opinions on combined therapy, glp + metformin?

[Cluni0n]

Hi everyone, I’m currently talking with my doctor to decide which medication would be best for me. I’m significantly overweight (224lbs, 5'4F) and have hiigh HOMA score (7.9), but my fasting glucose, A1C, cholesterol, no fatty liver and other test results are all within normal ranges (perks of having tons of muscle mass tho). I’ve been reading a bit about combined therapy, and it seems to yield good results: you don’t lose as much muscle mass, taking less metformin means fewer side effects, low ozempic doses, and it targets different mechanisms in terms of hormones. I actually found it very interesting, so I’d like to know if anyone has tried this method before, if you could share your experience it would be great, thanks!

 

[Calm Logic]

I take Jardiance from India with my GLPs sometimes. No issues with hypoglycemia. (I cycle Jardiance because I get tired of peeing more. So I wait to take it when I am on a GH peptide as well, to help prevent fluid retention on GH peptides.)

 

[Habibibi]

Hi everyone, I’m currently talking with my doctor to decide which medication would be best for me. I’m significantly overweight (224lbs, 5'4F) and have hiigh HOMA score (7.9), but my fasting glucose, A1C, cholesterol, no fatty liver and other test results are all within normal ranges (perks of having tons of muscle mass tho). I’ve been reading a bit about combined therapy, and it seems to yield good results: you don’t lose as much muscle mass, taking less metformin means fewer side effects, low ozempic doses, and it targets different mechanisms in terms of hormones. I actually found it very interesting, so I’d like to know if anyone has tried this method before, if you could share your experience it would be great, thanks!

Metformin will lower glucose and A1C, but it usually doesn't do much for weight loss. Some people report stomach issues on metformin, but they will be generally less severe than semaglutide.

Frankly, if your goal is to lose weight, semaglutide or tirzepatide alone are superior. You would only use metformin for glucose control, but it looks like you don't need that.

Muscle mass loss on GLP1 is overblown, assuming you have decent nutrition (read: protein) and do some physical activity. Keep in mind that apparent muscle mass reductions are due in part to less fat accumulating in the muscle, and thus the muscle losing some volume. This was verified by measuring by CT. In studies, a big portion of lean mass loss actually comes from liver mass and other internal organs, which shrink as systemic inflammation and fat storage.

 

[Calm Logic]

Yeah, metformin was essentially just an exercise in diarrhea for me, when I took it for prediabetes before taking GLPs. On its own, minimal weight loss, if any, with metformin. So would be better for maintaining weight than losing weight.

Switching from Ozempic to Zepbound (or grey tirz) would be far more effective than adding metformin for weight loss and health markers.

 

[Smiter]

but my fasting glucose, A1C, cholesterol, no fatty liver and other test results are all within normal ranges (perks of having tons of muscle mass tho)

As an ex-diabetic I have used both, and if you really want to use metformin, only use it as a senolytic. But in your case, metformin might be useful for the anti-gluconeogenesis effect. I'm using it myself every 3 days to enhance glycogen replenishment in muscles.

 

[tubby]

Metformin can help with weight loss on its own. It's not normally prescribed specifically for that purpose and results will vary, but it's incorrect to to say that it's not associated with weight loss. If you're considering both, it couldn't hurt to have your doctor write you a prescription for both.

If you do choose to do both, I would not recommend starting both at the same time, as GI side effects are very common with both and you may not want your first week of treatment with maximum side effects. I'd think it would make more sense to start one and stabilize before starting the other. Even if you're not sure you'll take it, metformin is an old generic that's dirt cheap so there's no harm in getting a prescription and having it filled simply so you have the option to start taking it if you choose to later (vs having to hit up your doctor again). That would give you plenty of time to ease into a GLP and do further reading up on metformin rather than feeling under the gun as you may right now.

I personally discontinued metformin when I started a GLP (despite minimal side effects with metformin) and from what you've said, I'm not sure there's a strong reason for you to include it with the GLP. That will be especially true if you experience any significant GI side effects from metformin.

