Metformin: Risk/Reward Profile (Tradeoff Considerations; Balancing of Factors; Cost-Benefit Analysis) [Author: Type-IIx]

[Type-IIx]

Metformin: Risk vs. Reward Profile

Author: Type-IIx

Here are the basic contours of risks versus rewards for the practical use of Metformin, a biguanide, for bodybuilding, that I will build out with more depth and breadth if readers want to delve deeper:

Metformin: anti-hyperglycemic and an insulin-sensitizing agent.

The efficacy of Metformin XR is about 12 h. IR 6 h.

Risks:

1. Hypertrophy attenuation (↓ muscle growth in response to progressive resistance training [PRT])
   1. AMPK activation inhibits mTORC1/P70S6K1 phophorylation [1]
   2. Abrogates (blocks) the adaptive preferential shift from type I to type IIA fibers (resulting in a tendency towards reduced strength gains) [1]
   3. Reduces testosterone (free & total) & increases SHBG in healthy men [2] (relevant for those who do not use exogenous androgens)
2. Abrogates endurance training enhancement of insulin sensitivity (blocks cardio's effect to ↑insulin sensitivity) [1]
3. No difference in fasting glucose, glucose response, insulin sensitivity versus progressive resistance training (PRT) alone [1]
4. Attenuation of lipid oxidation from ET (↓ fat oxidation by cardio)
   1. Inhibition of mitochondrial complex I overrides AMPK activation (PRT/PRT+ET indicates against metformin) [1]
5. Gastrointestinal dysregulation (bloating, diarrhea, nausea, abdominal distension)
6. Vitamin B12 deficiency [4]
   1. Consequent increase in homocysteine levels (if B vitamins not supplemented) [3]
7. Potential birth defects (data needed)

Rewards:

Principally applies to those who are on rhGH and/or aromatizing androgen:

1. Insulin sensitizing properties attenuate the increase in blood glucose from rhGH [10]
2. Improved glucose and fatty acid oxidation via AMPK activity [10]
3. Likely improves symptoms of erectile dysfunction (ED) + PDE5 inhibitor vs. PDE5 inhibitor alone [5]
4. Increases serum IGF-I in combination with rhGH [6]
5. Likely improves palmitate-induced inflammation in skeletal muscle [2]
6. Applies to those on testosterone:
   1. Likely attenuates BPH risk [7]
   2. May (highly speculative) ameliorate AAS-induced cardiac changes [9-10]

Conclusion:

Unless you're on rhGH or aromatizing androgen, or insulin resistant/prediabetic, weigh Metformin's risks (particularly acute in abating certain training adaptations) vs rewards.

