How do the new generation of weight loss drugs (Semaglutide, tirzepatide) work and why are they seemingly so effective?

Submitted by harpoonhambone t3_10cbocm in askscience

These drugs are getting a lot of buzz online and in the news, and I've struggled to find good explanations elsewhere online or within this subreddit.

I understand that they work to reduce appetite and slow the digestion of food. But how is it that they do this? And why are these drugs seemingly so much more effective than other appetite suppressants that we've developed in the past? Everything just mentions that they slow the digestion of food and that leads to weight loss, but this feels like an incomplete explanation. Presumably other drugs have been able to suppress appetite, so ultimately my question is if some other mechanism is at play.

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WellQuiet t1_j4flqbj wrote

These medicine are of a class called GLP-1 receptor agonists. They work by mimicking the effect of GLP-1 which is endogenous to the body. Normally enzymes in your body break down and inactivate GLP-1, these drugs however stay in circulation for days.

They were developed for diabetes because they lower blood sugar levels by stimulating the release of insulin when you eat -the main function of your body’s own GLP-1. But they found weight loss at pretty high levels, which is good for people with type 2 diabetes.

The exact weight loss mechanism is unknown, as far as I’m aware, but we do know there are GLP-1 receptors in the brain, and it seems to regulate appetite. People that take these medicine just eat less, they are even reported to enjoy food less.

There are in fact other effective weight loss medicines (amphetamine -like substances) but they suffer from side effects. It’s always complicated with drugs that affect the brain. So far the GLP1 class of drugs seem relatively safe. But unregulated use because people want to lose weight quickly is a bad thing imo.

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grumble11 t1_j5avs0q wrote

By jacking insulin levels do they cause hypoglycaemia or insulin resistance over time?

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catiecat25 t1_j4g038g wrote

GLP1 (and GIP, tirzepatide is different than semaglutide, liraglutide, and other GLP1 agents as it works on both) moderate hunger/satiety. These agents help patients feel full quicker and stay full longer, helping to cut down on portion sizes, snacking, etc.

We’ve had Saxenda approved for years (liraglutide) and recently got Wegovy approved in 2021 (semaglutide), and hopefully will see tirzepatide approved for a weight management indication soon - currently is only approved under a diabetes indication. Wegovy, and tirzepatide for weight loss (see SURMOUNT clinical trials if interested) have demonstrated much greater weight loss than other indicated agents for weight management, approaching the amount of weight loss we see from some types of bariatric surgery.

These agents are a big deal in the management of overweight/obesity due to long term safety- patients stay on these agents for potentially their lifetime in the diabetes indication, and they are safe and continue to be effective. It’s truly a turning point in seeing and treating overweight/obesity as a chronic medical condition- not just a moral failing that quick diet/diet pill schemes can fix in a few weeks. As a provider that manages patients with chronic medical conditions, my patients on this class of medications for weight management are doing incredibly well- but as stated above, it HAS to go along with lifestyle modifications (exercise, dietary modification) and appropriate check ins with the medical team, just like any other chronic medical condition.

As a patient myself, I’ve lost a significant amount of weight with Wegovy over the past year and a half, and it has completely changed my outlook on my health, both physical and mental. I’m the healthiest I have ever been because I’ve been able to get control of the processes in my brain that encouraged me to eat, treat stress with desserts, and I finally feel in control of something I have never felt in control of before.

The issue is several insurance plans (including any government plans - Medicare, Medicaid, etc) do not cover treatment for weight management, as it was seen as ~cosmetic~ when these rules were initially put in place. That’s where the diabetes backorders came from- providers knew these agents would be clinically beneficial in their patients, but couldn’t get the “weight loss “ branded version, so prescribed the diabetes version.

I certainly wish the pharmaceutical companies (looking at you, Novo) would quit advertising Ozempic, Rybelsus, etc here on Reddit, and use that money to lobby Congress (why else are y’all employing Queen Latifah to be a spokesperson) to allow coverage of weight management treatments, now that we have safe and effective ways to manage it as a chronic condition.

Soapbox over.

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sedatedforlife t1_j4gtvbm wrote

It would also be nice if these drugs were cheap enough to buy without insurance. Many people would be willing to pay a couple hundred a month out of pocket to change their lives, but can’t afford the 1200/month + price tag these drugs carry.

I’ve witnessed the miracle these drugs have performed on two coworkers. It’s been an incredible transformation!

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DukeSuperior_Truth t1_j4izbf2 wrote

Fellow physician here. Why does it have to be paired with exercise/certain diet? It doesn’t work on your metabolism without exercise?

That sounds to me like the old stigma is still going strong. Unless you mean the wink-wink kind of lifestyle mod we do for cholesterol or hypertension…it is certainly nice if folks exercise and eat plants, but the drug either works and is safe and we use it to treat a medical condition…or its doesn’t. Patients shouldn’t have to adhere to a certain program to be given necessary medication.

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PsychoticGiggle t1_j4jdokz wrote

It definitely works without lifestyle modification, because it still reduces appetite. But all the research has been done on patients that they also promoted lifestyle modification to. And ultimately if someone stops taking the medication hopefully it has helped with lifestyle changes to reduce the amount of weight regained.

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PandaExpress3d t1_j4gvvyb wrote

Adding on to the mechanism: Insulin has negative feedback on release of ghrelin, which is the hormone responsible for appetite. So GLP-1 agonist causes release if insulin which decreases amount of circulating ghrelin = you aren’t hungry.

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cheaganvegan t1_j4hrudt wrote

Thanks for that. I was trying to explain a negative feedback loop to someone and couldn’t come up with an example. Going to send this one.

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Gmn8piTmn t1_j4jjlwq wrote

Specifically on the stomach the glp-1 receptors on the vagus nerve increase the stretch sensitivity of the stomach which then translates in lower muscle motility and acid secretion.

In the brain it seems to work both directory in indirectly through neuropeptide y and agouti related peptide. NPY is directly implicated with hunger via increase of agouti and also over expression of y is related to emotional (and physical) pain which a lot of people alleviate by over eating

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