Has anyone knowledge about this drug? Its from Japan, I suppose. And it can be “a new better version” of metformin.
Maybe someone knows any reviews from some smart guys like Johnson or Sinclair or Kaeberlein?
The following analysis evaluates the scientific and clinical evidence for Imeglimin (Twymeeg), specifically focusing on its potential impact on healthspan and longevity beyond its approved use for Type 2 Diabetes (T2D).
Executive Summary
Current Status: Imeglimin is a first-in-class oral medication (“Glimin”) approved in Japan for T2D.1
Longevity Verdict: Promising but unproven. While it shares critical mechanistic pathways with Metformin (AMPK activation) and NAD+ precursors (mitochondrial bioenergetics), clinical evidence is currently limited to glycemic control and safety. No human data currently supports lifespan extension, and large-scale cardiovascular outcome trials (CVOTs) are lacking.
Key Differentiator: Unlike Metformin, which inhibits mitochondrial Complex I “blindly,” Imeglimin appears to modulate Complex I while correcting Complex III dysfunction, potentially reducing Reactive Oxygen Species (ROS) without the metabolic rigidity (e.g., lactate risk) sometimes seen with biguanides.2+1
1. Mechanism of Action: The Longevity Case
Imeglimin’s primary appeal for longevity lies in its unique ability to target mitochondrial bioenergetics, the “engine room” of aging.3
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Mitochondrial Modulation: Imeglimin acts directly on the mitochondrial respiratory chain.4
- Complex I Inhibition: Similar to Metformin, it partially inhibits Complex I.5 This creates a mild energetic stress that activates AMPK (Adenosine Monophosphate-activated Protein Kinase), a master regulator of metabolism and a key pro-longevity pathway.
- Complex III Correction: Unlike Metformin, Imeglimin reportedly corrects dysfunctional activity at Complex III.6 This is crucial because Complex III dysfunction is a major source of superoxide (ROS) generation.
- NAD+ Synthesis: Preclinical data indicates Imeglimin enhances the expression of NAMPT (Nicotinamide phosphoribosyltransferase), the rate-limiting enzyme in the NAD+ salvage pathway.7 Elevated NAD+ levels are essential for Sirtuin activity (DNA repair, epigenetic maintenance) and generally decline with age.
- mPTP Inhibition: It inhibits the opening of the Mitochondrial Permeability Transition Pore (mPTP) .8Preventing mPTP opening protects cells from apoptotic death during stress (e.g., ischemia/reperfusion injury), suggesting potential cytoprotective effects for the heart and brain.9
2. Clinical Evidence (Human Trials)
Most high-quality data comes from the TIMES (Trials of IMeglimin for Efficacy and Safety) program in Japan.10
A. Glycemic & Metabolic Health (Proven)
- Efficacy: The TIMES 1, 2, and 3 trials demonstrated significant HbA1c reductions (monotherapy and combination).11
- Dual Mechanism: It is the only oral agent that simultaneously amplifies Glucose-Stimulated Insulin Secretion (GSIS) and improves insulin sensitivity.12 This preserves Beta-cell mass (pancreatic longevity) in preclinical models, theoretically delaying the progression of diabetes.13
B. Cardiovascular & Renal Health (Secondary/Exploratory)
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Kidney Function: Safety has been established in patients with Chronic Kidney Disease (CKD) up to stage 3b/4.14 Small retrospective analyses suggest it may reduce proteinuria (albuminuria), a marker of kidney aging/damage, likely via endothelial protection.15
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Cardiovascular: There are no large-scale CVOTs (like EMPA-REG for Empagliflozin) proving Imeglimin reduces heart attacks or strokes. However, it does not appear to increase CV risk.
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Biomarkers: Recent studies have noted reductions in circulating cell-free mitochondrial DNA (a marker of systemic mitochondrial stress) and inflammatory cytokines (IL-6) in treated patients.16
C. The “Erythrocyte Lifespan” Confounder
An interesting finding from the INFINITY trial suggests Imeglimin may prolong the lifespan of red blood cells (erythrocytes) .17
- Significance: While this technically means “cellular life extension,” in a clinical context, it confounds HbA1c readings (making them artificially high because older blood cells accumulate more sugar). This requires clinicians to use other markers (like Glycated Albumin) to gauge true efficacy.
3. Preclinical Evidence (Animal/Cellular)
This is where the strongest “longevity” signal exists, though it has not yet translated to humans.
