Imeglimin. A new and novel drug thats better than Metformin

#75

Just noticed this message from a while back… here is the response from Gemini 3 Pro:

Contraindication Analysis: Imeglimin and Rapamycin (Sirolimus)

There is currently no scientific or clinical evidence indicating that imeglimin is contraindicated for individuals taking rapamycin. On the contrary, existing pharmacokinetic and pharmacodynamic data suggest the two compounds are structurally independent and potentially synergistic in mitigating the metabolic side effects of mTOR inhibition.

Pharmacokinetic (PK) Independence

The primary safety concern when stacking compounds with rapamycin is the modulation of cytochrome P450 3A4 (CYP3A4), as rapamycin is heavily dependent on this enzyme for hepatic metabolism.

  • Renal Excretion vs. Hepatic Metabolism: Imeglimin is excreted largely unchanged in the urine via active renal secretion (utilizing OCT1/OCT2 and MATE transporters). It undergoes minimal hepatic metabolism.
  • Absence of CYP Interference: In vitro and in vivo human studies confirm that imeglimin has no significant induction or inhibition potential toward CYP450 enzymes, including CYP3A4. Therefore, co-administering imeglimin will not artificially elevate or depress systemic rapamycin trough levels, avoiding acute toxicity or sub-therapeutic dosing.

Pharmacodynamic (PD) Synergy

Rapamycin is utilized in longevity protocols to inhibit the mTORC1 pathway, a mechanism that reliably delays cellular senescence but frequently induces metabolic toxicity. Long-term sirolimus use dampens peripheral insulin signaling and increases hepatic gluconeogenesis, often resulting in insulin resistance, hyperglycemia, and hypertriglyceridemia (clinically documented as New-Onset Diabetes After Transplantation, or NODAT).

Imeglimin presents a compelling mechanistic countermeasure to this specific side-effect profile:

  • Mitochondrial Rescue: Rapamycin-induced insulin resistance is driven by peripheral tissue metabolic stress. Imeglimin targets mitochondrial bioenergetics (mildly inhibiting Complex I while stimulating Complex II), reduces reactive oxygen species (ROS), and upregulates glucose-stimulated insulin secretion without exhausting $\beta$-cells.
  • Clinical Application for mTOR Toxicity: Recent clinical reviews explicitly identify medications targeting compromised mitochondrial function, specifically citing imeglimin, as therapeutic interventions to rescue blood sugar control and metabolic homeostasis in patients suffering from immunosuppressant-induced diabetes (including those on sirolimus).

Knowledge Gaps & Required Data

While informed speculation strongly supports the safety and metabolic utility of this combination, significant evidentiary gaps remain in the literature.

  • Translational Void: There are zero Randomized Controlled Trials (RCTs) directly evaluating the co-administration of imeglimin and rapamycin in healthy human populations for healthspan extension or sarcopenia prevention.
  • Data Requirements: To definitively validate this protocol, crossover clinical trials are required. These studies must quantify whether imeglimin’s activation of upstream metabolic sensors (such as Akt or AMPK) unintentionally blunts rapamycin’s geroprotective mTORC1 suppression at the skeletal muscle or organ level. Furthermore, continuous glucose monitoring (CGM) and cross-sectional lipid tracking in a co-administered cohort are required to quantify the exact magnitude of imeglimin’s rescue effect on rapamycin-induced dyslipidemia.
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#76

Imeglimin Shows Sustained Real-World Efficacy in Aging Diabetics, But High-Dose Metformin Combo Triggers Gut Distress

Mitochondrial modulators are gaining traction in the longevity and metabolic health space, and imeglimin—a novel oral tetrahydrotriazine—is showing promise outside of strictly controlled clinical trials. A new retrospective cohort study analyzed the 12-month real-world efficacy of imeglimin in individuals with type 2 diabetes. The drug, which targets mitochondrial complex I to enhance insulin secretion and suppress hepatic gluconeogenesis, effectively reduced HbA1c by an average of 0.8% across all age groups over the study period.

