#492

Are you sure that they sell Empa that way even if they had a version of the pill like that they used in the trial.

I ask because of the comment by AgelessRX above saying the below which suggest that is not how Empa (or Dapa) are sold nowadays…

We obtained tablets from all 5 approved SGLT2i meds. Only canagliflozin was amenable to breaking in half. The other tabs were oddly shaped (likely on purpose if I were a cynic) and could not be easily broken.

Btw, this is suggesting that eod (even with a half pill) might work:

We have preliminary data that taking half tab of 300mg canaglizflozin (150mg) every other day seems to provide a decent amount of glucosuria every day (not just the day taken).

For both and more see:

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#493

No, it is not sold this way, actually the manufacturers leaflet suggests it shouldn’t be broken in half, but a while ago I found a study using the half of 25mg (12.5mg) and not 10mg sold. There is no reason it couldn’t be broken in half (albeit with some skill and pill cutter). I asked my doctor if I can do that and she said: “It is not me who said yes, but yes, you can.”
Probably the only reason why the manufacturer is not suggesting braking it in half it is profit. They charge the same for both 10 and 25mg pills and they never sought approval of 12.5mg dose in trials even if this would be the most logical.

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#494

My pharmacist told me it’s mainly because you can have for example 5mg il one half and 20 in the other. But considering the half life of empa, it should not really be problematic. Some fragile molecule can oxydize nevertheless.

#495

Could you please send me links to these discussions? I don’t think I’ve read them.

I agree that these are different notions. Still, I think that “decreasing all-cause mortality” helps to reach the goal of “increasing maximum life span”. Preventing incurable diseases helps as well. And it turns out that in all longitudinal studies I found on people with T1D, T2D, CKD, or HF, after several years, we see lower all-cause mortality and lower comorbidities (cancer, Alzheimer’s, other dementia, Parkinson’s, depression, atrial fibrillation, arrhythmia, T2D, CKD, HF, etc.). [And often, empa or dapa perform a bit better than cana.] Given that diabetes + pre-diabetes + CKD + pre-CKD + HF + pre-HF = the vast majority of the US population above 65yo, one can assume SGLT2 will increase maximum lifespan in this group, and that it might translate to the general population.

Mendelian randomization studies I found, most of them don’t look at deaths/all-cause mortality unfortunately:

Anyway, @Neo, if you really believe in SGLT1 inhibition, I’d love to submit an application for sotagliflozin (“the first dual SGLT inhibitor”) with you for the ITP: About the ITP | National Institute on Aging Anyone else, feel free to join this effort!

The only comparison of dual SGLTi vs SGLT2i-only is this one and they conclude: Metabolic, Intestinal, and Cardiovascular Effects of Sotagliflozin Compared With Empagliflozin in Patients With Type 2 Diabetes: A Randomized, Double-Blind Study 2022

In summary, sotagliflozin and empagliflozin did not show any major differences in overall glycemic and BP control or in selected metabolic, urinary, and intestinal parameters. In contrast, mechanistic differences were confirmed. Inhibition of SGLT1 by sotagliflozin was accompanied by prolonged lowering of plasma GIP levels as well as a postprandial increase in aGLP-1. For the most part, the current study was unable to identify obvious features that would convincingly relate to a different clinical impact of dual versus single SGLT inhibition in patients with T2D, but the potential benefit of lower GIP levels on cardiovascular outcomes suggests the need for additional studies to determine if prolonged sotagliflozin-mediated lowering of plasma GIP levels contributes to improved cardiovascular outcomes observed with this drug.

The authors also make an interesting remark on GIP:

However, they highlight the effect of the two SGLT inhibitors, particularly sotagliflozin, on GIP levels, noting that recent research suggests that GIP inhibition may be cardioprotective, contrary to the development of GLP-1/GIP co-agonists to treat type 2 diabetes.
Walther and team suggest this paradox may be explained if GIP agonists work by “desensitizing” the GIP receptor, leading to a decrease rather than an increase in GIP receptor signaling.

