Hi Jan - I agree, was always taught to beware lactic acidosis, but from what I’ve read over the past 20 years I think the risk is smaller than initially thought. The earlier biguanides had much more risk I think. Not sure if you get NEJM Journal Watch, but this recent “Informing Practice” review was really interesting for wonks like us. I’ll copy and paste as it might be behind a paywall, and I’m still obscure enough to do so:
How Safe Is Metformin in Stage 4 Chronic Kidney Disease?
David S. Weisman, DO, FACP, reviewing Lambourg EJ et al. Am J Kidney Dis 2025 Feb
Diabetic patients with eGFRs <30 mL/minute/1.73 m2 who continued metformin had lower mortality at 3 years.
Metformin is excreted renally and is contraindicated (according to U.S. prescribing information) in patients with estimated glomerular filtration rates (eGFRs) <30 mL/minute/1.73 m2 to prevent lactic acidosis. However, some evidence suggests that continuing metformin below this eGFR threshold is safe and beneficial. Researchers analyzed a Scottish national database of patients with diabetes to identify those taking metformin whose chronic kidney disease progressed to stage 4 or 5 (eGFR, <30 mL/minute/1.73 m2) and who then either continued metformin for ≥6 months (≈2600 patients) or discontinued it (≈1700 patients). The researchers used a target-trial emulation study design, which can reduce — but not eliminate — residual confounding.
In adjusted analyses, stopping metformin was associated with higher 3-year all-cause mortality (hazard ratio, 1.23); 63% survived among those who stopped metformin, and 70% among continuers. The leading causes of death were cardiovascular events (34%), cancer (17%), and respiratory diseases (10%). The incidence of major adverse cardiovascular events did not differ between groups, but significantly fewer respiratory deaths occurred in metformin continuers. About half of the patients who continued metformin during the study period eventually stopped.
COMMENT
These results are surprising in two ways. First, many physicians continued patients on metformin despite eGFRs <30 mL/minute/1.73 m2; second, the survival benefit was not driven by cardiovascular causes. Another recent study also points to a survival benefit for continuing metformin in these patients (eClinicalMedicine 2024; 71:102568). A compromise might be to continue metformin at lower doses when eGFR fluctuates near 30 mL/minute/1.73 m2 but to discontinue it when eGFR persists below this threshold. These cases should involve shared decision making with patients.
CITATIONS
Lambourg EJ et al. Stopping versus continuing metformin in patients with advanced CKD: A nationwide Scottish target trial emulation study. Am J Kidney Dis 2025 Feb; 85:196.https://doi.org/10.1053/j.ajkd.2024.08.012
Thanks Kathryn! I went back and added a graphic from the study I linked to showing some more information about T cell markers and overall immune system effects. Let me get back to you about more specifics later, too. And regarding COPD, another great question and I’ll do a follow up search on that. Scroll up a little in the comments and check out the study I quote to Jan… there is a little indirect evidence here regarding reduced respiratory illness mortality in patients with kidney problems who continue metformin anyway :
“The incidence of major adverse cardiovascular events did not differ between groups, but significantly fewer respiratory deaths occurred in metformin continuers.”
Thanks Gina. I don’t know about this one either. Since this is a comment field and not a deep dive, I hope you don’t mind if I use Perplexity to give you a framework for answering this in the future:
There is growing clinical and preclinical evidence supporting the use of Akkermansia muciniphila as a probiotic, though its application is still emerging:
• Human Studies: A randomized, double-blind, placebo-controlled pilot study demonstrated that pasteurized A. muciniphila supplementation improved insulin sensitivity, reduced cholesterol, and decreased inflammation in overweight/obese individuals without adverse effects (NCT02637115). The European Food Safety Authority has also approved pasteurized A. muciniphila as a novel food.
• Animal Studies: Numerous studies in mice have shown benefits such as enhanced intestinal barrier function, reduced inflammation, and improved resistance to infections like Salmonella and Listeria monocytogenes.
• Mechanisms: Its effects are linked to modulating immune responses, promoting gut barrier integrity, and influencing metabolic pathways.
While promising, more extensive human trials are needed to confirm its efficacy and safety across broader populations.
I just had an A1C of 7.4, previously slightly less than 7. Have not been exercising since I had a hernia repair in November, 2024, and it is still very painful. My cardiologist just prescribed Jardiance for me. What are the pros/cons of Jardiance vs. Metformin?