Crucially for longevity protocols targeting older demographics, imeglimin maintained its efficacy and favorable tolerability profile in the very elderly, including those aged 75 and older. However, the data revealed a significant translational caveat for combination therapies: co-administering imeglimin with high-dose metformin (1,000 mg/day or more) significantly increased the frequency of gastrointestinal disturbances. Because both drugs inhibit mitochondrial complex I and share structural similarities, their stacked use likely amplifies gut toxicity. Patients whose biguanide doses were reduced or discontinued when starting imeglimin experienced fewer GI events, but they also saw less robust HbA1c reductions compared to those who maintained their biguanide dose, highlighting a stark efficacy-versus-tolerability trade-off.

Beyond glycemic control, the study noted favorable off-target metabolic effects. Over 12 months, subjects exhibited significant reductions in body weight, triglycerides, and liver enzymes, specifically ALT, AST, and gamma-GTP. These secondary outcomes suggest imeglimin may possess hepatoprotective properties, potentially offering a therapeutic vector against metabolic dysfunction-associated steatotic liver disease (MASLD), a major driver of systemic aging.

  • Paper: Real-world effectiveness and safety of imeglimin: a single-center retrospective cohort study in Japan
  • Context: This research was conducted by scientists at the Central Japan International Medical Center, Gifu University, and Kyoto University in Japan.
  • Journal: It was published in Frontiers in Clinical Diabetes and Healthcare.
  • Impact Evaluation: The impact score of this journal is 2.2, evaluated against a typical high-end range of 0–60+ for top general science, therefore this is a Low impact journal.
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#77

Looking at imeglimin literature, I was currently focusing on the effect on mitochondria, and a few papers were interesting enough to share here in a batch (with brief commentary from me).

There has been talk here about imeglimin vs metformin in regard to exercise, and a question about the possibility that imeglimin might be similarly suboptimal in the context of exercise. It seems not. In fact, there might be synergies between imeglimin and exercise - at least resistance exercise (free article).

Combination of imeglimin and resistance exercise improves mitochondrial function and glucose metabolism in skeletal muscles

“These findings suggest that the combination of imeglimin and RT [Resistance Training] is a promising therapeutic approach to enhance mitochondrial function and glucose metabolic capacity.”

There have been suggestions that some drugs that were used in T2DM were actually beneficial for CV health, such as SGLT2i. Well, it looks like perhaps imeglimin might join the club, insofar as it might mitigate atherosclerosis - who knew!

Molecular mechanism for pancreatic β-cell dysfunction and atherosclerosis

“Recently we have reported that imeglimin exerts beneficial effects on mitochondria morphology in β-cells and/or number and quality of insulin granules. In addition, we have reported that imeglimin shows favorable effects against the development of atherosclerosis independently of glycemic and lipid control.”

That part about the effect on atherosclerosis was independent of glycemic and lipid control is very important, because it tells us that this effect is not solely due to imeglimin being an anti-diabetic agent, and also because it can be used as an addition to LLT (statins, ezetimibe etc.), and the effects on atherosclerosis should therefore stack.

How does imeglimin work in beta cells? Overview.

Current understanding of imeglimin action on pancreatic β‐cells: Involvement of mitochondria and endoplasmic reticulum homeostasis

A big part of fighting aging is centered around the inflammatory process that is downstream from LPS propagation. It looks like imeglimin might be helpful here (free article).

Imeglimin attenuates NLRP3 inflammasome activation by restoring mitochondrial functions in macrophages

“We demonstrated for the first time that imeglimin reduces LPS-induced NLRP3 inflammasome activation by inhibiting mPTP opening in THP-1 macrophages. These results suggest that imeglimin could be a promising new anti-inflammatory agent for treating diabetic complications.”

The next paper speaks for itself - mitochondrial ROS is a fundamental driver of aging, so it’s nice to see imeglimin might be helpful here (free article).