(from a news article commenting on the paper Sotagliflozin effects differ from empagliflozin only at breakfast)

Also: Managing heart failure in diabetics with dual acting sotagliflozin—A review 2023

Sotaglifozin is equally effective at inhibiting SGLT-2 as the specific SGLT-2 inhibitors dapaglifozin and canaglifozin, although it is ten times more potent at inhibiting SGLT-1 than these drugs. Less is known about its impact on SGLT-1 in various tissues. According to the information available, sotaglifozin doesn’t appear to affect renal SGLT-1, indicating that its low affinity only has clinical effects in the gut and other tissues where SGLT-1 is highly expressed. Because sotaglifozin concentrations in the intestinal lumen is higher than that in the bloodstream as a whole, another explanation is that sotaglifozin functions as a powerful intestinal SGLT1 inhibitor [30].

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#496

A SGLT1 inhibitor will most likely avoid UTI risk, so it has that going for it. It seems to be entirely different if it works in the intestine.

#497

Your reasoning only works for SGLT1-only inhibitors, correct? I don’t think any company is developing one.

By the way, sotagliflozin’s maker wants to extend its indication to hypertrophic cardiomyopathy (HCM, can be caused by tracrolimus btw): https://twitter.com/MasriAhmadMD/status/1746370987380322445

This could be a unique benefit of sotagliflozin and, therefore, make the case for dual SGLT1/2 inhibition.

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#498

Yes, this. I wouldn’t use market share as any kind of guide for which medicine is better. Different pharmaceutical companies can afford to (or choose to afford to) invest in more sales reps, more lunches/dinners for medical providers, etc, which has a much bigger influence on prescribing habits than we’d like to admit (even if we think we’re too smart to be influenced). Also, just as importantly if not moreso, drug companies make back-room deals with insurance companies for their particular drug to be on-formulary, such that Jardiance is preferred by insurance company X (have to try/fail Jardiance first before another SGLT2i is covered, for instance). In addition, there are “discount cards” for insurance copays that can make drug X more attractive than drug Y or Z ($5 copay card vs $20 copay card for another drug). This is how it works in the USA, at least.

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#499

Yes but there is SGLT1 in the kidneys as well so I guess it would have to be only selective for intestinal SGLT1.

Tacrolimus is not a mTOR inhibitor.

Downside of SGLT1 inhibition in the intestine is that it will block oral rehydration therapy:

Sodium absorption occurs in two stages. The first is via intestinal epithelial cells (enterocytes). Sodium passes into these cells by co-transport with glucose, via the SGLT1 protein. From the intestinal epithelial cells, sodium is pumped by active transport via the sodium-potassium pump through the basolateral cell membrane into the extracellular space.[41][42]

The sodium–potassium ATPase pump at the basolateral cell membrane moves three sodium ions into the extracellular space, while pulling into the enterocyte two potassium ions. This creates a “downhill” sodium gradient within the cell. SGLT proteins use energy from this downhill sodium gradient to transport glucose across the apical membrane of the cell against the glucose gradient. The co-transporters are examples of secondary active transport. The GLUT uniporters then transport glucose across the basolateral membrane. Both SGLT1 and SGLT2 are known as symporters, since both sodium and glucose are transported in the same direction across the membrane.[citation needed]

The co-transport of glucose into epithelial cells via the SGLT1 protein requires sodium. Two sodium ions and one molecule of glucose (or galactose) are transported together across the cell membrane via the SGLT1 protein. Without glucose, intestinal sodium is not absorbed. This is why oral rehydration salts include both sodium and glucose.
Oral rehydration therapy - Wikipedia

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#500

This is true in the US, less so (or not at all) in countries with single-payer healthcare, such as most European countries. Of course, market share per se doesn’t indicate which medicine is better, but I find it an interesting signal that all around the world, people abandon canagliflozin. Another signal: among the 140 clinical trials of SGLTi started over the past year, only 3 studied canagliflozin. So it’s not only about marketing, researchers in academia as well are less and less interested in canagliflozin, while being more and more interested in studying SGLTi in general.