 

[Calm Logic]

2.1 percent weight loss with metformin after 2+ years :

Long-term Weight Loss with Metformin or Lifestyle Intervention in the Diabetes Prevention Program Outcomes Study

A recent systematic review and meta-analysis reported an average weight loss of 1.1 kg with metformin used for varying periods (18). In the DPP/DPPOS, the metformin group had an average weight loss of 2.1% after 2 years, and remarkably, the group maintained ~2% weight loss for the next 10 years (19). Taken together, it appears that long-term metformin treatment is associated with an average ~1–2% weight loss when assessed among all of those given the drug.

Medication Mechanism Average Weight Loss (%) Trial Duration Metformin Biguanide ~2.1% ~3 years Jardiance SGLT2 Inhibitor ~3.0% ~3.1 years (median) Semaglutide GLP-1 RA ~14.9% 68 weeks (~1.3 years) Tirzepatide GLP-1/GIP RA ~20.9% 72 weeks (~1.4 years) Retatrutide Triple Agonist ~24.2% 48 weeks (~11 months)

 

[Turbo-Farmer]

The side effects of metformin were to much for me. It gave me muscle cramps that made my daily runs uncomfortable. I have a couple years worth from my prior struggle with high blood sugar.

There is recent research on metformin negating some of the benefits of aerobic exercise for diabetics.

https://share.google/ZXsfaOQYOm1iwwuNu

 

[woundcarping]

2.1 percent weight loss with metformin after 2+ years :

Checking your browser - reCAPTCHA

Is that 2.1% placebo adjusted?

 

[Calm Logic]

Is that 2.1% placebo adjusted?

Technically no, but placebo group had less than 0.1% weight loss [PubMed: 22442396]:

After 2 years, weight loss was 2.1 ± 5.7% in the metformin group compared with 0.02 ± 5.5% ( P

 

[WLBLD]

A Dr a saw was a big fan of Glps he said take the Glp then use metformin to maintain.

I have tried it previously & did not lose weight on it, but it did help me sleep very well & helped with pain

 

[mybodyisasewer]

A lot of things here I've never heard - metformin being muscle sparing on a deficit, didn't know about stomach issues or diarrhea, or using it as a senolytic. Also never heard of jardiance, but on first glance seems interesting, it makes you pee out sugar? So it looks like I have a bunch of rabbit holes to go down.

Personally I just used metformin years ago to control my blood sugar when I was fatter and started HGH. It worked well I guess, I can only assume it helped keep my blood sugar normal, and I had no noticeable side effects. I don't need it anymore, especially when I'm taking reta, combining these two would lower blood sugar a lot.

According to the bro science, you should try it. Metformin is cheap, safe, and as far as I knew until now, well tolerated. It's a low risk high reward bet.

 

[Jfrick11]

Hi everyone, I’m currently talking with my doctor to decide which medication would be best for me. I’m significantly overweight (224lbs, 5'4F) and have hiigh HOMA score (7.9), but my fasting glucose, A1C, cholesterol, no fatty liver and other test results are all within normal ranges (perks of having tons of muscle mass tho). I’ve been reading a bit about combined therapy, and it seems to yield good results: you don’t lose as much muscle mass, taking less metformin means fewer side effects, low ozempic doses, and it targets different mechanisms in terms of hormones. I actually found it very interesting, so I’d like to know if anyone has tried this method before, if you could share your experience it would be great, thanks!

A HOMA of 7.9 is actually a pretty significant marker of insulin resistance, even with normal fasting glucose and A1C. A lot of people are missing this piece because they're focused only on whether youre “diabetic” or if metformij a good choice for weight loss.

The reason your doctor is considering something like metformin isn’t necessarily because it’s a powerful weight-loss medication by itself. It’s because it targets the underlying insulin resistance that your labs are showing.

HOMA basically looks at the relationship between your fasting glucose and fasting insulin levels. You can still have normal glucose while your body is producing a LOT of insulin behind the scenes to keep it there. That elevated insulin all thentikenspace can make fat loss harder, increase hunger/cravings for some people, and over time may progress toward prediabetes or metabolic dysfunction.