Hi Howard and Mary. Hard to exercise after hernia repair for a while, no doubt. Hopefully your surgeon knows how long this is taking though? Cardiologists really like Jardiance lately, but the cardiovascular benefit is mostly seen in people with diabetes who also have known cardiovascular disease already. Here is a long answer for you comparing Jardiance (empagliflozin) and metformin across several key areas.
Efficacy & Outcomes:
Metformin has long been considered the first-line treatment for Type 2 diabetes, with extensive long-term data showing it reduces A1C by about 1-1.5%. The landmark UKPDS trial demonstrated significant reductions in diabetes-related complications and mortality.
Jardiance has shown impressive cardiovascular outcomes data in the EMPA-REG OUTCOME trial, demonstrating a 38% relative risk reduction in cardiovascular death and 35% reduction in heart failure hospitalization. It typically reduces A1C by 0.5-0.8%. It also provides benefits for heart failure patients even without diabetes, as shown in the EMPEROR trials.
Cost:
Metformin is significantly less expensive, typically costing $4-10 per month for generic versions. Jardiance, as a branded medication, usually costs $500-600 per month without insurance coverage.
Side Effects:
Metformin:
GI side effects (diarrhea, nausea, abdominal discomfort) are common initially
Vitamin B12 deficiency with long-term use
Lactic acidosis (very rare but serious)
Generally weight neutral or modest weight loss
Jardiance:
Genital yeast infections
Urinary tract infections
Volume depletion/hypotension
Diabetic ketoacidosis (rare)
Associated with weight loss (can be beneficial for many patients)
Additional Considerations:
Metformin can be used in earlier stages of kidney disease, while Jardiance has restrictions based on eGFR
Jardiance has additional benefits for heart failure and chronic kidney disease
Metformin has decades more safety data
Jardiance can be used alone or in combination with other diabetes medications
The choice between these medications often depends on patient-specific factors including cardiovascular risk, kidney function, cost considerations, and other comorbidities. Many patients may benefit from using both medications as part of a comprehensive treatment plan.
Now getting back to the CV risk reduction question specifically... if you really want to show off (and perhaps even challenge your cardiologist), here is more nuanced detail of the CV risk reduction with Jardiance:
The EMPA-REG OUTCOME trial studied 7,020 patients with Type 2 diabetes who had established cardiovascular disease (prior MI, significant coronary disease, stroke, or symptomatic PAD). The population was predominantly male (71%), with mean age 63 and diabetes duration of 13 years. The trial showed a 38% relative risk reduction in cardiovascular death and 35% reduction in heart failure hospitalization.
EMPEROR-Reduced studied 3,730 patients with heart failure with reduced ejection fraction (≤40%), demonstrating a 25% reduction in the combined primary outcome of cardiovascular death or heart failure hospitalization.
EMPEROR-Preserved enrolled 5,988 patients with preserved ejection fraction (>40%), showing a 21% reduction in the same combined endpoint. Both EMPEROR trials included patients regardless of diabetes status, establishing Jardiance's benefits across the spectrum of heart failure.
These results significantly expanded the proven benefits of Jardiance beyond just diabetic patients with established CV disease, leading to its approval for heart failure treatment regardless of ejection fraction or diabetes status.
So, if I’m reading correctly, the article cited above means that a placebo was 29% effective in preventing progression to T2D but metformin was only 22% and lifestyle changes were 14%? Help me understand.
According to the 2002 study, 29% of patients with pre-diabetes progressed to T2D if they were taking the placebo during the time frame of the study, while only 22% of those taking metformin did so. It appears from this study that lifestyle changes are the most effective preventive measure.
More recent studies suggest that reduction in visceral adipose tissue is a key strategy. For patients with pre-diabetes who don't respond to lifestyle changes, I would combine metformin with continued physical activity and dietary modifications.
FWIW, I concur with prescribing metformin for patients with pre-diabetes who have not seen a reduction in their HbA1c with physical activity and dietary interventions.
Thanks Mick, I appreciate you weighing in with your experience and obvious commitment to keeping up with evidence-based practice. Diet, exercise, and weight loss remain the foundational pillars here, but we have to be realistic, individualistic, and meet people where they are…
“…we have to be realistic, individualistic, and meet people where they are…”
Totally agree! The “generally speaking” question I have is: Should PCPs prescribe metformin before their patients with pre-diabetes have given lifestyle interventions a try, waiting to see if it is successful, or just go ahead and prescribe metformin plus lifestyle modification at the outset?
