Interesting Science: New Weightloss Drugs (including an oral option)

[PedroDaGr8]

I've mentioned here previously I take tirzepatide and am down over 100 lbs since Feb 2024. Because of this and because I am a scientist, I follow incretin mimetics (the proper name for drugs commonly called GLP-1s) and other related drugs in this space pretty closely. This is partly for personal reasons (keeping an eye on safety, risks, etc.) but also because this category has the greatest chance of improving the quality of our lives as a whole of any category of drugs since antibiotics. That's not hyperbole if you consider how much of our life is impacted by obesity. Considering some good news was released today, I figured I would throw together a quick post:

Eli Lilly just announced the Phase III results for orforglipron, a once daily oral small-molecule GLP-1 agonist. Long story short: Orforglipron performs on par with Ozempic (injectable semaglutide).

While extremely effective because they bypass the liver, injectables have a number of drawbacks (require refrigeration, resistance to needles, etc.), so oral forms have been a strong area of research. Despite the amount of research in this area, there is only one oral GLP-1 (oral semaglutide, Rybelsus) on the market and it isn't great. The horrible bioavailability of Rybelsus (around 1%) means it works far worse than the injected form of semaglutide (Ozempic) and has been overall disappointing. Additionally, Pfizer just announced they halted their Phase III trial for an oral GLP-1 due to safety issues related to their molecule. There are others in the pipeline but they are further back (mostly Phase I or Phase II).

Being a small molecule that doesn’t require the complex injectors and is easier to synthesize, pricing will likely be more reasonable than current incretin mimetics. In Type 2 Diabetics (a notably weight loss resistant population) orforglipron showed mean weight loss of 6-8% at 40 weeks and reductions in A1c of 1.5% with 65% achieving normal A1c values. More importantly, there was no sign of a plateau in weight loss at 40 weeks implying the total weight loss at the end of the trial will be larger than this. According to some rumors I have heard, this drug will be targeted mainly for post loss maintenance (since once a day drugs are a bit better for this) and for those who either can't take an injectable (lack of adequate refrigeration) or won't take an injectable (fear of needles).

This isn't the only drug in the pipeline that is exciting. Eli Lilly (EL) has two more and Boehringer Ingelheim (BI) has one:

Retatrutide (EL) - An injectable triple-agonist (GLP-1, GIP, and Glucagon) incretin mimetic which, based on preliminary data, is looking to be the most powerful weight loss drug ever made. This isn't an understatement. I have a contact who is a participant in the clinical trial for this drug and the data he shown me is astounding. We are looking at Bariatric Surgery levels of weight less (>30% of body mass) with women achieving higher than men. Not just that, the glucagon activity appears to increase energy output, fully reverse Non-alcoholic Fatty Liver Disease (NAFLD) a disease which currently has zero treatments, improves kidney function, and reduces cholesterol as well as a statin, etc. Even the most treatment resistant individuals are losing heavily on this drug. Some are losing slower than others but Lilly extended the trial because even though they were losing more slowly, they were still losing weight even 68 weeks out without sign of a plateau. It seems like they might be trying to see if they can't beat bariatric surgery for the number of people who reach a healthy body weight. To be clear, it isn't all sunshine and roses though. This drug is so strong there are signs that Lilly is a bit worried that it is TOO strong. They have actually had to drop the dosage for a number of patients because they were still losing in the trial and were at a healthy weight. As a result, Lilly has been investigating how to develop a maintenance plan around the drug. I haven't seen this done for any other weight loss drug because they usually only care that the end point goal gets reached. In this case, due to the strength, it makes some sense to develop the off ramp too. They are also likely planning to restrict recommendations for it to only for people with a starting BMI > 35.

Mazdutide (EL) – A double agonist (GLP-1 and Glucagon) developed as a collab between EL and Innovent (a Chinese biotech). This one was likely EL's hedge against Reta, in case it didn't pan out the way they expected. Turns out, Reta panned out way better. In developed markets, this will be targeted more at NAFLD and other related kidney and liver diseases that can benefit from the glucagon component. In China and some developing markets, it will also be targeted at weight loss. Performance is slightly better than Tirzepatide for weight loss but more like Retatrutide for kidney and liver disease.

Survodutide (BI) - A double agonist (GLP-1 and Glucagon) developed as a collab between BI and Zealand Pharma (a NZ biotech). Due to differing activation levels, this one performs closer to retatrutide on weight loss than Mazdutide but a tad worse on kidney/liver disease. This one will likely be the main competitor to Retatrutide in developed markets.

