Ozempic, and drugs like it,  are powerful, versatile, and have made a huge difference  in some people’s lives.

Semaglutide, the active ingredient in Ozempic, is FDA-approved for managing type 2 diabetes, chronic kidney disease, and yes, weight loss. That last one is by far the biggest,  leading to massive commercial success and celebrity endorsements everywhere you look.

And thanks to that popularity, dozens of drugs are in the pipeline looking to capitalize  on or even improve that formula. So let’s take a look at how  they work in order to understand what the science says about the  potential sequels to Ozempic. Could they be new and improved,  or an unwelcome remake? [♪ INTRO] Now, we don’t necessarily endorse  weight loss for its own sake.

You should talk to your doctor about it as  part of your personal overall health goals. Our social stigmas on weight  aren’t something a drug can fix, that’s something the human  condition needs to work on. What we can’t deny though is  that these are some seriously powerful drugs that are the  result of some serious science.

Ozempic first earned FDA approval back in 2017 to help manage type 2 diabetes  and related complications. The primary problem in type  2 diabetes is hyperglycemia, which is when your blood  sugar levels are too high. Usually when your blood sugar creeps up too high, your pancreas makes insulin which  tells your cells to gobble up some of the glucose in your blood,  bringing it back down to normal levels.

In type 2 diabetes, or T2D for short, the  pancreas either can’t make enough insulin, or your cells don’t do what they're  told when the insulin is there, which leaves the glucose in your bloodstream. Managing blood sugar levels  is super important in T2D, especially since hyperglycemia is  linked to heart disease and stroke. Which is where Ozempic comes in.

You’ve probably heard the term GLP-1  thrown around a lot in the media when it comes to Ozempic. GLP-1 stands for glucagon-like peptide 1, and it’s a naturally  occurring hormone in the body. Most of it is made by cells in your  intestines in response to a meal.

Then its big job is traveling to the  pancreas and binding to GLP-1 receptors, which tell the pancreas to release insulin, which then helps the cells  in your body pull the sugar from your blood and lower your blood sugar. Semaglutide, the active ingredient in  Ozempic, is a GLP-1 receptor agonist, or GLP-1 RA, meaning it's a mimic that  binds to the same receptor as GLP-1 and activates it to do all the same things. The receptor basically says “eh, close enough” and proceed with releasing  insulin from the pancreas.

So that’s why semaglutide works  great for Type 2 Diabetes, and by extension helps  reduce cardiovascular events. But recently its claim to  fame is as a weight loss drug, because those little receptors  aren’t exclusive to the pancreas. Back in your gut, activated  receptors can slow stomach emptying, which means you feel full for longer, and  you’re less likely to snack if you feel full.

You also have GLP-1 receptors in your brain, and researchers think that  semaglutide interacting with those can dampen the sensation of  hunger and reduce food cravings. Technically, for weight loss, semaglutide swaps its marketing name tag from Ozempic to Wegovy. Same stuff, just under a different  label with different dosing.

Semaglutide isn’t the only GLP-1 RA on the market that can help with weight loss though. There’s a bunch of them, mostly with long  unpronounceable names ending in -tide. One of the newest is orforglipron, which  was approved as recently as April 2026.

By the way, who comes up with these names?! I feel like they’re watching this video  now just waiting for me to trip up. Which I’m not going to.

I  practiced! Orforglip- AHHH. They’re all different formulations,  and that last one’s actually a pill instead of an injection, but they all  can bind to those GLP-1 receptors.

But GLP-1 RA’s aren't the only forms  these weight loss drugs can take. Zepbound, with its active ingredient tirzepatide, is both a GLP-1 RA and a GIP RA. Since a GLP RA was a mimic of GLP-1,  that makes GIP RAs a mimic of GIP.

But what’s this new acronym GIP? Well, it’s a different hormone  that stimulates insulin release in response to meals and helps to  manage hunger cues in the brain. So tirzepatide is a one-two punch  against hyperglycemia and cravings, activating both GLP and GIP receptors.

Right now, it’s the only  FDA-approved dual receptor agonist, but many drug companies  are looking to change that. So let’s talk weight loss drugs  currently in clinical trials. One such drug is called CagriSema.

It’s half semaglutide – the active ingredient  in Ozempic – and half cagrilintide. Since weight loss drugs are all about  pretending to be human hormones, this one mimics the hormone amylin, which can slow stomach emptying  and help people feel satiated. That means CagriSema uses the original GLP-1 path and this other amylin pathway  to help someone lose weight.

In clinical trials, this combo had strong results, with the duo drug working better than  either semaglutide or cagrilintide alone. Patients taking CagriSema dropped an  average of 20% of their body weight, whereas semaglutide was around 15%  and cagrilintide was around 11%. And a follow up trial was able to  replicate this weight loss success in patients with Type 2 Diabetes.

Plus the drug showed significant  reductions in hemoglobin A1c levels, a key indicator of blood sugar  levels over the last few months. The last of the phase 3 trials  are estimated to end in late 2026, and the drug company has  already applied for approval. But why inject two individual  drugs when biochemists can smash them together into one?

Enter amycretin, a peptide designed to bind to both GLP-1 and amylin receptors. It does the same thing as  CagriSema, but as a single molecule, so it’s a little more convenient. And unsurprisingly, people still  lost a significant amount of weight, with some dropping up to 24%  of their baseline body weight.