Because metformin has so many other benefits, I might favor employing both strategies right away, as well as suggesting that they purchase an OTC CGM for lifestyle biofeedback. Your thoughts?
I used to be more proactive with discussing metformin for IFG, but it seems the zeitgeist had been drifting away from that, and the ADA statement is kind of nuanced and iffy. I also used to think metformin helped with weight loss, but this seems doubtful in most patients (in my experience). So I think an individualized discussion with realistic feedback from the patient about how much they can really do differently/better informs this decision than a one-size-fits-all. That being said, with the Covid stuff coming out lately, and the Covid stuff not going away ever, it would lower the bar for me as a patient to take it.
Ryan, I wasn't suggesting a one-size-fits-all, but rather trying to get an overall feel for the current standard of care regarding pre-diabetes. Are the PCPs in your community on board with prescribing metformin for pre-diabetes, and if so, do they want their patients to first make a good-faith effort at lifestyle modification before taking it?
I fail to see any "iffiness" about the ADA's position in this article:
Thanks KB! Once again I struggle with the word counts, and at 2 AM last night I had enough. These are two excellent additional considerations and thanks for adding the links for others to read! The antipsychotic medication weight gain is really pertinent in primary care, too, as most psychiatrists don’t feel comfortable prescribing internal medicine drugs like metformin in my experience.
Dr McCormick , I just gifted my PCP a subscription. Is there a way for her to go back and see your previous articles? I saw that I could go back one week by using the PREVIOUS key. Do you have a list of previous articles and a way to access them? Thanks so much
Thank you for this deep dive on Metformin. I am a 78 year old male who began taking Metformin on the recommendation of my former PCP in 2015. At the time my weight was 205, my A1C was 5.4, and my fasting glucose was ~104. My PCP was a fan of Metformin and as I was close to the pre-diabetic area, he thought it would be a good medication for me. He also believed it had longevity support impacts although he advised me that data was not conclusive.
Fast forward 10 years, my A1C is 4.9, my weight is 185, my fasting glucose is 96. For the last two years my current PCP has been trying to persuade me that it is an unnecessary medication for me. So far she continues to authorize my prescription but views it as “off label” in light of my blood indicators. It was fascinating to me to read the impacts which you documented in this article.
Hi Gary - this is really a fascinating anecdote and thank you for sharing it. It sounds like your prior PCP is going on a well-informed hunch, though the benefits probably accrue in direct proportion to the need for the medication... i.e. larger benefits as hyperglycemia increases. Your stats look great though! As far as I know this statement is key:
"However, there's currently no definitive evidence that metformin extends lifespan in healthy humans. Major clinical trials like TAME and MILES are ongoing to investigate metformin's potential anti-aging effects in non-diabetic populations, which may provide more conclusive answers."
I'll hope to be around to present the TAME study results along with many other interested parties in the future!
Looks like they need more funding? If RFK Jr wants to redirect some of the dwindling federal research dollars towards chronic disease, this would be a good one.
Here is the MILES study result, small number of patients, and not outcome-oriented, but rather biochemical markers:
Thanks Daniel, I really appreciate the specialist level input, and please let me know if you hear anything about this before I do... though I suppose any proven cancer reduction results in the general population will be quite well-reported.
Given the decent quality of the studies in people with diabetes, though not RCTs with primary endpoints of cancer prevention, it does seem like yet another vote of confidence in using metformin first line for DM2
What a remarkable drug! I will confess my favorite thing was to learn—accompanied by a photo of this humble, yet powerful flower, no less—that “Metformin, originally derived from French lilac, has evolved from a medieval remedy to one of modern medicine's most versatile drugs.” Thank you so much.
That might have been the most pithy thing I learned writing this, too! Pretty intuitive and cool that this was apparently used for "diabetes-like symptoms," which reminds us of the diagnostic world of darkness that existed in the world until recently. Thanks for stopping by :)
Okey dokey. Here’s a rebuttal to Metformin use for someone like me whose body can’t tolerate Metformin. I was first put on Metformin sometime around 2000. My metabolism was wonky, gaining then losing weight ad nauseum, and my blood sugar varied from 90-100 with corresponding dips in energy, so my doc at the time thought Metformin might help stabilize me. That started 20+ years of using it for a year or two, then stopping, again ad nauseum, but the results were always the same: I hated it.