Suppressing Mitochondrial ROS Production is Beneficial in Multiple Preclinical Models of Human Disease

Finally, the last paper is just a case report, but I liked it because it used three classes of drugs, which many of us have an interest in: SGLT2i, ARB and glimin. As a small additional factor, the ARB in question is olmesartan which I have increasing interest in.

Mitochondrial Nephropathy With m.5538G>A Mutation Within the tRNA-Trp Region Assessed by Mitochondrial Function Analysis: A Case Report

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#78

I use acarbose 100mg each meal, dapa 10mg and tirz 3mg + the imeglimin

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#79

Do you track your blood glucose at all with a CGM? I would love to see your charts… how is your waking blood glucose? Any issues with low blood sugar… low energy, etc.?

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#80

A few week report on imeglimin + dapaflogzen (??) an SGLT2. I put on a CGM, continuous glucose monitor, stelo, not that good but works and cheap.

500mg am imeglimin was ok, + 10mg dapa was ok slightly better. taken upon rising, before brushing teeth re timing. I have a pronounced dawn effect of a 30pt rise from pre wakening in bed. 75-80 rising to 110-120.

Upping to the suggested 1000mg imeg at rising + 10mg dapa knocked that back down under 100.

Flat through AM, early afternoon. Then prior to dinner, 4pm for us, I take another 500mg imeg + 10mg dapa (though std dose is 10mg alll day) and I’m flat through our meat dinner, wine, cheese desert, often some dark chocolate that has std sucrose…

I’m VERY happy getting this imeg tip here from THIS thread. THANK YOU guys!!!

Next experiment is to add a blood pressure drug; telimsartan, a low toxisity, gp for general health drug similar to imeg in that it has wider benefits then just small nudges on blood pressure that I don’;t have any problem with. This prospect came to me as a low toxic low risk alternative to carderine a thermogenic with a cancer rumor (probably out of context). Reading that telimisartan also nudges better glucose control.

IMHO lower glucose (70-90 flat all day is the goal) thus lower to flat insulin leads to lower all forms of inflammation, leads to lower inflam-aging and lower disease.

Both of us have taken this groups guessing and moved to 6mg rapa every 2 weeks. I do more due to my past testing experience of low absorption re my blood testing.

Good luck and health to all, curt

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#81

Maybe a bit impatient (on my part) but I think we are due another update from you @cl-user on imeglimin. Share what you can, FG, Exercise, any effect on markers (if you had labs lately) etc…Thanks,

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#82

@Kelman Wearing a CGM, Lingo, seemed to work the best. I wore 2 Stelo’s both died in the 2nd week.

1000mg imeglimin upon waking, and 500mg prior to dinner. And 10mg dapaflogzen (??) at AM and either 5mg or 10mg of dapa upon dinner;

Diet: low carb high protein and 2 meals aday. AM might be protein powder + left over meat/fish/cottage cheese, or all of the above. And at 4pm some meat or fish. A french style desert or 2nd course of cheese. Usually some dark chocolate. I aim for 120grams of protein. Honestly probably under 50g of carbs. Fat is just in the cheese and flat iron steak. I do add ghee, butter, to coffee/bone broth each AM. I also add a teaspone of sheep tallow to a vitamin mix; adding steric acid and also a teaspone or 2 of high oliec olive oil. Decently high fish oil incluiding decently high dosing of PRMs from prodrom.com .

YET without this glucose control my glocose will have a dawn effect running from 90’s while sleeping up into 120/130 by 8am without a food based reason. Through the day normal glucose will vary between 120 and down to 90’s. An allopathic endo would say my glucose is perfect. An anti-aging researcher would say I’m too high.

You’d think this low carb (IE <<100g/day some might say is lowish carb, yet I think I’m under 50) I’d be bouncing at 70 with ease. My wife can, not so much me. But she has a slow pancreas/eyelets and she can spike. She’s slow at uptake new things so so far is not on these drugs.