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Organ Protection:
- Heart: In rat models of metabolic syndrome, Imeglimin improved left ventricular function and reduced fibrosis.18
- Liver: In models of MASH (Metabolic dysfunction-Associated Steatohepatitis), it reduced hepatic steatosis and fibrosis by improving mitochondrial biogenesis and fat oxidation.19
- Neuroprotection: Limited animal data suggests reduction in ischemia-induced brain damage, likely due to the mPTP inhibition mechanism mentioned above.20
4. Comparative Analysis: Imeglimin vs. Metformin
| Feature | Metformin | Imeglimin |
|---|---|---|
| Primary Target | Mitochondrial Complex I (Inhibition) | Complex I (Inhibition) + Complex III (Correction) |
| AMPK Activation | Strong | Yes (Likely similar potency) |
| NAD+ Effect | Indirect | Direct (via NAMPT upregulation) |
| ROS Production | Can increase ROS if dosage is toxic | Decreases ROS (prevents oxidative stress) |
| Gut Tolerance | Poor (Diarrhea common) | Moderate (Better tolerated than Metformin) |
| Lactate Risk | Rare but possible (Lactic Acidosis) | Lower theoretical risk (no inhibition of lactate metabolism) |
| Cost | Extremely Low | High (Patented) |
5. Critical Gaps & Risks
- No Lifespan Data: There are no studies (even in mice) demonstrating that Imeglimin extends maximum lifespan.
- Lack of Global Approval: It is currently only approved in Japan (and potentially other Asian markets).21The FDA/EMA have not approved it, largely due to corporate strategic shifts (Poxel/Sumitomo) rather than safety failures, but this limits the data pool.
- Unknown Long-term Safety: We lack the multi-decade safety data that exists for Metformin.22
Conclusion
Scientifically, Imeglimin is a “super-Metformin” candidate. Its mechanism hits the “holy trinity” of metabolic longevity: Mitochondrial quality control, ROS reduction, and NAD+ synthesis.23
Clinically , it is a robust anti-diabetic agent with a favorable safety profile.24 However, there is zero direct clinical evidence currently supporting its use as a geroprotector (anti-aging drug) in healthy humans. It remains a speculative optimization for those who cannot tolerate Metformin or wish to target mitochondrial dysfunction more specifically.
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Looks very promising.
Ofcourse, some time should pass to loose its patented status, get approvals worldwide… Meanwhile some new studies will come.
Maybe it will be more accessible.
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It appears to be widely available from India at a reasonable price. I will be ordering some to try, as I can no longer use metformin because it causes gastrointestinal problems.
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Great find. I am going to replace my 1.5 gms of Metformin with this. I will order it at the earliest. I have been worried about my kidneys as albumin excretion seems to have increased per my last test. This will be another leg of mitochondrial support along with SS31, MOTSc and NAD+ injections.
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The fact that this new drug is available from India inexpensively makes it much more interesting. If I were taking metformin on a regular basis I would definitely look into the idea of switching to this drug. I also think the ITP should probably look at this drug as a potential longevity drug.
My key area of interest was related to exercise effects, and thus this prompt:
Given the mechanisms of action for Imeglimin compared to metformin, is it likely to have the same exercise hypertrophy blunting effect that metformin has, as outlined in this paper: Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double‐blind, placebo‐controlled, multicenter trial: The MASTERS trial - PMC
Gemini Pro response:
Based on recent clinical and mechanistic data (including studies from 2024–2025), Imeglimin is unlikely to blunt exercise adaptations to the same degree as Metformin.
In fact, emerging human evidence suggests Imeglimin may enhance muscle strength and mitochondrial function when combined with resistance training, marking a critical divergence from Metformin.
1. The Clinical Verdict: Imeglimin vs. Resistance Training
While the Walton et al. (MASTERS trial) paper you referenced confirmed that Metformin blunts muscle hypertrophy in older adults, a prospective cohort study published in late 2024/early 2025 (Shimada et al., Journal of Diabetes and its Complications) found the opposite functional outcome for Imeglimin:
- The Finding: T2D patients taking Imeglimin who engaged in resistance training showed significantly greater improvements in knee extension strength (+13%) compared to controls (+2.1%).