I’ll comment on each of Ryan’s observations as they applied to me:
“Beyond diabetes management, metformin shows promising potential across multiple areas:” yeah, no, not for me. I spent every day having hot flashes & every night having night sweats. Ugh.
“Prevention of diabetes in prediabetic patients” I wouldn’t know. I’ve never had prediabetes.
“Reduction of long Covid risk” I’ve never had Covid, so I don’t know.
“Possible anti-cancer properties, particularly in diabetic patients” I had breast cancer with a 7mm tumor that grew for an estimated 7 years & I took Metformin for much of those 7 years. So, no, didn’t work for me.
“Treatment of PCOS” I had PCOS back in the day, but had a radical hysterectomy in 1996, before I took Metformin. Bummer.
“Potential anti-aging effects (though evidence is still mixed)” hahahaha. Um, no, although I am totally a walkin’ machine!
“Promising results in reducing influenza severity and complications” i was on Metformin the last time I had flu, which was back in Dec 2019. Didn’t alleviate symptoms with the exception that it didn’t settle in my chest. So, okay, I’ll agree somewhat. Now I get flu, RSV & Covid vaccines routinely, and wear a mask if I hear anyone wheezy-couching or sneezing in my vicinity. So far, so good, knock on wood.
‘Recent evidence suggesting benefits for asthma patients” I have asthma but I ca’t remember the last time I had to use an inhaler. Another possible positive for Metformin!
“The drug works through multiple mechanisms, including improving insulin sensitivity, modifying gut microbiome, and exhibiting antiviral and anti-inflammatory properties.
Metformin is generally safe, inexpensive, and well-tolerated, though it can cause initial GI side effects that typically improve over time.” My gut was on overtime. Although I tried increasing my dosage every time I retried Metformin, the max dosage I could take was 2 pills daily instead of the 4 that were prescribed. I had near constant diarrhea. Combine that with all the sweating & it was my own personal hell. It did nothing for my inflammation, but I never (knock on wood again) got Covid so it may be because of the Metformin or even the combo masks, Metformin and finally vaccines. 🤷♀️
If Metformin works for you, yay! But for those of you who have adverse reactions to it, keep taking the blood pressure meds & other medications your doc prescribes. And seriously, y’all, research, research, research on the medical websites! Don’t make your doctor take the whole burden of your health on his or her shoulders. You must become an equal partner of sorts in order to thrive.
Hi Kerry - I appreciate the thorough response and individual considerations. People really are unique, and your experience with Gi side effects in particular sounds rough! Some of my patients would totally agree with you, and have been taking other medications instead for diabetes. Always try to avoid medications if possible, but lifestyle changes are challenging for different people for different reasons. Anyway, counterpoints taken, thanks again for sharing! Totally agree with personal health journey collaboration, as cheesy as that may sound.
After reading this, I think I want to go back on metformin!
Happy to collaborate with you soon! Depends on goals, side effects, personal experience, etc. No rush :)
I still remember when there was concern about lactic acidosis--I think metformin is a wonder drug, and thanks to you, I know so much more about it.
Hi Jan - I agree, was always taught to beware lactic acidosis, but from what I’ve read over the past 20 years I think the risk is smaller than initially thought. The earlier biguanides had much more risk I think. Not sure if you get NEJM Journal Watch, but this recent “Informing Practice” review was really interesting for wonks like us. I’ll copy and paste as it might be behind a paywall, and I’m still obscure enough to do so:
How Safe Is Metformin in Stage 4 Chronic Kidney Disease?
David S. Weisman, DO, FACP, reviewing Lambourg EJ et al. Am J Kidney Dis 2025 Feb
Diabetic patients with eGFRs <30 mL/minute/1.73 m2 who continued metformin had lower mortality at 3 years.
Metformin is excreted renally and is contraindicated (according to U.S. prescribing information) in patients with estimated glomerular filtration rates (eGFRs) <30 mL/minute/1.73 m2 to prevent lactic acidosis. However, some evidence suggests that continuing metformin below this eGFR threshold is safe and beneficial. Researchers analyzed a Scottish national database of patients with diabetes to identify those taking metformin whose chronic kidney disease progressed to stage 4 or 5 (eGFR, <30 mL/minute/1.73 m2) and who then either continued metformin for ≥6 months (≈2600 patients) or discontinued it (≈1700 patients). The researchers used a target-trial emulation study design, which can reduce — but not eliminate — residual confounding.