Post imeg/dapa; sleeping glucose bounces off 70 and always under 80, dawn effect very slight up to 90, and day time can drop into the 80s, and stay flat under 90 through dinner. Even small carbs, berries, chocolate can have little effect. Crap deserts with synthetic ultra-glycemic can spike to 120 even 130 but that is low compared to naked of 140-150.

No side effects; stomach, intestinal, any… Pills chew easily and swallow with water quickly. Are cheap from alldaychemist.com. Or other Indian sources.

IMHO these 2 drugs are life time and can’t see any reason to not take.

Its 5pm, less then 45 min post dinner just tested for ketones with a keto-mojo. 0.2. Which is amazing given I should have some insulin… Which I must not have much else I’d not be producing ketones this close to food!! Meaning these drugs allow my insulin to stay so low I still produce ketones. Which IMHO is the total goal, super low insulin.

With peptide boosts of HGH, the secretagogs, minor excersize grows good muscle. Even on rapa, low carb, low insulin. I have very good muscle. Can curl 45# hand weights x 10 reps. Most body builders believe one needs to feed carbs and run insulin high to grow muscle…

Pre drugs my fasting insulin was under 3.5, very very low. I’m taking these drugs to go from good glucose control to excellent. This all is on top of the usual; Alpha lipoic acid and friends.

My total cholesterol is too low at 165, 72 HDL. At 72yo male I’d prefer LDL above 125 maybe more. Some I believe because we eat only regeneratively grown grass finished beef; an example is flat iron steaks from piedmontese.com, miller bio farm in PA, Frankies grass finished beef… Piedmontese is easiest to order from. Also very very good frozen trout from smokeinchimneys.com . Grill fast on charcole stuffed with onion, dill and lemon. 3.5min a side.

Good luck, curt

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#84

Can you share your thoughts on why you would like higher cholesterol? Is it because you think it’s needed for adequate sex hormone production, or perhaps because of the theories that it benefits the immune system? I have been trying to keep mine very low so I am interested in an alternative perspective.

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#85

My mother is full blown diabetic at 7.6 HBA1C. She is taking 2 g Metformin and 25 mg Empagliflozin daily. If I were to add Imeglimin, would I have to cut down on the Metformin? Would all 3 meds be too much for her? @CronosTempi @desertshores

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#86

In general, imeglimin lowers A1c less than metformin. But imeglimin addresses more defects in the diabetic pathways than metformin. Therefore if metformin is not effective in a given patient, imeglimin might be a better choice. That was the reasoning of @cl-user for whom metformin was ineffective (fwiw, it’s ineffective for me too) and so he switched to imeglimin and I believe has had some success, though we’d have to get a report wrt. A1c.

As to combining metformin with imeglimin, I have not come across any clinical data, so that’s an unknown. I would try imeglimin alone first. If not effective, I would try a GLP-1RA rather than combining metformin with imeglimin.

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#87

why you would like higher cholesterol

We’ve been going to Low carb/Metabolic Health, Metabolic Symposium confs for 5 yrs now. 100% of speakers dis the low cholesterol is heart health theory. 100% mention studies of how anti-healthy (with only a few exceptions) statins are. True they lower inflammation but at a huge expense of joint health/pain, and brain loss of health. So if the brain is starved of what its made of (fats and cholesterol) and you run higher dementia risk why take a statin?

I ran off the tracks above where I only ment to set the table;

  • As we age we need cholesterol, yes preferably the bigger particle LDL vs smaller, for joint health, feeding the immune system.
  • Covid stats found folks with higher cholesterol had much better out comes.
  • Sex hormones AND vit D are made from cholesterol. I’m sure it would be buried science if ED/sterility,loss of sex drive was tracking with statin use, but it would be my guess.
  • I don’t have studies, but generalizations from the “stage” that as we age we are healthier with higher LDL and of course higher HDL.

== How I’ve gone from decent total cholesterol of 225 ish now 175 is a mystery. I once found a study of the bioregulator Vesugen lowers LDL. I now can’t find that study via google (a mystery or not). Also alot of the anti aging nutricals that are std in most mixes have some LDL lowering properties. So my quest to raise my LDL seems doomed.

