Imeglimin. A new and novel drug thats better than Metformin

#17

Ordered some from India.

For me it’s more a replacement for Plioglitazone which works well but has some safety issues.
Also my DEXA fat % went from 14% to 16% with Plioglitazone.

Metformin did not do anything at all for me.

I did a Gemini Pro deep research: Bioenergetic Pharmacotherapy in Type 2 Diabetes: A Comprehensive Analysis of Imeglimin Interactions, Comparative Safety, and Physiological Adaptations

That includes interaction with rapamycin, empagliflozin, exercise, etc.

Table 1: Comparative Safety and Efficacy Profile: Imeglimin vs. Pioglitazone

Feature Pioglitazone (TZD) Imeglimin (Glimin) Clinical Consequence
Primary Target Nuclear PPARγ Receptor Mitochondrial Complex I/III Imeglimin avoids nuclear transcription side effects.
Heart Failure Risk Increased (Boxed Warning) Neutral (Potential Benefit) Imeglimin is safer for patients with cardiac history.
Edema Frequent (Renal Na+ reabsorption) Rare / Absent Imeglimin preferred in patients prone to volume overload.
Bone Fracture Risk Increased (Marrow adipogenesis) Neutral Imeglimin preferred in postmenopausal women/elderly.
Weight Effect Weight Gain (Adipogenesis + Fluid) Neutral Imeglimin avoids exacerbating obesity.
Liver Fat Reduces (Potent) Reduces (Moderate) Both benefit MASH, but Pioglitazone has more data.
Onset of Action Slow (Weeks/Months) Rapid Imeglimin offers faster glycemic control.

Table 2: Mechanism of Interaction: Imeglimin + Empagliflozin

Component Empagliflozin Contribution Imeglimin Contribution Synergistic Outcome
Glycemia Urinary glucose excretion (Insulin Independent) Insulin sensitization + GSIS (Insulin Dependent) Potent HbA1c reduction covering all mechanisms.
Cardiac Hemodynamic unloading + Ketone fuel Mitochondrial efficiency + Endothelial function Structural and metabolic cardiac remodeling.
Renal Reduced glomerular pressure Reduced oxidative stress Preservation of nephron mass.
Liver Reduced hepatic fat Reduced lipogenesis + fibrosis Mitigation of MASH progression.

Table 3: Summary of Imeglimin Interactions and Effects

Domain Interaction / Comparison Key Outcome / Mechanism
Pharmacology vs. Metformin Competitive vs. Non-competitive Complex I inhibition; Imeglimin rescues Complex III and amplifies GSIS.
Safety vs. Pioglitazone Imeglimin has NO heart failure, edema, or bone fracture risk. Weight neutral.
Synergy w/ Tirzepatide Complementary beta-cell effects: Tirzepatide stimulates, Imeglimin protects (mitochondrial buffering).
Synergy w/ Empagliflozin Full Cardio-Renal protection: SGLT2i (hemodynamic) + Imeglimin (metabolic/endothelial).
Longevity w/ Rapamycin Imeglimin (AMPK/SIRT1) rescues mitochondrial biogenesis inhibited by Rapamycin (mTORC1 blockade).
Muscle Strength Training Increases strength (~13%) without hypertrophy. Improves NMJ/Bioenergetics.
Muscle Endurance Enhances PGC-1α and mtDNA. Potentially additive to exercise adaptations.
Renal TWINKLE Study Safe in eGFR < 45 mL/min (unlike Metformin). No lactic acidosis signal.
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#18

Also cited in the post of Dr. Fraser (citation #7)

In the present study, only imeglimin enhanced insulin secretion and the effect on insulin sensitivity was similar between imeglimin and metformin; however, the reduction of HbA1c in both drugs was similar at 24 weeks. This may be explained by that metformin has the glucose‐lowering effect via mechanisms not involving insulin signal such as enhancing release of glucose into the intraluminal space of the intestine or influencing the gut microbiota.

Is that a desired result? Isn’t increased insulin age accelerating?

In humans, epidemiological studies suggest a pro-aging effect of insulin. Insulin resistance increases with aging, but centenarians usually preserve normal glucose tolerance, low levels of fasting insulin and higher insulin sensitivity, when compared with adults > 75 years of age (52–54). The higher longevity in shorter men is also associated with lower fasting insulin concentrations (55).