So when people say, “metformin won’t make you lose weight,” they’re kind of missing the point of why it’s being prescribed in cases like yours. The goal is often improving insulin sensitivity and lowering the amount of insulin your body has to produce.... not just chasing scale loss alone but also so that you CAN lose weight.

And honestly, your doctor’s thought process about combination therapy is not unusual at all anymore. Lower-dose GLP1s combined with metformin can sometimes:

improve insulin sensitivity from multiple angles

help appetite/satiety

allow lower doses and fewer side effect

support mpre metabolic improvement

help preserve lean mass better when paired with adequate protein and resistance training

Also, your point about muscle mass matters more than people realize. Someone with higher muscle mass can absolutely have normal looking glucose and A1C for a long time because muscle helps buffer glucose effectively... Mmwhile insulin resistance is still developing underneath. That’s exactly why fasting insulin and HOMA can be so helpful clinically.

You’re asking smart questions and looking beyond “which drug causes the fastest weight loss,” which is honestly the more important long term conversation with that HOMA.

 

[lessthanhalf]

If tirzepatide is an option available to you as well as semaglutide, I think picking it is a better option than semaglutide. Given you would like to lose a lot of weight, it is simply more effective for weight loss, and typically causes less side effects at the same time. Both of these reduce the odds of developing diabetes dramatically, and one of the reasons for using them in your case is to prevent type 2 diabetes, I believe tirzepatide is also more effective at that than semaglutide.

Metformin also causes a little bit of weight loss, reduces the odds of developing diabetes, but not as much as GLP drugs, and combining it with GLPs is reasonable, but as metformin and GLPs both have high rates of gastrointestinal side effects, do not start them both at the same time.

The main advantage of tirz over sema is more long term weight loss.

 

[Calm Logic]

A HOMA of 7.9 is actually a pretty significant marker of insulin resistance, even with normal fasting glucose and A1C. A lot of people miss that piece because they focus only on whether someone is “diabetic” or not.

The reason your doctor is considering something like metformin isn’t necessarily because it’s a powerful weight-loss medication by itself. It’s because it targets the underlying insulin resistance that your labs are showing.

HOMA basically looks at the relationship between your fasting glucose and fasting insulin levels. You can still have normal glucose while your body is producing a LOT of insulin behind the scenes to keep it there. That elevated insulin all thentikenspace can make fat loss harder, increase hunger/cravings for some people, and over time may progress toward prediabetes or metabolic dysfunction.

So when people say, “metformin won’t make you lose weight,” they’re kind of missing the point of why it’s being prescribed in cases like yours. The goal is often improving insulin sensitivity and lowering the amount of insulin your body has to produce.... not just chasing scale loss alone but also so that you CAN lose weight.

And honestly, your doctor’s thought process about combination therapy is not unusual at all anymore. Lower-dose GLP1s combined with metformin can sometimes:

improve insulin sensitivity from multiple angles

help appetite/satiety

allow lower doses and fewer side effect

support mpre metabolic improvement

help preserve lean mass better when paired with adequate protein and resistance training

Also, your point about muscle mass matters more than people realize. Someone with higher muscle mass can absolutely have normal looking glucose and A1C for a long time because muscle helps buffer glucose effectively... Mmwhile insulin resistance is still developing underneath. That’s exactly why fasting insulin and HOMA can be so helpful clinically.

You’re asking smart questions and looking beyond “which drug causes the fastest weight loss,” which is honestly the more important long term conversation with that HOMA.

https://www.reddit.com/r/InsulinResistance/s/CEVZ5LekEG

"6 months Metformin - weight down but HOMA up?"



So another reason I would focus on Zepbound/tirz more than anything. Or maybe grey reta.

I don’t know what my fasting insulin was when I started, but my A1c went from 6.1 to 5.3 in a year, mostly from tirz by itself. Fasting insulin is normal/great now.