(for me, given my personal and family history of depression, I rule out using canagliflozin until we have better data on its effect on depression as one study showed it might be associated with higher risks, while dapagliflozin was associated with lower risk: The potential antidepressant effect of antidiabetic agents: New insights from a pharmacovigilance study based on data from the reporting system databases FAERS and VigiBase 2023, it’s a weak signal, only from one study, but I won’t take the risk.)

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#501

By the way, talking about negotiations, I didn’t know that empagliflozin (Jardiance) and dapagliflozin (Farxiga) were among the 10 drugs selected for price negotiation by the U.S. Department of Health and Human Services (HHS), as part of Biden’s Inflation Reduction Act: https://www.cnbc.com/2023/08/29/most-used-drugs-on-medicare-price-negotiation-list-see-the-top-three.html

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Hopefully, they’ll become cheaper as well in the private sector?

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#502

I wonder why manufacturer stopped marketing it in EU? Maybe because it was approved only for DT1?

#503

Yes - I suspect you are very right on this. The markets in Europe seem less “commercially corrupted” in the medication use area. I don’t think the drug companies have such free reign to pay off the doctors, and other intermediaries to gain market / use advantage as in the USA. And of course, in the US, Advertising drugs to the end user is a huge business… as if the average person has enough knowledge or expertise to evaluate medications.

In theory - since the government and doctors are going to be primarily interested in patient outcomes, they “should” use what they perceive as the most effective drug (though prices of the drugs to the medical system may vary, so there could be a cost / benefit analysis also going on).

This is all in theory - there may be other factors involved I don’t know about… like the slowness of adoption of new drugs in Single Payer markets due to institutional lethargy? Perhaps some doctors in Europe can comment on what the key drivers of medicine adoption / use is?

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#504

Yes it’s in theory but in practice you also have negotiations like “We’re a French company, we have N jobs in France, we pay n€ of taxes in France so… you gonna be nice and give us a better deal for this drug? It would be sad if we were to leave France? :smiling_imp:” And then they get to be reimbursed by the social security and not their competitor. Or they get a better deal. Still, it’s not as bad as in the US. Dapagliflozin out of pocket without an insurance costs €/$40 in Europe vs $400 in the US?

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#505

Yes it’s weird. They first marketed it for T1D. Then they withdrew it and said they would re-file it for T2D but… Never did! :man_shrugging:

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#506

Started to look a bit more at MR studies:

Mendelian randomization revealing the protective effect of sodium-glucose cotransporter 2 inhibition on prostate cancer with verified evidence from electronic healthcare and biological data

Just a pre-print, but interesting - and a surprisingly large effect size?

In this study, Mendelian randomization (MR) was applied in 140,254 men (79,148 with prostate cancer), and suggested that genetically proxied SGLT2 inhibition showed an effect on 44%, 48% and 73% reduced risk of total-, advanced- and early-onset prostate cancer in the general male population

https://www.medrxiv.org/content/10.1101/2023.10.10.23296790v1#:~:text=Added%20value%20of%20this%20study,in%20the%20general%20male%20population.

SGLT2 Inhibition, Choline Metabolites, and Cardiometabolic Diseases: A Mediation Mendelian Randomization Study

Interesting that it boosts glycine?

Results: SGLT2 inhibition (per 1 SD, 6.75 mmol/mol [1.09%] lowering of HbA1c) was associated with lower risk of T2D and CAD (odds ratio [OR] 0.25 [95% CI 0.12, 0.54], and 0.51 [0.28, 0.94], respectively) and positively with total choline (β 0.39 [95% CI 0.06, 0.72]), phosphatidylcholine (0.40 [0.13, 0.67]), and glycine (0.34 [0.05, 0.63]). Total choline (OR 0.78 [95% CI 0.68, 0.89]) and phosphatidylcholine (OR 0.81 [0.72, 0.91]) were associated with T2D but not with CAD, while glycine was associated with CAD (0.94 [0.91, 0.98]) but not with T2D

—-

Outside of Mendelian randomization - different from different ethnicities?