In adjusted analyses, stopping metformin was associated with higher 3-year all-cause mortality (hazard ratio, 1.23); 63% survived among those who stopped metformin, and 70% among continuers. The leading causes of death were cardiovascular events (34%), cancer (17%), and respiratory diseases (10%). The incidence of major adverse cardiovascular events did not differ between groups, but significantly fewer respiratory deaths occurred in metformin continuers. About half of the patients who continued metformin during the study period eventually stopped.
COMMENT
These results are surprising in two ways. First, many physicians continued patients on metformin despite eGFRs <30 mL/minute/1.73 m2; second, the survival benefit was not driven by cardiovascular causes. Another recent study also points to a survival benefit for continuing metformin in these patients (eClinicalMedicine 2024; 71:102568). A compromise might be to continue metformin at lower doses when eGFR fluctuates near 30 mL/minute/1.73 m2 but to discontinue it when eGFR persists below this threshold. These cases should involve shared decision making with patients.
CITATIONS
Lambourg EJ et al. Stopping versus continuing metformin in patients with advanced CKD: A nationwide Scottish target trial emulation study. Am J Kidney Dis 2025 Feb; 85:196.https://doi.org/10.1053/j.ajkd.2024.08.012
I'm that old, too. We were scared to death of the stuff and were very cautious. Who would have thought it would turn out to be such a workhorse?
Wow, thank you for this deep dive! It was a great read.
Thank you for such a thorough summary. While I avoid taking medications, I can see potential value for metformin.
Another amazing article! What are the markers for T cell exhaustion? And would the ant inflammatory agents benefit COPD?
Thanks Kathryn! I went back and added a graphic from the study I linked to showing some more information about T cell markers and overall immune system effects. Let me get back to you about more specifics later, too. And regarding COPD, another great question and I’ll do a follow up search on that. Scroll up a little in the comments and check out the study I quote to Jan… there is a little indirect evidence here regarding reduced respiratory illness mortality in patients with kidney problems who continue metformin anyway :
“The incidence of major adverse cardiovascular events did not differ between groups, but significantly fewer respiratory deaths occurred in metformin continuers.”
Thank you so much for always being so thorough and helpful!
Very interesting and informative! I’m curious if taking Akkermansia muciniphila itself, for improving gut biome, is worthwhile
Thanks Gina. I don’t know about this one either. Since this is a comment field and not a deep dive, I hope you don’t mind if I use Perplexity to give you a framework for answering this in the future:
There is growing clinical and preclinical evidence supporting the use of Akkermansia muciniphila as a probiotic, though its application is still emerging:
• Human Studies: A randomized, double-blind, placebo-controlled pilot study demonstrated that pasteurized A. muciniphila supplementation improved insulin sensitivity, reduced cholesterol, and decreased inflammation in overweight/obese individuals without adverse effects (NCT02637115). The European Food Safety Authority has also approved pasteurized A. muciniphila as a novel food.
• Animal Studies: Numerous studies in mice have shown benefits such as enhanced intestinal barrier function, reduced inflammation, and improved resistance to infections like Salmonella and Listeria monocytogenes.
• Mechanisms: Its effects are linked to modulating immune responses, promoting gut barrier integrity, and influencing metabolic pathways.
While promising, more extensive human trials are needed to confirm its efficacy and safety across broader populations.
https://www.perplexity.ai/search/is-there-any-clinical-evidence-5tSuSc7BRPS_FC.2G16MsA
Thank you, this was very helpful!
I just had an A1C of 7.4, previously slightly less than 7. Have not been exercising since I had a hernia repair in November, 2024, and it is still very painful. My cardiologist just prescribed Jardiance for me. What are the pros/cons of Jardiance vs. Metformin?
Hi Howard and Mary. Hard to exercise after hernia repair for a while, no doubt. Hopefully your surgeon knows how long this is taking though? Cardiologists really like Jardiance lately, but the cardiovascular benefit is mostly seen in people with diabetes who also have known cardiovascular disease already. Here is a long answer for you comparing Jardiance (empagliflozin) and metformin across several key areas.
Efficacy & Outcomes:
Metformin has long been considered the first-line treatment for Type 2 diabetes, with extensive long-term data showing it reduces A1C by about 1-1.5%. The landmark UKPDS trial demonstrated significant reductions in diabetes-related complications and mortality.