@Tilmitt Curious: do you have morning sore feet, joints, difficult to find comfortable sleeping position due to stiff joints? Have you tested your hormones and if no HRT what are they? Hows your sickness resistance? Just asking for an N=1 of symptoms from someone working to keep LDL low?

I get a CAC, calcium scan every other year via investing in a lifetime full body scan offer by an EBC, electron beam scan service, https://www.virtualimagingatl.com and others, and my CAC score as is my wife’s on full carnivor = zero, nothing, zero calcium anywhere in our bodies, at 72yo. If my cholesterol was a blessed 500 I’d still be thankful. OBTW at the conferences; they cited a study of Familial High Cholesterol, >>300, and same or better mortality vs the general population. IE familial high cholesterol folks did not have members dieing early from heart disease… Its shocking that the Statin research got by on such slim stats in this light.

No need here to get into what does predict heart disease but generally; inflammation including elevated insulin and Triglicerides >>150. IMHO the best risk indicator of heart disease is triglicerides, lesser A1C, hsCRP is ok, APO-b ok, APO-a ok, triglicerides = highly predictive. True APO-a/b, hsCRP usually very high as well when triglicerides is high. But every chemistry panel includes triglicerides.

All is JMO, Best to all, curt

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#88

Statins have been proven to at least partially reverse plaque (the stuff that kills you in ASCVD). All other approaches have, at best, been shown to give a marginal improvement on top of statins.
Furthermore, studies show that statins mostly have a neutral effect on dementia rates. After all, all cells in the body are perfectly capable of producing their own cholesterol. Natural does not mean good. Cancer is natural and so is diabetes. As for joint pain, only a small minority of people get them (myself included), the rest can take high statin doses and the worst thing that happens to them is a 0.1 point increase in HbA1C.

As we age we need cholesterol, yes preferably the bigger particle LDL vs smaller, for joint health, feeding the immune system.

All particles are damaging.

Sex hormones AND vit D are made from cholesterol. I’m sure it would be buried science if ED/sterility,loss of sex drive was tracking with statin use, but it would be my guess.

No statistically significant difference in testosterone levels even on the highest doses of atorvastatins. Only small difference with simvastatin.

I don’t have studies, but generalizations from the “stage” that as we age we are healthier with higher LDL and of course higher HDL.

The effect disappears once we adjust for causal reasons such as cancer, liver failure etc. We end up with a straight line where higher cholesterol equals more death.

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#89

@DeStrider IMHO your mother #1 has a diet problem. Drugs are a bandaid. Sorry to offer this view but I’m hard on the side of the body responds to what its fed, excersize, muscle % … I saw my mother game her use of insulin so she could over eat carbs. She didn’t die quietly in her sleep as she kept pushing back on my nagging. A bad stroke the night of a high (bad) fat / high carb meal, death thankfully 6 mo later. 2 mo ago went to a conference, Meat Stock in Gatlinburg TN. The stage spoke of Type II, huge weight loss not on just GLP-1, but moving to high protein diet from a SAD. BUT a lower dosed GLP-1 is a very good help for Type II.

@CronosTempi Only my decission making I added an SGLT-2 to imeglimin to boost foot print of control. No defensible reason but I chose Dapagliflozen over the other flozens.

Best to all , curt

#90

@Virilius From the stage it was offered a middle ground re statins. If one’s CAC, calcium score is low to zero, then ignore cholesterol and don;t take a statin, especially if hsCRP, ApoB, triglicerides are low. My guess would be alot of folks would not need to be on the universally prescribed statin.

We all can believe what we choose. Its good you believe differently then me.

Best wishes curt

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#91

And wait for soft plaque to develop? No way. Triglycerides are just another aspect of apoB and statins lower them too.

My guess would be alot of folks would not need to be on the universally prescribed statin.

Then they would die as nature intended.

We all can believe what we choose. Its good you believe differently then me.