---

References

[1] Walton, R. G., Dungan, C. M., Long, D. E., Tuggle, S. C., Kosmac, K., Peck, B. D., … Peterson, C. A. (2019). 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. Aging Cell. doi:10.1111/acel.13039
[2] Shegem NS, Nasir AM, Jbour AK, Batieha AM, El-Khateeb MS, Ajlouni KM. Effects of short term metformin administration on androgens in normal men. Saudi Med J. 2002 Aug;23(8):934-7. PMID: 12235466.
[3] Zhang, Q., Li, S., Li, L., Li, Q., Ren, K., Sun, X., & Li, J. (2016). Metformin Treatment and Homocysteine: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients, 8(12), 798. doi:10.3390/nu8120798
[4] Roy RP, Ghosh K, Ghosh M, Acharyya A, Bhattacharya A, Pal M, Chakraborty S, Sengupta N, Mukhopadhyay S. Study of Vitamin B 12 deficiency and peripheral neuropathy in metformin-treated early Type 2 diabetes mellitus. Indian J Endocr Metab 2016; 20:631-7
[5] Rey-Valzacchi, G. J., Costanzo, P. R., Finger, L. A., Layus, A. O., Gueglio, G. M., Litwak, L. E., & Knoblovits, P. (2011). Addition of Metformin to Sildenafil Treatment for Erectile Dysfunction in Eugonadal Nondiabetic Men With Insulin Resistance. A Prospective, Randomized, Double-Blind Pilot Study. Journal of Andrology, 33(4), 608–614. doi:10.2164/jandrol.111.013714
[6] Type-IIx. hGH + Metformin: A Good Thing (Metformin does not lower, but rather increases IGF-1). 2021 Apr. Source: hGH + Metformin: A Good Thing (Metformin does not lower, but rather increases IGF-1)
[7] Mosli HH, Esmat A, Atawia RT, Shoieb SM, Mosli HA, Abdel-Naim AB. Metformin Attenuates Testosterone-Induced Prostatic Hyperplasia in Rats: A Pharmacological Perspective. Sci Rep. 2015;5:15639. Published 2015 Oct 23. doi:10.1038/srep15639
[8] Crocker CL, Baumgarner BL, Kinsey ST. β-guanidinopropionic acid and metformin differentially impact autophagy, mitochondria and cellular morphology in developing C2C12 muscle cells. J Muscle Res Cell Motil. 2020;41(2-3):221-237. doi:10.1007/s10974-019-09568-0
[9] Lv, L., Zheng, N., Zhang, L., Li, R., Li, Y., Yang, R., … Shan, H. (2020). Metformin ameliorates cardiac conduction delay by regulating microRNA-1 in mice. European Journal of Pharmacology, 881, 173131. doi:10.1016/j.ejphar.2020.173131
[10] Li, J., Minćzuk, K., Massey, J. C., Howell, N. L., Roy, R.J., Paul, S., … Kundu, B. K. (2020). Metformin Improves Cardiac Metabolism and Function, and Prevents Left Ventricular Hypertrophy in Spontaneously Hypertensive Rats. Journal of the American Heart Association, 9(7). doi:10.1161/jaha.119.015154
[11] Kwon B, Querfurth HW. Palmitate activates mTOR/p70S6K through AMPK inhibition and hypophosphorylation of raptor in skeletal muscle cells: Reversal by oleate is similar to metformin. Biochimie. 2015 Nov;118:141-50. doi: 10.1016/j.biochi.2015.09.006. Epub 2015 Sep 5. PMID: 26344902.

 

[lonewolf54321]

Metformin: Risk vs. Reward Profile

Author: Type-IIx

Here are the basic contours of risks versus rewards for the practical use of Metformin, a biguanide, for bodybuilding, that I will build out with more depth and breadth if readers want to delve deeper:

Metformin: anti-hyperglycemic and an insulin-sensitizing agent.

The efficacy of Metformin XR is about 12 h. IR 6 h.

Risks:

1. Hypertrophy attenuation (↓ muscle growth in response to progressive resistance training [PRT])
   1. AMPK activation inhibits mTORC1/P70S6K1 phophorylation [1]
   2. Abrogates (blocks) the adaptive preferential shift from type I to type IIA fibers (resulting in a tendency towards reduced strength gains) [1]
   3. Reduces testosterone (free & total) & increases SHBG in healthy men [2] (relevant for those who do not use exogenous androgens)
2. Abrogates endurance training enhancement of insulin sensitivity (blocks cardio's effect to ↑insulin sensitivity) [1]
3. No difference in fasting glucose, glucose response, insulin sensitivity versus progressive resistance training (PRT) alone [1]
4. Attenuation of lipid oxidation from ET (↓ fat oxidation by cardio)
   1. Inhibition of mitochondrial complex I overrides AMPK activation (PRT/PRT+ET indicates against metformin) [1]
5. Gastrointestinal dysregulation (bloating, diarrhea, nausea, abdominal distension)
6. Vitamin B12 deficiency [4]
   1. Consequent increase in homocysteine levels (if B vitamins not supplemented) [3]
7. Potential birth defects (data needed)

Rewards:

Principally applies to those who are on rhGH and/or aromatizing androgen:

1. Insulin sensitizing properties attenuate the increase in blood glucose from rhGH [10]
2. Improved glucose and fatty acid oxidation via AMPK activity [10]
3. Likely improves symptoms of erectile dysfunction (ED) + PDE5 inhibitor vs. PDE5 inhibitor alone [5]
4. Increases serum IGF-I in combination with rhGH [6]
5. Likely improves palmitate-induced inflammation in skeletal muscle [2]
6. Applies to those on testosterone:
   1. Likely attenuates BPH risk [7]
   2. May (highly speculative) ameliorate AAS-induced cardiac changes [9-10]

Conclusion:

Unless you're on rhGH or aromatizing androgen, or insulin resistant/prediabetic, weigh Metformin's risks (particularly acute in abating certain training adaptations) vs rewards.