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#19

again using AI to help: Imeglimin (brand name Twymeeg) is a first-in-class oral antidiabetic approved in Japan since 2021 for Type 2 diabetes. It shares some mechanisms with metformin but works differently at the mitochondrial level, which is why longevity enthusiasts are interested in it.​

How It Differs from Metformin

Feature Metformin Imeglimin
Complex I Non-competitive inhibition (blunts respiration) Competitive modulation (preserves oxidative capacity)
Complex III No effect Corrects dysfunction, reduces ROS
NAD+ effect Indirect Direct upregulation via NAMPT
Insulin secretion None (works via liver) Amplifies glucose-stimulated insulin secretion (GSIS)
GI tolerance Often poor (diarrhea) Generally better tolerated
Lactic acidosis risk Rare but possible Lower theoretical risk
HbA1c reduction ~1.0–1.2% at full dose ~0.6–0.9% (head-to-head similar to lower-dose metformin)
Cost Very low (generic) High (patented)

​

Longevity Angle

The appeal for healthspan is its “mitochondrial optimizer” profile—it reduces ROS via reverse electron transport while preserving ATP production, and it boosts the NAD+ salvage pathway through NAMPT induction. However, no human clinical data currently support lifespan extension, and no large cardiovascular outcome trials (CVOTs) exist yet.​

Exercise and Muscle

Unlike metformin, which can blunt muscle hypertrophy (per the MASTERS trial), emerging data suggest imeglimin may enhance muscle strength (~13% improvement in one cohort) without blocking exercise adaptations. It activates Akt signaling (which supports mTORC1/growth) rather than purely braking it through AMPK, and it enhances PGC-1α for mitochondrial biogenesis.​

Practical Notes

  • Dose: 1,000 mg twice daily (Japan-approved); dose reductions for CKD are off-label but used clinically.​
  • Availability: Not approved in the US/EU, but available from Indian generics (e.g., Zydus) at reasonable cost.​
  • Rapamycin interaction: Mechanistically, imeglimin’s AMPK/SIRT1 activation may actually rescue mitochondrial biogenesis that rapamycin’s mTORC1 blockade inhibits—potentially complementary rather than counteractive.​

Bottom Line

Imeglimin is a promising “super-metformin” candidate for those who cannot tolerate metformin or want more targeted mitochondrial support, especially if they exercise regularly. The glycemic efficacy is slightly weaker than full-dose metformin, but the safety profile (no lactic acidosis signal, better GI tolerance, neutral on weight/heart failure/bone) and potential exercise compatibility make it attractive. That said, it remains speculative for longevity until human outcome trials are completed

#20

Certainly a valid concern. However, it is super important to try to understand the MOA (mechanism of action) of any drug before making a decision about taking it. There are drugs that increase insulin output, such as sulfonylureas, meglitinides, glp-1ra etc. However, you have to ask about the MOA of any particular class of drugs. If the drugs force greater insulin output from beta cells leading to beta cell exhaution, that can be a long term negative. But what if your pancreas would release a “normal” amount of insulin in response to glucose levels, but it’s prevented by some kind of defect in some beta cell pathway, either production or release or whatever. Then, removing that defect simply restores insulin levels to “normal” - in that scenario increased insulin levels are not a negative.

That’s why it is so crucial to try to establish the MOA. But let us assume that imeglimin increases insulin production through repairing a defect along the beta cell pathway.

Imeglimin Amplifies Glucose-Stimulated Insulin Release from Diabetic Islets via a Distinct Mechanism of Action

https://www.biorxiv.org/content/10.1101/2020.10.20.346841v1

Does that mean you should add imeglimin to your drug stack if you have elevated A1c? Not necessarily. Let us go back to a fundamental concept, frequently invoked by Ralph DeFronzo, that diabetes (and prediabetes is just along the spectrum of poor glucose control) is a multifactorial disease with many causes, as in the defect may be along any pathway of glucose control. If it so happens, that your poor glucose control is down to a specific defect in the beta cell pathway that imeglimin addresses, you are golden: go take this drug. But that may not be the case at all. For example, many prediabetics, or even people who are normoglycemic have very high insulin levels. Clearly their problem is not an inadequate production or release of insulin by the pancreas. In that scenario, trying to fix a non-existant defect in the pancreas with imeglimin as a way to normalize glucose metabolism might not yield the desired results. Addressing any disease starts with the correct diagnosis. You must establish - and the more precisely the better - where does the defect in glucose metabolism lie in your case. And once you’ve established that, you can try to address it with the appropriate drug.

