Orforglipron: The next big thing?

[druell235]

Have any of the studies covered how Orforglipron interacts with metformin. I am still on metformin and don't want to quit when I start researching this.

 

[Calm Logic]

I doubt there are such studies yet, but it should be fine.

Obesity specialists have been adding metformin occasionally for some people already on a GLP, like when someone on sema or tirz wants a boost but can't raise the dose yet due to the dosing schedule.

 

[Calm Logic]

By the way, brand-name Jardiance is available from India.

Personally, I don't see the need for having Jardiance or metformin along with a GLP, since a GLP is much stronger. (My internist wanted me to increase the dose for tirz even weekly, if necessary.)

OTOH, metformin increases the body's natural production of GLP-1. So it may be good while on a strict dosing schedule. Like people tend to feel hungrier on day five of a weekly dose of tirz.

 

[byefatlicia]

By the way, brand-name Jardiance is available from India. But I personally don't see the need for having Jardiance or metformin along with a GLP, since a GLP is much stronger.

Have you seen anything on skyrizy?

 

[Calm Logic]

Have you seen anything on skyrizy?

Not really. The one reputuble-looking seller on IndiaMart sells it for over $1,000 USD, which is still cheap compared to the price at GoodRx. And according to Google Gemini, it is still under a patent in India.

 

[byefatlicia]

Not really. The one reputuble-looking seller on IndiaMart sells it for over $1,000.

Okay thanks🙂 the brand name goes for 19k :0

 

[Calm Logic]

Yeah, I just noticed that and included the link to GoodRx. Insane.

 

[Calm Logic]

Have any of the studies covered how Orforglipron interacts with metformin. I am still on metformin and don't want to quit when I start researching this.

From an article on polypharmacy:

Why Do GLP-1 Drugs Stop Working, and What to Do About It?

Everybody has a set point, and every weight loss intervention eventually leads to a plateau, so it helps to have a variety of tools to support patients.

www.medscape.com

"You don't see this in the studies, which are focused on just one drug, but many of our patients are on combination therapy. They're on a GLP-1 drug plus phentermine/topiramate plus metformin, and more. They're usually on three, four, five drugs, similar to what we would see with resistant hypertension."

 

[Calm Logic]

Source

 

[Habibibi]

View attachment 11105

Source

This is only true if 10% weight loss is considered "considerable " efficacy, I guess

 

[Calm Logic]

Yes, to get good efficacy, one would ideally switch from orfo to tirz (or reta) at some point. At 12 weeks, orfo is almost similar to tirz in effect. As time goes on, the average differences become painfully obvious, according to the studies. This is similar in idea to switching from sema to tirz.

 

[druell235]

From an article on polypharmacy:

Why Do GLP-1 Drugs Stop Working, and What to Do About It?

Everybody has a set point, and every weight loss intervention eventually leads to a plateau, so it helps to have a variety of tools to support patients.

www.medscape.com

"You don't see this in the studies, which are focused on just one drug, but many of our patients are on combination therapy. They're on a GLP-1 drug plus phentermine/topiramate plus metformin, and more. They're usually on three, four, five drugs, similar to what we would see with resistant hypertension."

Thank you for sharing!!

 

[Calm Logic]

Gemini puts orfo in the same category as sema for effectiveness:

FINAL RANKING OF MEDICATIONS BY WEIGHT LOSS EFFECT (Highest to Lowest)