That drug began phase III clinical trials in 2026, both as an obesity drug and as another  option for controlling Type 2 Diabetes, because a phase II trial  showed almost 90% of patients reached acceptable A1c levels. It’s likely that some version of  this semaglutide and amylin hybrid will be approved in the next few years. And there are other two-target  combos being worked on too.

There’s even some three-target  drugs in development. For example, retatrutide. This drug is able to bind GLP-1 and GIP receptors, similar to tirzepatide aka Zepbound, but  then it also can bind glucagon receptors.

Glucagon is a hormone in the body  that kind of counteracts insulin. Where insulin works to get sugar out  of the bloodstream and into storage, glucagon works to pull glucose out of  the storage and into the bloodstream. So while insulin helps prevent hyperglycemia, glucagon helps prevent hypoglycemia.

Kind of sounds like the opposite of  what a weight loss drug should do, but the physiology behind these  hormones is rarely that straightforward. In addition to increasing blood sugar,  glucagon increases insulin secretion, which is something that should help  counteract that increased blood sugar. Studies also suggest that  glucagon decreases appetite and slows stomach emptying, with  some researchers hypothesizing that this happens due to cross-reactivity  with GLP-1 receptors.

So there is evidence that it  could help with weight loss and blood sugar management. But retatrutide doesn’t just  bind those three receptors as if it were the natural hormones. It binds the GIP receptor way  stronger than the natural stuff, while the GLP-1 and glucagon  receptors get weaker binding.

So in addition to doing the job  of three different hormones, it also customizes how much  each receptor is stimulated, something the natural stuff just can’t do. And stronger isn’t always better,  especially in pharmacology. Being able to dial in stronger and  weaker binding to different receptors can have a big impact on drug efficacy and safety.

So far the balance this drug  strikes seems to work pretty well. Early, phase I trials showed that it was safe, and could help decrease weight and A1c levels. At the highest dose in phase II trials, participants saw an average of a 24%  decrease in body weight after a year of use.

And while it will still be several  years before all of the phase 3 trials for the drug wrap up, some of the  published results already report almost 30% body weight losses and significant  improvements in A1c levels. Plus this drug is being  investigated for other uses too, like reducing cardiovascular events  and managing chronic kidney disease. So it’s not just the massive weight loss market that these drug developers are trying to court.

But one problem with pretty much all  of these drugs is the side effects, which pretty consistently include nausea  or some other type of stomach upset. And although some versions like tirzepatide  try to minimize those side effects, the only real way to deal  with them has been starting with low doses and slowly increasing. Plus, stomach upset isn’t the  only risk with these drugs.

Other, more severe side effects that  can come up include kidney damage, pancreatitis, and thyroid cancer. Other problems are being worked out too. One phase II clinical trial combined  semaglutide and a drug called bimagrumab in an attempt to focus body weight loss  on fat while preserving muscle weight.

That combination was successful in  making large reductions in body weight. And adding bimagrumab to semaglutide resulted in about 20% less muscle loss than semaglutide alone. But all of these drugs are  kind of variations on the same glucagon and glucagon-like pathways.

Which is fine. They’re definitely  the most trendy targets right now, but they aren’t the only ones. A different option is the cannabinoid receptor.

You might be familiar with  the term “the munchies”, which describes the increase  in cravings and appetite associated with cannabis use. Both consumers of cannabis and  scientists agree that there is a strong relationship between  cannabinoid receptors and hunger. And because of that relationship, those receptors are an attractive target  for controlling hunger and losing weight.

Progress on drugs targeting  this receptor has been slow, partially because regulatory  bodies generally frown upon a weight loss drug whose  side effect is “gets you high”. Okay, that’s not the literal problem, but messing with your reward  pathway seems problematic. So it took drug makers some time to  figure out how to utilize this receptor for weight loss without inducing a  high or affecting your reward pathways.

Those kinds of drugs are  in the super early stages, but they all aim to inhibit the  receptors and suppress hunger. Only one such drug, called Monlunabant, has completed two phase II clinical trials so far. But it isn’t super promising  because at the highest dosage, over 90% of participants saw adverse  effects, including psychiatric side effects.

Although it’s worth noting that  a weirdly high amount of people in the placebo group saw adverse effects as well. Still, in the high dose scenario,  over 40% of participants withdrew because of the side effects. Which means a cannabinoid receptor-based approach to weight loss might still be a ways off.

These drugs aren’t the sequel to Ozempic,  but maybe they’ll make the threequel. Neuropeptide Y-2 receptor agonists are  also being investigated for weight loss, though they are similarly early and troubled. That’s another receptor involved  in appetite suppression.

One phase I clinical trial was hoping  to alleviate some of the GI issues by using a neuropeptide Y-2  receptor agonist with a GLP-1, and while it found some additive effects for  weight loss, the GI issues still persisted. Another study in mice found that  the drug could enhance the efficacy of a dual glucagon and GLP-1 receptor agonist, but didn’t induce significant  weight loss when taken alone. These studies are only from the last few years, so it may just be that drug companies need more time to tweak it before it’s  successful in clinical trials.

In fact a lot of these drugs,  whether GLP-1 based or not, need more research before they can  reach these Ozempic levels of fame. There is a lot of active research going  on behind all the headlines you hear. But one thing is clear.

Drug companies and patients alike have a real appetite for some kind of sequel to Ozempic. [♪ OUTRO]