If someone chooses to ignore scientific consensus and the literal fact that statins have been proven to (partially) reverse plaque buildup, they need to be called out on that. Especially now that the LHMR study got retracted because they attempted to hide the primary outcome (huge plaque increase) which once and for all proves that it’s not muh flamation causing ASCVD but those fatty little particles in our blood.

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#92

I understand the impatience for an update! I was recently on vacation in New Mexico for some trail running and hiking, and I intentionally kept my internet use to a minimum.

I have some news regarding my Imeglimin progress. I had an HbA1C test done just before my vacation, marking 20 weeks of Imeglimin at 1000mg BID. The results were somewhat disappointing, as my HbA1C remained unchanged at 5.9.

Despite this, I remain positive. Studies indicate that adding Imeglimin to a GLP1-RA may not significantly lower HbA1C further. In my case, 5.6mg/week of Tirzepatide and 25mg of Empagliflozin also resulted in no HbA1C reduction. I know the Tirzepatide is legitimate, as my wife has seen significant results on a lower dose, while I have not lost any weight.

On the positive side, Imeglimin has been effective at reducing my fasting glucose. My levels dropped from slightly above 100 mg/dl to around 90 mg/dl, and my nightly glucose now stays between 85 and 95. This is a clear improvement.

Regarding the stubborn HbA1C, my genetic data suggests I have SNPs related to over-glycation, a higher glucose set point, and beta cell dysfunction. Importantly, Imeglimin did not impact my physical performance. I recently completed the Boston marathon in under four hours, which was my target.

In summary, Imeglimin has successfully normalized my liver glucose output, even if it hasn’t addressed other glucose-related issues. My next step will likely be a full glucose tolerance test including Insulin and C-Peptide measurements.

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#93

Thank you, @cl-user for this report. I was holding off asking about any results until you had a couple of A1c readings. I am not very surprised that your A1c has not moved. In my experience, for some people the A1c is extremely stubborn (like me!), and multiple interventions can’t seem to address it. For others it seems very easy, like losing weight, exercise or diet - laughably ineffective for me.

Re: fasting glucose. Here’s an interesting experience. In the past 15 years or so, my dawn effect has gradually drifted up, until hitting 110-112 mg/dL. Very stubborn and treatment resistent. Until empagliflozin. I started with 12.5mg/day and it dropped my FBG to below 100 in the morning… and that was good for a few months, and it started drifting back up to 105-110. I escalated the dose to 25mg/day and it again knocked it below 100, to 95-98, and this time it stuck - so far (about a year). In all this time my A1c didn’t budge 5.7 - 5.9.

I wish that CGMs worked for me - they emphatically do not (I have tried, repeatedly). Because I’d be curious to see a report from say, a week’s readings across 24 hours continuous monitoring to see where exactly the A1c gets bumped - there has to be some pathway that is causing this, perhaps hepatic production, beta cell insuffiency or whatnot.

In any case, I am planning to add imeglimin to my stack down the road, toward the end of the year - right now I’m trying to get back to my full exercise regimen (restriced by surgeon following ACDF surgery) and want to be fully with the drug/diet/exercise program before adding anything.

Frankly, I am not counting on imeglimin necessarily affecting my A1c - though I’d be thrilled if it did - but I suspect it can further lower my FBG. Anyhow it will be interesting to see if there is any effect on any other biomarkers. It seems like a very interesting roll of the dice.

Glycation - A deep dive into genetic pathways for actionable insights
#94

BTW, for those interested, here is what Opus 4.8 thinks about that. #2 is an interesting point.

The four factors that explain why your HbA1c didn’t move

1. You’re not the trial population

Your baseline HbA1c is 5.9% (pre-diabetes), not 7–10% (T2D). The TIMES trials excluded patients like you. The most directly relevant study is the recent Diabetes Obes Metab 2026 dual-action mechanism paper (PMC12992193), where patients with baseline HbA1c 6.9% showed only 6.9% → 6.7% = −0.2% at 20 weeks. That’s a near-perfect baseline-comparator for you. Imeglimin’s effect size scales with baseline hyperglycemia — when you start lower, you move less. The Satheesan mitochondrial function study (PMC12353691) explicitly attributes lower monotherapy efficacy to “lower baseline HbA1c levels.”