Jardiance has shown impressive cardiovascular outcomes data in the EMPA-REG OUTCOME trial, demonstrating a 38% relative risk reduction in cardiovascular death and 35% reduction in heart failure hospitalization. It typically reduces A1C by 0.5-0.8%. It also provides benefits for heart failure patients even without diabetes, as shown in the EMPEROR trials.
Cost:
Metformin is significantly less expensive, typically costing $4-10 per month for generic versions. Jardiance, as a branded medication, usually costs $500-600 per month without insurance coverage.
Side Effects:
Metformin:
GI side effects (diarrhea, nausea, abdominal discomfort) are common initially
Vitamin B12 deficiency with long-term use
Lactic acidosis (very rare but serious)
Generally weight neutral or modest weight loss
Jardiance:
Genital yeast infections
Urinary tract infections
Volume depletion/hypotension
Diabetic ketoacidosis (rare)
Associated with weight loss (can be beneficial for many patients)
Additional Considerations:
Metformin can be used in earlier stages of kidney disease, while Jardiance has restrictions based on eGFR
Jardiance has additional benefits for heart failure and chronic kidney disease
Metformin has decades more safety data
Jardiance can be used alone or in combination with other diabetes medications
The choice between these medications often depends on patient-specific factors including cardiovascular risk, kidney function, cost considerations, and other comorbidities. Many patients may benefit from using both medications as part of a comprehensive treatment plan.
Now getting back to the CV risk reduction question specifically... if you really want to show off (and perhaps even challenge your cardiologist), here is more nuanced detail of the CV risk reduction with Jardiance:
The EMPA-REG OUTCOME trial studied 7,020 patients with Type 2 diabetes who had established cardiovascular disease (prior MI, significant coronary disease, stroke, or symptomatic PAD). The population was predominantly male (71%), with mean age 63 and diabetes duration of 13 years. The trial showed a 38% relative risk reduction in cardiovascular death and 35% reduction in heart failure hospitalization.
EMPEROR-Reduced studied 3,730 patients with heart failure with reduced ejection fraction (≤40%), demonstrating a 25% reduction in the combined primary outcome of cardiovascular death or heart failure hospitalization.
EMPEROR-Preserved enrolled 5,988 patients with preserved ejection fraction (>40%), showing a 21% reduction in the same combined endpoint. Both EMPEROR trials included patients regardless of diabetes status, establishing Jardiance's benefits across the spectrum of heart failure.
These results significantly expanded the proven benefits of Jardiance beyond just diabetic patients with established CV disease, leading to its approval for heart failure treatment regardless of ejection fraction or diabetes status.
So, if I’m reading correctly, the article cited above means that a placebo was 29% effective in preventing progression to T2D but metformin was only 22% and lifestyle changes were 14%? Help me understand.
According to the 2002 study, 29% of patients with pre-diabetes progressed to T2D if they were taking the placebo during the time frame of the study, while only 22% of those taking metformin did so. It appears from this study that lifestyle changes are the most effective preventive measure.
More recent studies suggest that reduction in visceral adipose tissue is a key strategy. For patients with pre-diabetes who don't respond to lifestyle changes, I would combine metformin with continued physical activity and dietary modifications.
What Mick said, 💯!
FWIW, I concur with prescribing metformin for patients with pre-diabetes who have not seen a reduction in their HbA1c with physical activity and dietary interventions.
Thanks Mick, I appreciate you weighing in with your experience and obvious commitment to keeping up with evidence-based practice. Diet, exercise, and weight loss remain the foundational pillars here, but we have to be realistic, individualistic, and meet people where they are…
“…we have to be realistic, individualistic, and meet people where they are…”
Totally agree! The “generally speaking” question I have is: Should PCPs prescribe metformin before their patients with pre-diabetes have given lifestyle interventions a try, waiting to see if it is successful, or just go ahead and prescribe metformin plus lifestyle modification at the outset?
Because metformin has so many other benefits, I might favor employing both strategies right away, as well as suggesting that they purchase an OTC CGM for lifestyle biofeedback. Your thoughts?