Rank	Medication(s)	Effectiveness Profile	Typical Weight Loss (1 Year)
1.	Setmelanotide (Imcivree)	Very High (Specific Genetic Use)	12.5% - 25.6% (Only for specific rare genetic conditions)
2.	Retatrutide (Investigational)	Very High / Investigational	17% - 24.2% of initial body weight
3.	Tirzepatide (Zepbound/Mounjaro)	Very High	15% - 22.5% of initial body weight
4.	Semaglutide (Wegovy/Ozempic)	High	10% - 15% of initial body weight
5.	Orforglipron (Investigational)	High (Oral)	9.2% - 12.4% of initial body weight
6.	Phentermine-Topiramate (Qsymia)	High/Moderate	7% - 11% of initial body weight
7.	Liraglutide (Saxenda)	Moderate	~8% of initial body weight
8.	Naltrexone/Bupropion (Contrave)	Moderate	5% - 10% of initial body weight
9.	Phentermine	Moderate (Short-Term Use)	3% - 10% of initial body weight
10.	Metformin & Jardiance (Combination)	Modest	3% - 6% of initial body weight[/b]
11.	Orlistat (Xenical/Alli)	Modest	~3% - 4% greater than diet alone
12.	Metformin	Modest	2% - 5% of initial body weight
13.	Jardiance (Empagliflozin)	Modest	2% - 3% of initial body weight
14.	Low-Dose Naltrexone (LDN)	Minimal/Variable	< 5% (Used alone, off-label)

SUMMARY OF DRUG CLASSES

• Very High Efficacy (Ranks 1-5): Primarily hormone agonists (GLP-1/GIP/Melanocortin system) that target the core biological mechanisms of appetite and metabolism.
  
• Moderate Efficacy (Ranks 6-9): Combination therapies and stimulants that use various mechanisms (appetite suppression, reward pathways) to achieve clinically significant, but generally lower, total weight loss.
  
• Modest Efficacy (Ranks 10-14): Older prescription drugs (Metformin, Jardiance) whose weight loss is a secondary effect, or fat-absorption blockers (Orlistat) and off-label single agents (LDN).

 

[tubby]

A pill form of GLP1 and GIP agonist would be revolutionary. I don’t know if a pill form of glucagon will be possible though, so oral tirzepatide would be the first goal. Oral retatrutide would be the dream.

Not a glucagon receptor agonist, but this drug accomplishes a similar effect, albeit a little more extreme:

JCI Insight - An orally available compound suppresses glucagon hypersecretion and normalizes hyperglycemia in type 1 diabetes

Edit: I don't think anyone should take it. I just mean that your dream could become reality if development on that drug continues.

 

[tubby]

No. Comparing to a control group is required, but it doesn't have to be a placebo control group. It's 100% acceptable, even required, to compare a new treatment to the standard-of-care treatment.

For example, if I were testing a new oral medication for Type 2 DM, I might randomize the participants to receive either the new med or metformin, which would act as the control. It would be unethical to randomize them to a placebo when they have a serious disease with a known effective treatment. This is my argument for GLP-1Ras, too.

It's tempting to ask for this, but it's not generally a good idea across the board.

When it comes to establishing efficacy (how well a drug works), a non-inferiority trial (what you're asking for) is suitable for that.

When it comes to establishing safety, it can be risky to allow for that. Here's a completely fictitious example:

Let's pretend Ozempic had a side effect where it deteriorated vision in 5% of people, while suffering from diabetes also had a 5% rate of vision deterioration. In conducting the original trial in diabetics, that safety signal would have been completely missed, since the people Ozempic saved from diabetes-related vision problems would now experience Ozempic-related vision problems. Perhaps those problems also take a couple years to show up. Approval is granted and nobody knows about that side effect, since just as many people in the control group as the active group had vision problems.

Next Wegovy (same active ingredient) is approved for weight loss (perhaps at a lower dose) based on a shorter trial in obese (but not diabetic people). Since it's a shorter trial length the vision problem isn't detected.

After that Zepbound is trialed (and we'll pretend it has that same side effect, but affects 8% of people). If Lilly ran Zepbound against a placebo then that risk would be discovered. Instead, Zepbound uses Wegovy (at its highest dose) as the control group. The small increase in vision problems isn't statistically significant and Zepbound is approved.

Next up is Retatrutide (let's say vision problems affect 10% of people). That would definitely be caught if the control group received a placebo, but since they receive Zepbound, it isn't noticed there either.

To be clear, I don't think any of these drugs cause vision problems. I'm just explaining why it's easy to miss safety signals in drug trials when the control group isn't receiving a placebo.