Predicted effect for your starting point: an HbA1c drop on the order of 0.1–0.3%, not 0.5–0.9%. A drop from 5.9% to 5.7% would be the expected effect. Going from 5.9 → 5.9 is plausibly within the measurement noise of HbA1c at this magnitude (analytical CV ~2-3%, biological CV ~1.5%, so a single 5.9 could really be anywhere from ~5.7 to 6.1).

2. Imeglimin actually distorts HbA1c upward

This is the finding I missed in the first reply. The INFINITY trial (Iitaka et al., Front Endocrinol 2026, PMC12591969) found that imeglimin prolongs erythrocyte lifespan, which causes HbA1c to understate the true glycemic improvement. Per the paper: “imeglimin may prolong erythrocyte lifespan, resulting in disproportionately elevated HbA1c levels relative to true glycemic status. Reliance on HbA1c alone may underestimate imeglimin’s early glycemic effects, highlighting the value of alternative markers such as GA and 1,5-AG.”

In INFINITY (n=18, baseline HbA1c 6.5-8.5%, 6 months imeglimin 1000 mg BID): HbA1c declined gradually while glycated albumin (GA) and 1,5-anhydroglucitol (1,5-AG) moved much faster. Erythrocyte lifespan was significantly prolonged in both the 1–3 month and 4–6 month periods. The mechanism is plausible: imeglimin reduces oxidative stress in RBCs (via NAD⁺ salvage / improved mitochondrial respiration), so RBCs survive longer and accumulate more glycation over their extended lifespan.

What this means for you: your HbA1c of 5.9 → 5.9 may actually be masking a real glucose improvement that imeglimin is producing. The only way to see this is glycated albumin (GA) or fructosamine — both with ~2–3 week half-lives that bypass the RBC-lifespan confound.

You had a Jan 2026 fructosamine of 239 µmol/L (in the published reference range for healthy 20-60 yr olds of 205-285). If you repeat fructosamine now, a value of 200–210 would be a real improvement, even though HbA1c didn’t budge. This is the single most important test to add to your next blood draw.

3. Rapamycin is pulling in the opposite direction

Your own genetic report flags this explicitly: rapamycin 12 mg q3wk contributes to HbA1c drift. The PEARL 2025 trial (Moel et al., Aging, NCT04488601, n=115) showed modest HbA1c signal in one rapamycin subgroup. Combined with your β-cell-secretion-impaired genetic background (CDKAL1 hom + KCNJ11/ABCC8 hom + INS-locus hom + TCF7L2 het), there’s a real headwind. The fact that imeglimin held HbA1c flat at 5.9% rather than allowing continued drift could itself be evidence imeglimin is working — it stopped the climb.

4. Tirzepatide + empagliflozin had already lowered the “easy” gains

In the TIMES 2 study, imeglimin monotherapy at 52 weeks gave −0.46% HbA1c, while combination with DPP4i gave −0.92%. Combination with GLP1-RA gave only −0.12% — the smallest incremental effect of any combination. The interpretation: when an incretin agonist is already aggressively engaging the β-cell, the marginal benefit of adding imeglimin’s secretagogue effect is reduced. You’re already on tirzepatide 2.6 mg twice weekly, which is a very effective incretin amplifier — leaving less room for imeglimin to add on the secretagogue side. The hepatic gluconeogenesis-reduction component remains, but that’s the smaller part of imeglimin’s effect.

Putting it together: was 16 weeks of imeglimin a “failure”?

