Ozempic/Wegovy and Mounjaro/Zepbound mimic and enhance the effect of a class of human peptide hormones called incretins, which are produced by the body when we break down the food we eat into glucose and which in turn signals the pancreas to produce insulin to escort that glucose out of the blood and into our muscle and organ cells. The Ozempic/Wegovy compound, semaglutide, is an analogue of the incretin GLP-1 (glucagon-like peptide 1) which acts on the body’s GLP-1 receptors. The Mounjaro/Zepbound compound tirzepatide goes one better, boosting the effect of GLP-1 and another hormone, GIP or glucose-dependent insulinotropic polypeptide.
Roughly speaking, these compounds work on three fronts: on the brain to shrink hunger, on the insulin/glucagon response to food to prevent sugar spikes, and on the gut by slowing food transit which, in turn, leads to a sense of fullness and lower glucose levels. This is why they work in people with type 2 diabetes who have a sluggish response to the initial rise in sugar following a meal. In the presence of rising glucose, GLP-1 stimulates the pancreas’ secretion of insulin and inhibits the secretion of glucagon, speeding up the clearance of glucose from the blood and minimizing unnecessary production of glucose from the liver. It’s hard to say the extent to which this mechanism is at play in non-diabetic patients but the GLP-1 effects in the brain and in the gut to shrink hunger and prolong fullness are powerful enough to explain why my non-diabetic patients are so successful in their weight loss journeys.
You might expect a drug that acts on so many different types of cells in the body to raise some serious safety concerns], especially considering the checkered history of weight-loss drugs, many of which were withdrawn from the market after toxic side-effects revealed themselves. Instead, the most significant long-term effects of the incretin drugs, besides appetite suppression and glycemic control, have been stunningly positive. One influential study published in The New England Journal of Medicine showed a 20% reduction in deaths from cardiovascular disease in people without diabetes
https://www.nejm.org/doi/10.1056/NEJMoa2307563, other studies have demonstrated protection against kidney disease, and promising early research is being done on Alzheimer’s Disease. Then there are the effects that have been reported, and are beginning to be studied, that we don’t yet have a good mechanistic explanation for, for instance, people being less drawn to addictive behaviors like excessive drinking, gambling, even watching porn.
Any potent drug comes with side-effects, in the case of the incretin drugs, mostly GI disturbance like nausea, diarrhea and constipation, which usually abate over time. The risk of serious GI disorders, like pancreatitis or bowel obstruction, is small, but real.
(https://jamanetwork.com/journals/jama/fullarticle/2810542#:~:text=Use%20of%20GLP%2D1%20agonists,CI%2C%200.89%2D2.53%5D). I’ve yet to see it in my practice. What I have seen is muscle loss that accompanies weight loss, something that lately has been much discussed in the medical literature. (The general rule of thumb is: one-quarter of the weight lost will be “lean body mass” – muscle, water, bone.) But this occurs with any successful weight loss therapy. You can combat that muscle loss with resistance training and, in men, with testosterone replacement therapy if hormone levels are low.
The other major area of controversy surrounding the incretin drugs concerns how long to stay on them. I do believe motivated patients, especially those who are not prediabetic, may be able to make diet and exercise upgrades that can lessen their dependence on the meds. (The same principle applies for people on statins or blood pressure meds.) But right now, for some of my patients with longstanding weight issues, the drugs have been nothing short of life-changing. As one patient told me recently, “I feel unchained from food.”