- The Nuance: Like Metformin, Imeglimin did not significantly increase Lean Body Mass (hypertrophy) in this short window. However, unlike Metformin, it did not prevent strength gains; it amplified them. This suggests Imeglimin improves muscle quality (efficiency) rather than just bulk.
2. Mechanistic Explanation: Why the Difference?
Metformin and Imeglimin both target mitochondrial Complex I, but their downstream effects on the hypertrophy signaling pathway (mTORC1) appear to differ.
| Feature | Metformin Effect | Imeglimin Effect | Impact on Muscle |
|---|---|---|---|
| AMPK Activation | Strong Activation. AMPK directly inhibits mTORC1 (the “muscle growth switch”). | Activation. Also activates AMPK (via AMP/ATP ratio shift). | Both: Theoretically brakes growth. |
| Akt Signaling | Inhibition/Neutral. Metformin often fails to phosphorylate Akt in muscle during exercise. | Activation. Studies (Ishiguro et al.) show Imeglimin increases Akt phosphorylation. | Imeglimin Advantage: Akt activates mTORC1, potentially counteracting the AMPK “brake.” |
| Mitochondria | Inhibition. Can limit ATP availability during high-demand exercise. | Optimization. Corrects Complex III, maintaining better ATP flux while reducing oxidative stress. | Imeglimin Advantage: Better fuel efficiency for contracting muscle. |
| ROS Hormesis | Blunting. Scavenges ROS “blindly,” potentially killing the signal for adaptation. | Targeted Reduction. Prevents Complex III superoxide leakage but increases PGC-1α (biogenesis). | Imeglimin Advantage: Enhances mitochondrial density without killing the exercise signal. |
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3. The “Hormesis” Factor
The primary fear with antioxidants (and Metformin) is that they blunt hormesis—the beneficial stress response where Exercise-Induced ROS signals the body to get stronger.
- Metformin tends to blunt this signal, leading to the “sub-optimal” training response seen in the MASTERS trial.
- Imeglimin appears to bypass this via the NAMPT/NAD+ pathway. By increasing intracellular NAD+, Imeglimin activates Sirtuins (SIRT1/SIRT3) and PGC-1α. This mimics the benefits of exercise (mitochondrial biogenesis) rather than just suppressing the signal.
Conclusion
Scientific evidence suggests Imeglimin is superior to Metformin for the active individual. While Metformin acts as a “metabolic brake” that can compromise the anabolic response to exercise, Imeglimin acts more like a “mitochondrial tuner.” It likely will not blunt strength gains and may synergize with exercise to improve sarcopenia risks, even if it doesn’t strictly act as a hypertrophy agent (muscle builder).
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Not medical advice. ChatGPT 5.2
Approved Japanese Prescribing Information (Summary)
Standard dose (normal renal function)
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1,000 mg twice daily (total 2,000 mg/day)
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Taken after meals (usually breakfast and dinner)
This is the only fully approved dose in the Japanese package insert.
Renal Impairment: What Is Known vs What Is Approved
Japan’s labeling is conservative. Dose reductions below are not formally approved indications, but are commonly cited in PK analyses, expert reviews, and post-marketing discussions.
| eGFR (mL/min/1.73 m²) | Dose Used / Suggested | Regulatory Status in Japan | Notes |
|---|---|---|---|
| ≥45 | 1,000 mg twice daily |
 Approved |
Standard dosing |
| 30–<45 | 500 mg twice daily |
 Not formally approved |
Based on PK modeling; monitor closely |
| 15–<30 | 500 mg twice daily |
Off-label / modeling only |
Very limited clinical data |
| <15 or dialysis | 500 mg once daily |
 Not recommended |
Not approved; insufficient safety data |
Key Regulatory Nuances (Important)
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Japanese labeling does NOT officially endorse dose adjustment for moderate or severe renal impairment.
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Instead, it states that use should be avoided or approached with extreme caution in advanced CKD.
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The reduced-dose schemes (500 mg BID or QD) come from:
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Pharmacokinetic simulations
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Small exposure studies
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Expert consensus (not large outcome trials)
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Safety Observations Relevant to Older Adults
Given your interest in glucose-lowering alternatives with mitochondrial relevance:
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Low hypoglycemia risk (no insulin stimulation)
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No lactic acidosis signal (unlike metformin)
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GI effects are usually mild and transient
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Long-term renal outcome data remain limited
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Price is affordable, Zydus is trustful.
But can it be counteractive with Rapamycin?