Sodium-glucose co-transporter-2 inhibitors and all-cause mortality: A meta-analysis of randomized controlled trials

Does anyone understand the bolded part below? Does anyone have access to the paper?

Treatment with SGLT2 inhibitors was associated with a significant reduction in all-cause mortality (MH-OR [95% CI] 0.86 [0.81, 0.91] P < .00001). Meta-regression analyses found a significant direct association of treatment effect only with the proportion of Asian subjects enrolled, and an inverse correlation with the proportion of Caucasian patients. In conclusion, SGLT2 inhibitors reduce all-cause mortality in randomized controlled trials.

—

Lower Risk of Death With SGLT2 Inhibitors in Observational Studies: Real or Bias?

Note also the issue with these trials being in sick people and not in healthy longevity optimizers:

In conclusion, the >50% lower rate of death with SGLT2i in type 2 diabetes reported by two recent observational studies is likely exaggerated by immortal time and time-lag biases

Lower Risk of Death With SGLT2 Inhibitors in Observational Studies: Real or Bias? - PubMed.

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#507

So the only MR causal study for any SGLT inhibitor, seems to be this one, which I think is the same one discussed by both @adssx and me above.

Seems to point to Mendelian randomization verified causal reduction in all course mortality?

Has no one really looked at this for SGLT2 i??? Are we just missing it? Hopefully we will see some MR study soon (the number of MR studies exploded the last few years).

Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk

Reduced intestinal glucose uptake may protect [this if from SGLT1 i and NOT SGLT2 i]

Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90).

The effect size does seems quite large? Or what are you used to seeing in MR @AnUser

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#508

For people who are concerned about UTIs and other infections, I wonder if intermittently taking a 'flozin with a shorter half-life would provide a better balance between efficacy and risks. Hypothetically, oscillating between on and off drug periods might make it harder for things to grow.

Remogliflozin etabonate is approved in India and has a short enough half-life that dosing is twice daily. In one study, the elimination half life was 120 minutes, suggesting a single dose would be effectively gone in about half a day. So maybe taking remogliflozin etabonate once daily before a main meal would provide some benefits while keeping things more hostile to bacteria and yeast.

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#509

I understand (but I’m not sure I’m correct) that SGLTi might decrease ACM more in Asians than in White people? :thinking:

This paper is cited by this one: Ethnic disparities in cardiovascular and renal responses to canagliflozin between Asian and White patients with type 2 diabetes mellitus: A post hoc analysis of the CANVAS Program 2023

The 2023 paper actually concludes the opposite as it found a “reduced risk in Whites (hazard ratio 0.84; 95% confidence interval 0.71-0.99) and a statistically non-significant increased risk in Asians (hazard ratio 1.64; 95% confidence interval 0.94-2.90).”

Probably better to avoid canagliflozin if you’re Asian? It might explain why no one uses it in Japan as well.

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#510

Two new papers on SGLTi:

Differing Efficacy of Dapagliflozin Versus Empagliflozin on the Risk of Incident Atrial Fibrillation in Patients With Type 2 Diabetes: A Real‐World Observation Using a Nationwide, Population‐Based Cohort: “This real‐world, population‐based study demonstrates that patients with type 2 diabetes using dapagliflozin may have a lower risk of developing nonvalvular atrial fibrillation than those using empagliflozin.”

SGLT2 Inhibitors Squeak Out a Win in Patients Post-MI: it’s a news article commenting on the recent paper is previously shared that showed the benefits of starting dapagliflozin after a stroke. It’s interesting that it’s now in the medical news and my friends who work in resuscitation rooms in French hospitals told me last week that they were discussing a lot using dapagliflozin after the publication of this paper. It’s not yet recommended by the national guidelines for that in France but I assume they’ll start using it anyway.

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#511

I use remogliflozin, not because of its transient nature, but because it’s ‘dirt cheap’ from IndiaMart and other places (money was tight at the time). Now thinking of looking at other SGLT2 inhibitors.

I’m going to do a head to head with canagliflozin (when I can get some) empagliflozin and remofloglozin and look at 24 hour urinary glucose output.

btw I take remofloglozin before each meal

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