Unfortunately, we face two problems. Problem one, is that we often are not sure where the problem lies, and problem two is that a given drug may have MOA that is not transparent to us, or has multiple pathways (a “dirty” drug, like metformin). Sure, you can say metformin/sglt2i/pio/glp-1ra “brings down A1c” - but if that’s all the study shows, you really can’t be sure that it will work for you or indeed that it is appropriate and not counterproductive.

Just as an example, I take myself. My A1c is consistently high (5.7-5.9). My morning fasting blood glucose is also high (~110mg/dL). However, my insulin levels are also high. It doesn’t seem like the problem for me is inadequate insulin release. For the amount of insulin I pump out, my glucose levels ought to be lower (HOMA-IR 1.7 in my case) as reflected by A1c. I therefore am going to hold off on imeglimin for the time being. It seems to me, the problem here is somewhere else - either insulin sensitivity or excessive hepatic neoglucogenesis. That would make pioglitazone more interesting to me (in my case). But the complication is of course that imeglimin also works along multiple pathways muddying the issue - is it worth hammering the pancreas with an unnecessary “fix” because the drug also suppresses hepatic neoglucogenesis? Maybe. Or maybe I’d prefer a more targeted intervention, a drug that addresses my defect and not anything else (maybe a luxury I don’t have!).

My point here is this: we often read that a given drug does something (lowers glucose, A1c, lipids, homocysteine whatnot) and we decide to spring for it, especially if we suffer from some issue (excessive glucose levels, lipid levels whatnot). But that may transpire to be a very unwise choice.

Instead you need to ask: given my problem (say, glucose control) - will drug X (say, imeglimin) help in my case? Unless you know, why take the drug? What is the MOA of that drug and what is your defect and etiology of your pathology, does that drug address it, or does it merely give you side effects without benefits or merely surface benefits which are disastrous longer term (insulin therapy for some T2DM cases). Perhaps imeglimin might work short term - but will it work for you long term, or be counterproductive?

And that’s why I’m interested in the MOA of this drug. And why it takes me a long time to research a drug before I even consider taking it. YMMV.

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#21

Is there a trusted pharmacy that is typically used?

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#22

See here:

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#23

Doing further research, I am wondering about drug interactions. For example, what if your version of poor glucose control does not result from any defect in beta cells GSIS, and since one way in which imeglimin works is that it “fixes” GSIS, you may surmise that imeglimin might not be for you. But what if you are also taking another drug, say, sirolimus, which longer term or with some protocols (daily dosing?) actually damages beta-cells GSIS? Now you might be adding this defect to your glucose control issues, and what if under those circumstances (i.e. you taking sirolimus) taking imeglimin might make sense, whereas without sirolimus it does not.

Evidence for Rapamycin Toxicity in Pancreatic β-Cells and a Review of the Underlying Molecular Mechanisms

https://diabetesjournals.org/diabetes/article/62/8/2674/34093/Evidence-for-Rapamycin-Toxicity-in-Pancreatic

Quote:

“Overall, the majority of these studies demonstrate significant effects of rapamycin on glucose homeostasis, and the combined evidence strongly suggests that rapamycin adversely affects GSIS from β-cells.”

Of course, GSIS from beta-cells can be impacted through various mechanisms, so it remains to be shown whether imeglimin can “fix” the damage sirolimus does to beta-cells. Again we need to take a closer look at the MOA of both drugs to guess at any possible interaction, and then test it. The research continues.

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#24

“suppresses hepatic neoglucogenesis” “fixes GSIS”

Aren’t these good things? GSIS declines with age.

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(Gemini)

"Yes, Imeglimin suppresses hepatic gluconeogenesis (the production of new glucose by the liver). It is a core part of its “dual-benefit” mechanism of action, which targets the liver, skeletal muscle, and pancreatic beta cells.

Mechanism in the Liver

Imeglimin reduces excessive glucose production through several mitochondrial-dependent pathways:

Mitochondrial Rebalancing: It acts on the mitochondrial respiratory chain by partially and competitively inhibiting Complex I and restoring the activity of Complex III.