---

References

[1] Walton, R. G., Dungan, C. M., Long, D. E., Tuggle, S. C., Kosmac, K., Peck, B. D., … Peterson, C. A. (2019). 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. Aging Cell. doi:10.1111/acel.13039
[2] Shegem NS, Nasir AM, Jbour AK, Batieha AM, El-Khateeb MS, Ajlouni KM. Effects of short term metformin administration on androgens in normal men. Saudi Med J. 2002 Aug;23(8):934-7. PMID: 12235466.
[3] Zhang, Q., Li, S., Li, L., Li, Q., Ren, K., Sun, X., & Li, J. (2016). Metformin Treatment and Homocysteine: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients, 8(12), 798. doi:10.3390/nu8120798
[4] Roy RP, Ghosh K, Ghosh M, Acharyya A, Bhattacharya A, Pal M, Chakraborty S, Sengupta N, Mukhopadhyay S. Study of Vitamin B 12 deficiency and peripheral neuropathy in metformin-treated early Type 2 diabetes mellitus. Indian J Endocr Metab 2016; 20:631-7
[5] Rey-Valzacchi, G. J., Costanzo, P. R., Finger, L. A., Layus, A. O., Gueglio, G. M., Litwak, L. E., & Knoblovits, P. (2011). Addition of Metformin to Sildenafil Treatment for Erectile Dysfunction in Eugonadal Nondiabetic Men With Insulin Resistance. A Prospective, Randomized, Double-Blind Pilot Study. Journal of Andrology, 33(4), 608–614. doi:10.2164/jandrol.111.013714
[6] Type-IIx. hGH + Metformin: A Good Thing (Metformin does not lower, but rather increases IGF-1). 2021 Apr. Source: hGH + Metformin: A Good Thing (Metformin does not lower, but rather increases IGF-1)
[7] Mosli HH, Esmat A, Atawia RT, Shoieb SM, Mosli HA, Abdel-Naim AB. Metformin Attenuates Testosterone-Induced Prostatic Hyperplasia in Rats: A Pharmacological Perspective. Sci Rep. 2015;5:15639. Published 2015 Oct 23. doi:10.1038/srep15639
[8] Crocker CL, Baumgarner BL, Kinsey ST. β-guanidinopropionic acid and metformin differentially impact autophagy, mitochondria and cellular morphology in developing C2C12 muscle cells. J Muscle Res Cell Motil. 2020;41(2-3):221-237. doi:10.1007/s10974-019-09568-0
[9] Lv, L., Zheng, N., Zhang, L., Li, R., Li, Y., Yang, R., … Shan, H. (2020). Metformin ameliorates cardiac conduction delay by regulating microRNA-1 in mice. European Journal of Pharmacology, 881, 173131. doi:10.1016/j.ejphar.2020.173131
[10] Li, J., Minćzuk, K., Massey, J. C., Howell, N. L., Roy, R.J., Paul, S., … Kundu, B. K. (2020). Metformin Improves Cardiac Metabolism and Function, and Prevents Left Ventricular Hypertrophy in Spontaneously Hypertensive Rats. Journal of the American Heart Association, 9(7). doi:10.1161/jaha.119.015154
[11] Kwon B, Querfurth HW. Palmitate activates mTOR/p70S6K through AMPK inhibition and hypophosphorylation of raptor in skeletal muscle cells: Reversal by oleate is similar to metformin. Biochimie. 2015 Nov;118:141-50. doi: 10.1016/j.biochi.2015.09.006. Epub 2015 Sep 5. PMID: 26344902.

This is a topic I'm really interested in. I've been researching it a bit as a couple of people whose opinion I respect advocate taking metformin. I hope more people are interested so you explore this topic more in depth.

 

[29trt]

All well and good, but without actual numbers all this is kind of eh..

So it decreases hypertrophy.. by how much in a dosed up bodybuilder?

if AAS increases hypertrophy by lets say 90% and metformin reduces it by 10,no big deal... if it's 50% than yeah we have a problem...
Can an aproximation be made regarding this?