I don’t think so, and here’s how I’d reframe it:

Predicted effect of imeglimin in your specific clinical context (baseline HbA1c 5.9%, on tirzepatide + empagliflozin + rapamycin, with imeglimin’s RBC-lifespan confound):

  • True glycemic improvement (by GA / 1,5-AG / fructosamine): probably real but small, in the −0.1 to −0.2% HbA1c-equivalent range
  • Observed HbA1c improvement: probably near zero or even slightly underestimated, because of the erythrocyte-lifespan extension
  • Hepatic gluconeogenesis suppression: harder to see in fasting glucose alone but could be visible on CGM

Citations (new sources from this update)

  • Dubourg J et al. Efficacy and Safety of Imeglimin Monotherapy Versus Placebo (TIMES 1). Diabetes Care 2021;44:952–959. PMID 33574125 (open access).
  • Dubourg J et al. Long-term safety and efficacy of imeglimin (TIMES 2). Diabetes Obes Metab 2022 (open access).
  • Reilhac C et al. TIMES 3: imeglimin add-on to insulin. Diabetes Obes Metab 2022. PMID 34984815 (open access).
  • Dubourg J et al. Dose-ranging Phase 2b imeglimin trial in Japanese T2D. Diabetes Obes Metab 2021. PMID 33275318 (abstract-only).
  • Iitaka H et al. Imeglimin may affect hemoglobin A1c accuracy via prolongation of erythrocyte lifespan: insights from the INFINITY clinical trial. Front Endocrinol 2026;16:1699591. PMC12591969 (open access). ← Critical to the interpretation.
  • Furuyoshi S et al. Dual action of imeglimin on insulin secretion and sensitivity in type 2 diabetes. Diabetes Obes Metab 2026 Apr. PMC12992193 (open access).
  • Satheesan A et al. Effect of imeglimin on mitochondrial function in T2DM: prospective cohort. Front Endocrinol 2025. PMC12353691 (open access).
  • Real-world Japan retrospective cohort. PMC12747980 (open access).
  • INDI-TIMES real-world India n=8,301. PMC11925818 (open access).
  • Moel M et al. PEARL trial: rapamycin in healthy adults. Aging 2025. NCT04488601 (open access).
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#95

To all, @cl-user tnx for the interesting details. I wore 2 brands of non prescription CGMs, Ligo vs Stelo, both showed my before / after dual dapa+1000mg imeg that my already good 24hr glucose (A1C 5.4 on rapa) down to an even better glucose. Where before on a low carb diet my dawn effect could rise by 8am to 120. Then chop around 90-110 through the day and a possible spike to 120 after dinner of meat, cheese and small amount of dark chocolate. IMHO my native glucose has never been good to me.

Post 10mg dapa + 1000mg imeg upon waking AND another 10mg sometimes 5mg dapa and 500mg imeg prior to dinner my glucose rarely is over 100 and through the day bounces between 75-90 pretty flat. Where prior my glucose has more zigs. My goal is flat and sub 95 through the day.

I am aware, thx Dr Bikman et al, that starving 7 days a week of carb spikes (cheat day, bolices of fruit, resistant starch) the pancrease/eyelets will get lazy and loose the initial bolice of insulin thus causing a higher spike when a cheat is eaten, waiting for the native new mfger of insulin to proceed taking some times hours. I agree that cheat days / events have value to keep the beta cells trained. Some how, I’m remaining idealistic and wishing to think I will avoid cheat days all together. ;-| ;-| I’m very trained and will eat kraut / kimche vs crackers as a snack. I do quest for more cheese but dairy alergy/MCAs slows that cheat down. I’m not as angelic as I’m sounding. I’m certain I will not use dapa+imeg as a means to eat worse, but to genuinely get better 24x7 flatter glucose with risks of sporatic worse spikes should a piece of cheese cake fall my way, mysteriously. Knowing that my taking dapa+imeg will keep the spike much lower than otherwise.

N=1, experiment has been amazingly successful. And metformin gives me a lethargic feeling so stopped taking and that box is just on the shelf. Glad to ship to anyone who can take an Indian source of 500’s/1000’s bought off alldaychemist. PM me.

No side effects from dapa+imeg so its a permanent addition for me.

Best to all, curt

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