 

[Jfrick11]

https://www.reddit.com/r/InsulinResistance/s/CEVZ5LekEG

View attachment 23112

I’d be careful applying someone else’s experience directly to the OP here. This commenter is an entirely different person with a different metabolic profile, different labs, different symptoms, different body composition, and a different medical history.

The OP’s doc is making recommendations based on their actual clinical picture and there’s science behind that approach. A random Reddit anecdote isn’t really enough information to say what the OP should or shouldn’t do.

Also, not every elevated HOMA situation automatically means ‘just use tirzepatide instead.’ Medicine is a little more nuanced than that.

I’d be careful applying one person’s Reddit experience directly to the OP here. They’re completely different individuals with different metabolic profiles, labs, symptoms, body composition, medical histories, and treatment goals.

The OP’s doc is making recommendations based on their specific clinical picture, and there’s actual evidence behind that approach. A single anecdote from someone else online really isn’t enough to conclude what will or won’t work for the OP.

Side effects are also highly individual. Some people tolerate metformin perfectly, others do better with extended release, slower titration, dose adjustments, or simply giving their body time to adapt. And yes, for some people it ultimately isn’t the right medication.... that’s valid too. But deciding it will definitely be awful or useless before even trying it feels unnecessarily defeatist.

And not every elevated HOMA case automatically means ‘skip everything and go straight to tirzepatide.’ Medicine is more nuanced than reducing every metabolic issue to one medication.

 

[Calm Logic]

Why is the doc recommending semaglutide instead of tirzepatide? Is it insurance, availability, or something else? Tirz also has less incidence of nausea/vomiting.

Or did the OP (@Cluni0n) simply use Ozempic as an example? The OP has reta on the way, anyway:

[archived internal link]

So to be more specific, perhaps we need to compare reta + metformin vs. reta alone for things like HOMA:


And perhaps the OP needs to be more honest with their doctor about any future reta use, if wanting the best results for her specific situation. Given that reta is considered more effective than Ozempic/sema for insulin resistance, the need for adding metformin may be less.

 

[Gt3294a]

A lot of things here I've never heard - metformin being muscle sparing on a deficit, didn't know about stomach issues or diarrhea, or using it as a senolytic. Also never heard of jardiance, but on first glance seems interesting, it makes you pee out sugar? So it looks like I have a bunch of rabbit holes to go down.

Personally I just used metformin years ago to control my blood sugar when I was fatter and started HGH. It worked well I guess, I can only assume it helped keep my blood sugar normal, and I had no noticeable side effects. I don't need it anymore, especially when I'm taking reta, combining these two would lower blood sugar a lot.

According to the bro science, you should try it. Metformin is cheap, safe, and as far as I knew until now, well tolerated. It's a low risk high reward bet.

Metaformin has a lot of side benefits, too. A lot of people that took with HGH just continue to take it. Particularly anybody that might have had high blood pressure. Lots of data on it.

 

[Cluni0n]

Why is the doc recommending semaglutide instead of tirzepatide? Is it insurance, availability, or something else? Tirz also has less incidence of nausea/vomiting.

Or did the OP ( @Cluni0n ) simply use Ozempic as an example? The OP has reta on the way, anyway:

[archived internal link]

So to be more specific, perhaps we need to compare reta + metformin vs. reta alone for things like HOMA:

And perhaps the OP needs to be more honest with their doctor about any future reta use, if wanting the best results for her specific situation. Given that reta is considered more effective than Ozempic/sema for insulin resistance, the need for adding metformin may be less.

OP here, I have 2 options, ordering some grey Reta, oooor metformin+ozempic, I still haven't bought reta bc i wanted to receive all my lab results+abdominal ultrasound first, and also bc I'm waiting for the EU restock to decide lol, so yes just doing as much research as I can to see what would work best in my case , I started reading more about this combined therapy a few days ago so that's why I posted this thread.

OG tirz isn't an option, totally out of my budget, grey tirz could be an option yes, but in that case i think i'd prefer reta.

Hope it's clearer now!

 

[Habibibi]

Choose the option that allows you to both lower A1c, fasting insulin, and lose weight.