 

[Type-IIx]

All well and good, but without actual numbers all this is kind of eh..

So it decreases hypertrophy.. by how much in a dosed up bodybuilder?

if AAS increases hypertrophy by lets say 90% and metformin reduces it by 10,no big deal... if it's 50% than yeah we have a problem...
Can an aproximation be made regarding this?

LOL, absolutely fucking not. This is what's referred to as a Perfect Solution Fallacy.

 

[Type-IIx]

Somebody elsewhere asked a great question that made me put on my thinking cap.

I will share it here:

Great post that summarizes all i have read about it and even more !
Still are the negative sides on cardio and strength relevant for enhanced bodybuilders on high test, androgens and l carnitine for instance ??
What about hydro berberine ??

Since the mechanisms by which Met:

A) Blunts hypertrophy (by inhibiting mTORC1/P70S6K1 phophorylation) are independent from the mechanisms by which AAS/T act (AR-mediated effects that do not implicate mTOR – see [link], with special reference to the section heading "✖ Translational efficiency")

&

B) Blunts fat oxidation via aerobic-endurance training (by inhibiting mitochondrial complex I) are independent from the mechanisms by which L-Carnitine (theoretically, but not demonstrated in humans) i. acts on fat oxidation by augmenting fatty-acid transport from the cytosol to the mitochondria for β-oxidation via the carnitine system due to malonyl CoA regulation in human skeletal muscle which acts as a feedback regultor to muscle carnitine, and/or ii. due to insufficient bioavailability in humans given exogenous L-Carnitine by any route

&

C) are different from those of hydroberberine, which blunts hypertrophy by two (2) novel mechanisms, including i. impairing mitochonidrial function stimulation of the expression of atrogin-1 expression without ii. affecting phosphorylation of forkhead (e.g., FOXO) transcription factors, which not only stimulates protein degradation (↑MPB) but also suppresses protein synthesis (↓MPS), causing muscle atrophy.

Atrogin-1 & MuRF1 are downstream in the IL-6 (Inflammatory Signaling) & Myostatin (Negative Muscle Growth Regulation) signaling & secondary messenger pathways & components of these are indeed acted upon (enhanced) by T/AAS (which inhibits these two negative growth regulators),

Since atrogin-1 is potently suppressed by Tren (> Test) & Test (i.e., AAS broadly), and Test attenuates proteolytic and inflammatory responses by reducing resting skeletal muscle expression of fibroblast growth factor-inducible 14 (Fn14), thereby exerting a protective effect against IL-6 signaling, & since Test negatively regulates Myostatin expression by cross-talk with it, it's hypothetically more likely that AAS/T can to some extent mechanistically claw back some lost anabolism from the use of hydroberberine, unlike Met. But this has not been demonstrated in any model (e.g., BBR + T measuring hypertrophy signaling and/or outcomes), it is merely theoretical.

 

[4Drago]

Can someone just make this shit easy for me? I'm diabetic and the only med I refuse to take is metformin. My glucose/diabetes is well controlled. I have bottles of the shit (metformin) but I have enough gut extension issues im trying to get control of. Hoping this cut and reduced food intake takes care of this issue. I'll be low carb as well so won't need as much insulin. I'm current taking 3iu hgh and will continue thru my cut cycle.

To metformin, or to not, is the question.

 

[UncleBuns]

All well and good, but without actual numbers all this is kind of eh..

So it decreases hypertrophy.. by how much in a dosed up bodybuilder?

if AAS increases hypertrophy by lets say 90% and metformin reduces it by 10,no big deal... if it's 50% than yeah we have a problem...
Can an aproximation be made regarding this?

Here's a link to the full paper from his 1st reference:

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13039

It's got more detail on hypertrophy.

 

[mrjodaa]

question: does berberine have the same negative effects on muscles as metformin? I am considering whether to use berberine or metformin on 4iu hgh

 

[sbdman]

 

[Type-IIx]

question: does berberine have the same negative effects on muscles as metformin? I am considering whether to use berberine or metformin on 4iu hgh

Somebody elsewhere asked a great question that made me put on my thinking cap.