Energy Regulation: This rebalancing lowers the ATP/ADP ratio and increases mitochondrial redox potential in hepatocytes, which reduces the driving force for gluconeogenesis."

Ref

"Age-Related Decline in GSIS

In humans, beta cell function generally declines with age, estimated at a rate of approximately 1% per year. This decline is often independent of peripheral insulin resistance or body mass index.

Reduced Stimulated Secretion: Islets from younger donors (<40 years) typically exhibit significantly higher GSIS than those from older donors.

Elevated Basal Secretion: Aging is often associated with an increase in basal (fasting) insulin secretion, which may represent a compensatory state but also reduces the cell’s “dynamic range” when stimulated by high glucose.

Mechanisms of Dysfunction."

Ref1

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#25

Apparently in a percentage of users SGLT2i can increase the risk of erythrocytosis (see paper below). If imeglimin prolongs how long erythrocytes persist in the serum, then wouldn’t the concurrent use of both drugs further elevate the risk of erythrocytosis?

From the canagliflozin thread, a paper posted by @Davin8r:

Erythrocytosis and thromboembolic risks associated with SGLT2 inhibitors in type 2 diabetes

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#26

It certainly could, and would be potentially even worse with testosterone + SGLT2i + imeglemin. T and SGLT2i mainly work by stimulating production of RBC, so if then you add in a drug that reduces RBC senescence/removal then I’d expect to see even more of an increase in hemoglobin/hematocrit.

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#27

Then slow titration should be used, with frequent blood draws. And looking for hemo increasing.

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#28

Got it. Starting today. BTW I already stopped Plioglitazone 3 weeks ago.
I will report back here.

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#29

Have you made any tests? Glucose maybe?

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#30

I’m starting today. I use a CGM and I take fingerpick glucose every morning.

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#31

Fantastic. Super interested in this. Please keep us posted. Also very interested in BG now that you’ve stopped pio, but before you start up on ime otherwise it’ll be hard to disentangle the effects of one vs the other. I think ime is less potent in glucose lowering than metformin, and since met did nothing much for you (did zilch for me), I think if there’s an effect, it’ll really be down to the different MOA.

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#32

Well, your reports with numbers will be much appreciated.

#33

Same for me. metformin did not change anything. That said imeglimin has more MOAs than metformin:

(Gemini 3 pro)

Imeglimin does everything Metformin does (sensitizes the body to insulin), but it also stimulates the pancreas to release insulin in response to glucose (Glucose-Stimulated Insulin Secretion, or GSIS).

Imeglimin promotes the synthesis of NAD+ (via the salvage pathway). Increased NAD+ leads to higher intracellular calcium levels in pancreatic beta-cells, which is the direct trigger for insulin release.

Imeglimin has been shown to prevent the opening of the Mitochondrial Permeability Transition Pore (mPTP) . When this pore opens, cells die (apoptosis). By keeping it closed, Imeglimin helps preserve pancreatic beta-cell mass, potentially slowing the progression of diabetes.

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#34

I ordered the same brand, and it’s on its way. I am hoping it will lower my fasting glucose levels.

Metformin worked fine for me until I developed an intolerance for it.
Glynase and empagliflozin do nothing for me, at least compared to metformin.

My fasting glucose is suboptimal, which is contrary to the rationale that we want all of our bloodwork to be optimal for longevity. I can lower my fasting glucose by fasting longer than usual and drinking lots of water before my blood test. My own in-home test tells a different story. My morning glucose reading after being up for two hours and fasting for 14 hours is always between 101 and 110. I would like it to be between 90 and 100.

Of course, my doctor is not concerned and will not prescribe further medications until my fasting glucose and A1C become significantly worse. Two doctors have told me that at my age, everything is okay. They are not longevity doctors.

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#35

Tracking fasting insulin, and A1c will also be very useful.

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#36

I just watched a video of an Indian talk about Imeglimin with lots of interesting slides such as that one:
(Note all the cool stuff about NAD+, CD38, etc.)

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Slightly less cool is that adding it to GLP1-RA does not reduce HbA1C by much.
That said they have theories about why and on the other hand the combination with a SGLT2i is OK.
As usual the effect size is highly dependent on individual variability so I’m hopeful.

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The full video is here:
Imeglimin Novel agent in T2D Armamentarium with Dual Benefits

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