I used to be more proactive with discussing metformin for IFG, but it seems the zeitgeist had been drifting away from that, and the ADA statement is kind of nuanced and iffy. I also used to think metformin helped with weight loss, but this seems doubtful in most patients (in my experience). So I think an individualized discussion with realistic feedback from the patient about how much they can really do differently/better informs this decision than a one-size-fits-all. That being said, with the Covid stuff coming out lately, and the Covid stuff not going away ever, it would lower the bar for me as a patient to take it.
Ryan, I wasn't suggesting a one-size-fits-all, but rather trying to get an overall feel for the current standard of care regarding pre-diabetes. Are the PCPs in your community on board with prescribing metformin for pre-diabetes, and if so, do they want their patients to first make a good-faith effort at lifestyle modification before taking it?
I fail to see any "iffiness" about the ADA's position in this article:
https://diabetesjournals.org/care/article/43/9/1983/35757/Metformin-Should-Not-Be-Used-to-Treat-Prediabetes
A great deep dive! A couple if things that I didn't see mentioned here.
Guidance Issued for Use of Metformin to Prevent Antipsychotic-Induced Weight Gain
https://www.drugs.com/news/guidance-issued-metformin-prevent-antipsychotic-induced-weight-gain-123069.html
Diabetes Drug Metformin Protects Against Skin Cancer, New Research Says
https://www.drugs.com/news/diabetes-metformin-protects-against-skin-cancer-new-research-says-123293.html
Note, not for melanoma
Is there anything that metformin doesn't do? :~)
Nice finds!
Thanks KB! Once again I struggle with the word counts, and at 2 AM last night I had enough. These are two excellent additional considerations and thanks for adding the links for others to read! The antipsychotic medication weight gain is really pertinent in primary care, too, as most psychiatrists don’t feel comfortable prescribing internal medicine drugs like metformin in my experience.
"Neither metformin nor lifestyle reduced major cardiovascular events in DPPOS over 21 years, despite long-term prevention of diabetes."
https://pmc.ncbi.nlm.nih.gov/articles/PMC9179081/
Dr McCormick , I just gifted my PCP a subscription. Is there a way for her to go back and see your previous articles? I saw that I could go back one week by using the PREVIOUS key. Do you have a list of previous articles and a way to access them? Thanks so much
I'm still on the fence about the GLP 1 for me.
Mike
Thank you Michael, that's quite an honor! I hope to live up to it!
There are a couple of ways to read "old" stuff on here.
One way is the curated list of more evergreen topics I maintain, organized by subject matter in a reading room (replete with an allergenic cat):
https://mccormickmd.substack.com/p/examined-reading-room
Or simply review organized by date of publication in "the archives" format:
https://mccormickmd.substack.com/archive
Again many thanks for making my day ;)
Thank you for this deep dive on Metformin. I am a 78 year old male who began taking Metformin on the recommendation of my former PCP in 2015. At the time my weight was 205, my A1C was 5.4, and my fasting glucose was ~104. My PCP was a fan of Metformin and as I was close to the pre-diabetic area, he thought it would be a good medication for me. He also believed it had longevity support impacts although he advised me that data was not conclusive.
Fast forward 10 years, my A1C is 4.9, my weight is 185, my fasting glucose is 96. For the last two years my current PCP has been trying to persuade me that it is an unnecessary medication for me. So far she continues to authorize my prescription but views it as “off label” in light of my blood indicators. It was fascinating to me to read the impacts which you documented in this article.
Thanks again.
Hi Gary - this is really a fascinating anecdote and thank you for sharing it. It sounds like your prior PCP is going on a well-informed hunch, though the benefits probably accrue in direct proportion to the need for the medication... i.e. larger benefits as hyperglycemia increases. Your stats look great though! As far as I know this statement is key:
"However, there's currently no definitive evidence that metformin extends lifespan in healthy humans. Major clinical trials like TAME and MILES are ongoing to investigate metformin's potential anti-aging effects in non-diabetic populations, which may provide more conclusive answers."
I'll hope to be around to present the TAME study results along with many other interested parties in the future!
https://www.afar.org/tame-trial
Looks like they need more funding? If RFK Jr wants to redirect some of the dwindling federal research dollars towards chronic disease, this would be a good one.
Here is the MILES study result, small number of patients, and not outcome-oriented, but rather biochemical markers:
https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(23)00085-5/fulltext
I’m aware of the TAME study and hope to last long enough to see some results. At 78, I recognize the runway in front of me is getting shorter!
