Retatrutide vs Wegovy vs Mounjaro

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First, we had Novo Nordisk’s Wegovy, a single receptor agonist called semaglutide, which has shown the potential to help people shed around 15% of their weight.

Then came Eli Lilly’s Mounjaro, a dual receptor agonist called tirzepatide, boasting an impressive weight loss of over 20%.

And now, Eli Lilly has introduced retatrutide, a triple receptor drug that has shown remarkable results, with people losing up to 24% of their weight.

It’s truly remarkable because patients who undergo bariatric surgeries, a much more invasive option for weight loss, typically anticipate around a 30% reduction in weight. So, to have a drug that can produce comparable results without the need for surgery is quite impressive.

However, retatrutide is still in the experimental phase and has not yet reached the market. In fact, it’s so new that I can’t even find out how to pronounce it properly! So, let’s delve into the latest research and examine what we can expect from this promising newcomer, retatrutide.

How Retatrutide works

Retatrutide is a triple agonist drug that targets not one, not two, but three different receptors in our body.

These receptors, known as G-protein coupled receptors (GPCRs), hold significant promise in the field of medicine, with researchers exploring their potential in various conditions like neurologic disorders, type 2 diabetes, and obesity.

GPCRs are particularly intriguing for weight loss and diabetes because they can impact insulin secretion, glucose regulation, digestion speed, and feelings of fullness.

So, what are these three receptors that retatrutide stimulates?

First, we have GLP-1, or Glucagon-like peptide-1. You might have heard about this one before. GLP-1 not only helps increase insulin secretion but also slows down our digestive system, making us eat more slowly.

On the other hand, we have GIP, or Glucose-dependent insulinotropic polypeptide. GIP shares similarities with GLP-1, as it also increases insulin production and slows down digestion.

However, whereas GLP-1 actively slows down the digestive system as a whole, GIP tends to mostly just reduce stomach acid secretions, making it more difficult to digest and break down food.

So although stimulating both GLP-1 and GIP lead to reduced food intake, weight loss, and some gastrointestinal problems like nausea or diarrhea, GLP-1 is probably the larger contributor here.

Additionally, GLP-1 also acts on the brain to increase feelings of fullness, while GIP doesn’t have the same effect.

The Glucagon agonist

Now, here’s where retatrutide stands out from the other drugs. In addition to stimulating GLP-1 and GIP receptors, it also targets the glucagon receptor, also known as the Gcg receptor.

The glucagon receptor works in a unique way compared to the other two. When stimulated, it has a thermogenic effect, essentially revving up our body’s energy burning capacity.

However, it also promotes the breakdown of liver glycogen and increases blood sugar levels. Now, this is where things get tricky, especially for individuals with diabetes, as stimulating the glucagon receptor can raise blood sugar levels, which is counterproductive for weight loss and diabetes.

In the past, experimental drugs that solely targeted the glucagon receptor didn’t yield significant results for diabetes or weight loss, and this was the likely reason why.

But when combined with GLP-1 agonists, stimulating the glucagon receptor became much more effective. The combined effects of retatrutide’s triple receptor stimulation appear to be synergistic, enhancing weight loss outcomes.

So what is likely happening here is that stimulating the glucagon receptor has a thermogenic effect and aids in calorie burning, while the increase in blood sugar levels is counteracted by the insulin increases brought about by stimulating GLP-1 and GIP. It’s like balancing a scale, ensuring the benefits outweigh the drawbacks.

Retatrutide vs Wegovy vs Mounjaro

But let’s go back to comparing Wegovy, Mounjaro and retatrutide. When it comes to weight loss, retatrutide seems to have the upper hand, showing some of the strongest effects among the three. Impressive, right? But what about its impact on diabetes?

Well, initial research indicates that retatrutide can reduce HbA1c, which is a marker of long-term blood sugar control, by up to 2 percent, while Wegovy sits at 1.9 percent. Surprisingly, Mounjaro beats retatrutide, with the ability to reduce HbA1c by well over 2 percent.

Remember how retatrutide stimulates the glucagon receptor, which can increase blood sugar levels? Well, that might be the reason why it’s less effective in managing blood sugar compared to Mounjaro, despite being stronger at managing weight.

Now, let’s talk about side effects. All three drugs are administered as once-a-week injections and have similar profiles in terms of side effects. The most common culprits are gastrointestinal troubles like nausea, diarrhea, and vomiting.

However, while retatrutide is still in early testing and lacks as many studies as the other two drugs, initial evidence suggests that patients taking retatrutide may have a significantly tougher time, with a whopping 37% experiencing gastrointestinal side effects at the highest dose, compared to around just 25% for the other two.