As an interesting aside, if everything goes to plan and the rumors are true, Lilly has a pretty detailed market segmentation plan to tackle obesity:
Tirzepatide - General weight loss for typical overweight and obese patients.
Retatrutide - Bariatric surgery level weight loss (BMI >35) and for highly treatment-resistant weightloss (like severe T2D).
Mazdutide - NAFLD other liver diseases that can benefit from glucagon.
Orforglipron - Maintenance after weight loss on Tirz/Reta, if staying on Reta/Tirz isn't working, and for those that can’t/won’t take injectables

[uklandrn]

Tirezepatide changed my life. Took me 2.5 years but I lost 112 pounds and have a new lease on life. Can’t say enough about how much I love this medication.


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[PedroDaGr8]

Tirezepatide changed my life. Took me 2.5 years but I lost 112 pounds and have a new lease on life. Can’t say enough about how much I love this medication.


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Same opinion here! I lost this much previously but thoughts about food occupied every waking moment. It just wasn't tenable spending so much mental energy around food. Tirzepatide removed that mental "food noise" which allowed me to focus my energy on making better and healthier choices. I'm excited to see what these next generation ones bring!

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[VirginiaCat]

I was taking the ORal Terzepatide and stopped. I had lost about 10 lbs in 90 days but not the results I was hoping for (I am 6'5" and about 293...got down to 283).

The biggest reason I stopped was the effects on my gut. Really had some issues.

Do you guys think the injectable would have same effect.

I have been looking at this site as a possible source: https://www.ivimhealth.com/

[PedroDaGr8]

I was taking the ORal Terzepatide and stopped. I had lost about 10 lbs in 90 days but not the results I was hoping for (I am 6'5" and about 293...got down to 283).

The biggest reason I stopped was the effects on my gut. Really had some issues.

Do you guys think the injectable would have same effect.

I have been looking at this site as a possible source: https://www.ivimhealth.com/

Heh, we are the same height. I started at 322 lbs and as of yesterday morning am 216 lbs.

Tirzepatide is known for causing some degree of GI discomfort (especially if you overeat or eat high fat/super spicy foods), so it may not be perfectly side effect free. Having said all of that, it should be notably better that oral because it diffuses through your body rather than being sent straight to your gut in a concentrated form. In my case, once I learned to not overeat and go easier when I am having high fat/spicy meals, the GI side effects were basically negligible. At this point, I have had one day where I had GI issues in the past 7-8 months and that was because I ate super fatty KBBQ.

[VirginiaCat]

Heh, we are the same height. I started at 322 lbs and as of yesterday morning am 216 lbs.

That is amazing results!!!!!!!!!!!!!!

I haven't been 216 since just after playing Basketball in college!!!!!!!!!!!!

[CGWildcat]

Ive been on Wegovy well over a year. No real changes at all, aside from my A1C staying in good range. I do need to stop drinking so much.

The VA has now switched me to tirzepatide two weeks ago. Just started it at 5mg weekly.

On the flip side, the VA pharmacy messed up and sent me 3 months worth of wegovy and they wont take it back. Completely unopened boxes, 2.4mg. Is there a black market for that stuff?

[PedroDaGr8]

That is amazing results!!!!!!!!!!!!!!

I haven't been 216 since just after playing Basketball in college!!!!!!!!!!!!

I got down to roughly this weight around 8 years ago. It wasn't sustainable though because I was basically white knuckling my diet. So much mental energy was spent around food, what I could eat to feel full the longest, etc. Tirz has been so much better, it quieted the food noise, so I can make healthier decisions around food not just which will make me the fullest. If you can stomach the needles (no pun intended), I think you will find the injectable form has far better outcomes than oral.

Ive been on Wegovy well over a year. No real changes at all, aside from my A1C staying in good range. I do need to stop drinking so much.

The VA has now switched me to tirzepatide two weeks ago. Just started it at 5mg weekly.

On the flip side, the VA pharmacy messed up and sent me 3 months worth of wegovy and they wont take it back. Completely unopened boxes, 2.4mg. Is there a black market for that stuff?

Yeah, drinking can definitely short-circuit drugs like these a little bit. Especially beer, which has a lot of calories in a pretty small volume. I have cut back my drinking pretty significantly to a couple beers a week.

As for your extra, there likely is but it's going to be as sketchy as you would expect a black market to be.

Good luck on Tirzepatide, its a notably powerful drug when it kicks in. It takes around 4 weeks for the concentration in your blood to reach a steady state level (link to a nice little dose plotter that shows blood concentration):

https://glp1plotter.com/?medication1...ate=2025-04-24

I never tried semaglutide but I know a few people that did and switched to tirzepatide and had way better results on tirzepatide. The activation of that additional GIP receptor really seems to aid in appetite suppression. One thing to note, everyone responds a bit differently. Some people lose heavily at 2.5 mg/week while for others it takes 10 mg/week before they really start seeing results, so be patient. Once you start losing, keep at the same dosage until your weightloss stalls for a month or so. Once that happens, then move up. Some doctors think you have to follow the titer schedule but going to higher doses when you are still losing just increases your risk of side effects.