I haven’t yet made the leap in my practice to prescribe metformin to reduce cancer risk. That being said I am aware of a handful of prospective trials currently in progress that could change things. A very interesting study the MILI trial in Europe is prospectively studying metformin to reduce risk of cancer in patients with Li Fraumeni Syndrome. https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-metformin-to-reduce-the-risk-of-cancer-in-people-with-li-fraumeni-syndrome-mili
Thanks Daniel, I really appreciate the specialist level input, and please let me know if you hear anything about this before I do... though I suppose any proven cancer reduction results in the general population will be quite well-reported.
Given the decent quality of the studies in people with diabetes, though not RCTs with primary endpoints of cancer prevention, it does seem like yet another vote of confidence in using metformin first line for DM2
What a remarkable drug! I will confess my favorite thing was to learn—accompanied by a photo of this humble, yet powerful flower, no less—that “Metformin, originally derived from French lilac, has evolved from a medieval remedy to one of modern medicine's most versatile drugs.” Thank you so much.
That might have been the most pithy thing I learned writing this, too! Pretty intuitive and cool that this was apparently used for "diabetes-like symptoms," which reminds us of the diagnostic world of darkness that existed in the world until recently. Thanks for stopping by :)
Okey dokey. Here’s a rebuttal to Metformin use for someone like me whose body can’t tolerate Metformin. I was first put on Metformin sometime around 2000. My metabolism was wonky, gaining then losing weight ad nauseum, and my blood sugar varied from 90-100 with corresponding dips in energy, so my doc at the time thought Metformin might help stabilize me. That started 20+ years of using it for a year or two, then stopping, again ad nauseum, but the results were always the same: I hated it.
I’ll comment on each of Ryan’s observations as they applied to me:
“Beyond diabetes management, metformin shows promising potential across multiple areas:” yeah, no, not for me. I spent every day having hot flashes & every night having night sweats. Ugh.
“Prevention of diabetes in prediabetic patients” I wouldn’t know. I’ve never had prediabetes.
“Reduction of long Covid risk” I’ve never had Covid, so I don’t know.
“Possible anti-cancer properties, particularly in diabetic patients” I had breast cancer with a 7mm tumor that grew for an estimated 7 years & I took Metformin for much of those 7 years. So, no, didn’t work for me.
“Treatment of PCOS” I had PCOS back in the day, but had a radical hysterectomy in 1996, before I took Metformin. Bummer.
“Potential anti-aging effects (though evidence is still mixed)” hahahaha. Um, no, although I am totally a walkin’ machine!
“Promising results in reducing influenza severity and complications” i was on Metformin the last time I had flu, which was back in Dec 2019. Didn’t alleviate symptoms with the exception that it didn’t settle in my chest. So, okay, I’ll agree somewhat. Now I get flu, RSV & Covid vaccines routinely, and wear a mask if I hear anyone wheezy-couching or sneezing in my vicinity. So far, so good, knock on wood.
‘Recent evidence suggesting benefits for asthma patients” I have asthma but I ca’t remember the last time I had to use an inhaler. Another possible positive for Metformin!
“The drug works through multiple mechanisms, including improving insulin sensitivity, modifying gut microbiome, and exhibiting antiviral and anti-inflammatory properties.
Metformin is generally safe, inexpensive, and well-tolerated, though it can cause initial GI side effects that typically improve over time.” My gut was on overtime. Although I tried increasing my dosage every time I retried Metformin, the max dosage I could take was 2 pills daily instead of the 4 that were prescribed. I had near constant diarrhea. Combine that with all the sweating & it was my own personal hell. It did nothing for my inflammation, but I never (knock on wood again) got Covid so it may be because of the Metformin or even the combo masks, Metformin and finally vaccines. 🤷♀️
If Metformin works for you, yay! But for those of you who have adverse reactions to it, keep taking the blood pressure meds & other medications your doc prescribes. And seriously, y’all, research, research, research on the medical websites! Don’t make your doctor take the whole burden of your health on his or her shoulders. You must become an equal partner of sorts in order to thrive.
Hi Kerry - I appreciate the thorough response and individual considerations. People really are unique, and your experience with Gi side effects in particular sounds rough! Some of my patients would totally agree with you, and have been taking other medications instead for diabetes. Always try to avoid medications if possible, but lifestyle changes are challenging for different people for different reasons. Anyway, counterpoints taken, thanks again for sharing! Totally agree with personal health journey collaboration, as cheesy as that may sound.