I will share it here:



Since the mechanisms by which Met:

A) Blunts hypertrophy (by inhibiting mTORC1/P70S6K1 phophorylation) are independent from the mechanisms by which AAS/T act (AR-mediated effects that do not implicate mTOR – see [link], with special reference to the section heading "✖ Translational efficiency")

&

B) Blunts fat oxidation via aerobic-endurance training (by inhibiting mitochondrial complex I) are independent from the mechanisms by which L-Carnitine (theoretically, but not demonstrated in humans) i. acts on fat oxidation by augmenting fatty-acid transport from the cytosol to the mitochondria for β-oxidation via the carnitine system due to malonyl CoA regulation in human skeletal muscle which acts as a feedback regultor to muscle carnitine, and/or ii. due to insufficient bioavailability in humans given exogenous L-Carnitine by any route

&

C) are different from those of hydroberberine, which blunts hypertrophy by two (2) novel mechanisms, including i. impairing mitochonidrial function stimulation of the expression of atrogin-1 expression without ii. affecting phosphorylation of forkhead (e.g., FOXO) transcription factors, which not only stimulates protein degradation (↑MPB) but also suppresses protein synthesis (↓MPS), causing muscle atrophy.

Atrogin-1 & MuRF1 are downstream in the IL-6 (Inflammatory Signaling) & Myostatin (Negative Muscle Growth Regulation) signaling & secondary messenger pathways & components of these are indeed acted upon (enhanced) by T/AAS (which inhibits these two negative growth regulators),

Since atrogin-1 is potently suppressed by Tren (> Test) & Test (i.e., AAS broadly), and Test attenuates proteolytic and inflammatory responses by reducing resting skeletal muscle expression of fibroblast growth factor-inducible 14 (Fn14), thereby exerting a protective effect against IL-6 signaling, & since Test negatively regulates Myostatin expression by cross-talk with it, it's hypothetically more likely that AAS/T can to some extent mechanistically claw back some lost anabolism from the use of hydroberberine, unlike Met. But this has not been demonstrated in any model (e.g., BBR + T measuring hypertrophy signaling and/or outcomes), it is merely theoretical.

Berberine (BBR) is functionally equivalent to hydroberberine.

 

[Type-IIx]

Here's a link to the full paper from his 1st reference:

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13039

It's got more detail on hypertrophy.

Yeah but he's asking for a quantification of to what degree this occurs with different dosages of different gear & Met, ridiculous shit. I basically answered it in post #5: it's unlikely AAS claw back any of this diminished hypertrophy or cardio adaptations because they don't work by the same mechanisms, but obviously you can blast so much it seems to make the effect less substantial because you grew, derp.

 

[UncleBuns]

Yeah but he's asking for a quantification of to what degree this occurs with different dosages of different gear & Met, ridiculous shit. I basically answered it in post #5: it's unlikely AAS claw back any of this diminished hypertrophy or cardio adaptations because they don't work by the same mechanisms, but obviously you can blast so much it seems to make the effect less substantial because you grew, derp.

Gotcha. I'm not familiar enough with hypertrophy or cardio adaptation pathways at that level to have an opinion either way. I wish the study was done with different dosages though. I'd like to assume that the negative effects are dose dependent. In that study participants took 1700mg a day.

Do you know if there is evidence whether some of the negatives, specifically hypertrophy blunting, diminished cardio lipid oxidation, and reduced insulin sensitivity adaptation can be partially mitigated with timing? Basically if metformin is only taken before bed and away from exercise would it still have the same level of negative outcomes?

 

[AlexDavis43]

Gotcha. I'm not familiar enough with hypertrophy or cardio adaptation pathways at that level to have an opinion either way. I wish the study was done with different dosages though. I'd like to assume that the negative effects are dose dependent. In that study participants took 1700mg a day.

Do you know if there is evidence whether some of the negatives, specifically hypertrophy blunting, diminished cardio lipid oxidation, and reduced insulin sensitivity adaptation can be partially mitigated with timing? Basically if metformin is only taken before bed and away from exercise would it still have the same level of negative outcomes?

If it is within your capacity, increasing exercise to counteract those effects is the answer.

But that's why we do the drugs, to make less work more effective. But sometimes have to do more work.

 

[UncleBuns]

If it is within your capacity, increasing exercise to counteract those effects is the answer.