Cardiovascular issues

But that’s not all. Retatrutide, unlike the other two drugs we’ve been discussing, has another concerning side effect, it increases heart rate. This has raised concerns among cardiologists and medical professionals.

While we’re still uncertain about the clinical significance of this effect, it’s worth noting that other substances with thermogenic weight loss properties, like ephedra, also tend to raise heart rate, and some of these thermogenic substances, including ephedra and synephrine, have even been banned by the FDA due to serious cardiovascular side effects.

Additionally, some of the weaker thermogenic substances like caffeine or phentermine, while not banned, still have their own considerations and precautions when it comes to the heart and its use in those with cardiovascular disease.

Considering that retatrutide also has thermogenic effects, which do help contribute to its weight loss strength, we’re left wondering about the cardiovascular risks.

Will they turn out to be negligible in the best-case scenario? Can they be managed by avoiding certain drugs or patients at risk of heart conditions in a less ideal scenario? Or worst-case scenario, will the risks be so significant that the drug needs to be discontinued?

Unfortunately, Eli Lilly, the manufacturer of retatrutide, has a history of medical injury lawsuits. Back in the 1990s, they were sued for allegedly failing to warn about the potential for violent behaviors and suicidal thoughts associated with one of their most popular drugs, Prozac.

By 2000, Eli Lilly had reportedly paid over $50 million to settle more than 30 lawsuits related to Prozac, and that doesn’t even include the undisclosed settlement amounts. That’s not exactly the greatest track record when it comes to drug safety.

Given the immense promise retatrutide holds in the lucrative weight loss drug industry, it wouldn’t be at all surprising if Eli Lilly tries to downplay any potential cardiovascular problems during their upcoming studies.

This raises a legitimate concern: will we get a good understanding of the drug’s cardiovascular effects before it comes out, or will we need to rely on post-marketing surveillance, and let the consumers be guinea pigs?

When is it available?

Regardless, there are a lot of people waiting for retatrutide come out. But it seems we’ll have to wait a bit longer.

Currently, Eli Lilly has only begun Stage 3 trials, with the first set of trials expected to conclude by the end of 2025. So, if everything goes smoothly and there are no unexpected surprises, we might see retatrutide hit the market as early as 2026.

Dr. Brian’s review

So, let’s break it down. The preliminary findings for retatrutide look promising, but I believe it’s important to wait for the results of Phase 3 trials to truly gauge its effectiveness. It appears to be more potent than other drugs in its class when it comes to tackling obesity.

However, when it comes to reducing HbA1c, it doesn’t seem to be significantly better. This leads me to think that the primary focus of this drug will be weight loss, rather than seeking initial approval for diabetes and then extending its use to weight loss like other drugs in its class have done in the past.

Now, let’s talk about the increase in heart rate. This is worrisome, considering what we know about other thermogenic drugs that can raise heart rate as well.

It’s important to note that this trial was funded by Eli Lilly. They have a vested interest in its success, so if there was any way to downplay this issue and not mention it in the study, they probably would’ve done that. But the fact that it is there and being mentioned at all, means that we shouldn’t overlook the potential cardiovascular risks that may be associated with the increased heart rate.

Also, retatrutide is one of the first triple receptor agonist drugs to get this far into testing, making it the first of its kind. Whether it actually will cause heart issues remains to be seen, but to be perfectly honest, I wouldn’t want to be one of the first ones to try it to find out.

Learn more about

• Wegovy vs Mounjaro
• Wegovy vs Danuglipron
• What to Expect With Wegovy
• Comparing other GLP-1 Agonists for Weight Loss
• Other weight loss medications

See also

• 
  Comparing Weight Loss Drugs in 2024
  Ozempic and Mounjaro are highly effective at treating obesity, however there are many other approved and off-label options that also work.
• 
  Bupropion vs Contrave vs Naltrexone
  Contrave is a synergistic combination of buproprion and naltrexone, which can be replicated to some degree using the generics individually.
• 
  New Obesity Drugs in 2024
  New obesity drugs target more than just GLP-1 and do much more than suppress appetite for a more nuanced approach to weight loss.
• 
  Mounjaro: Who Loses the Most Weight?
  White or Asian younger women who use metformin and have lower sugar and lipid levels tend to experience more weight loss with Mounjaro.
• 
  How does Oforglipron compare?
  Orforglipron, Semaglutide, and Danuglipron are oral GLP-1 agonists that are all similar enough that cost may end up being the winning factor.