But that's why we do the drugs, to make less work more effective. But sometimes have to do more work.

The reason I became interested in Metformin is because during a time period of heavy exercise, well above my normal weekly caloric output, I did labs and my A1c had risen by 0.5%. I had also done a 6 week cut about 2 weeks before the test. My A1c had been stable for years before that during any stage of training. The only thing different was that at that time I also was using 2.5 units GH nightly. The GH was the only thing that had changed which could have caused the rise. I was doing hours of cardio a week during that time as well as strength exercises. That GH dosage is not very high.

I am continuing to experiment and will check my A1c again with the addition of nightly metformin added to the GH. At this point I don't have enough info but my body may just spike blood glucose higher than most people from GH.

The answer isn't always "work harder". You are assuming a lot about me but I assure you that you know fuck all about what you seem to be very sure of. Any more effort than I already put in would be a detriment to my goals. I've overtrained a number of times before and I'm not fond of injury or digging a recovery hole.

 

[29trt]

Here's a link to the full paper from his 1st reference:

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13039

It's got more detail on hypertrophy.

well that study is just a great example of all this mess...
they did NOT observe a decrease in BG with the folks taking metformin... what the actual fuck... thats what it's meant to do and it does well hence being prescribed to prediabetics and they stay on met for years and years before going to full exo insulin...

and its all a bit contradictory as they noted them self's as other studies showed that metformin prevented muscle loss in sedentary elderly individuals... so how does this work? @Type-IIx

 

[clearheaded]

anyone really notice more lactic acid build up on metformin? didn't know that it apparently elevates even resting lactic acid levels.. ie some disfunction in metabolism..

I wonder if the anecdotes of poorer work outs aren't from lowered blood sugar but purely/party lactic acid...

 

[Bammdk]

What if you do Metformin IR 12 hours before training?
I train at 2 PM. And take IR 500mg at 10 PM. That’s 8 hours after training and 14 hours before. Should be out of the system?
Or is the inhibition also occurring after the drug has left the blood?

 

[29trt]

LOL, absolutely fucking not. This is what's referred to as a Perfect Solution Fallacy.

Nope... , just trying to make a point.... the controls gained a minuscule amount of "lean" tissue and the metformin group did not gain an even more minuscule amount of tissue... how much can you extrapole from this to AAS, HGH, INSULIN abusing individuals??

I mean if indeed metformin would cause a 30-40%(or whatever studies show) decrease in muscle accruel, you would think guys using it would notice a difference... do they? i have no clue, we should have a poll

 

[Type-IIx]

I'd like to assume that the negative effects are dose dependent. In that study participants took 1700mg a day.

Never assume dose-dependency without evidence of it – which we don't have here.

Often drug effects are drug effects per se and not a result of dose.

Do you know if there is evidence whether some of the negatives, specifically hypertrophy blunting, diminished cardio lipid oxidation, and reduced insulin sensitivity adaptation can be partially mitigated with timing? Basically if metformin is only taken before bed and away from exercise would it still have the same level of negative outcomes?

This is a really good question that we don't have the answer to – so I do not know.

This trial did not analyze effects with respect to time: neither vis-à-vis Met ingestion nor training (however I must note that their progressive resistance training plan was outstanding & far superior to what a lot of novice bodybuilders do). This time-agnosticism serves the interests of both ecological validity (being applicable to actual T2DM patients) & adherence (it's much harder to adhere to a strict timing schedule than to just take your Met in the morning with breakfast or what have you).

 

[Type-IIx]

What if you do Metformin IR 12 hours before training?
I train at 2 PM. And take IR 500mg at 10 PM. That’s 8 hours after training and 14 hours before. Should be out of the system?
Or is the inhibition also occurring after the drug has left the blood?

This is a really good question that we don't have the answer to – so I do not know.

This trial did not analyze effects with respect to time: neither vis-à-vis Met ingestion nor training (however I must note that their progressive resistance training plan was outstanding & far superior to what a lot of novice bodybuilders do). This time-agnosticism serves the interests of both ecological validity (being applicable to actual T2DM patients) & adherence (it's much harder to adhere to a strict timing schedule than to just take your Met in the morning with breakfast or what have you).