#485

I didn’t check dosage much but yes I think that canagliflozin has to be taken before the first meal whereas dapa and empa can be taken whenever you want during the day. Actually, it could be the reason why it’s less and less prescribed: because it’s less practical and flexible? (also some members here reported more side affects although the data I found said side effects were identical among SGLT2)

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#486

You guys have both provide some really good information on these drugs. Its an interesting question… why are the market shares so different with these drugs. One of the interesting things with patented small molecule drugs is that the patent is filed pretty early in the process, so when the drug is finally launched there may only be 10 years or so left of patent life. I also wonder if follow-on drugs go through the FDA approval processes more quickly simply because everyone is more familiar with the drug and issues related to it, and so it may be possible that follow-on drugs tend to end up with more functional patent life, and thus time before they go generic. Anyway, I’m thinking these factors influence marketing schedules (most of the marketing effort for a drug goes into the initial few years after launch, so after 3 years they are then off looking for new indications for the drug to extend their patent lives and new marketing opportunities.

Anyway, its hard (from outside the industry) to identify which drug has more marketshare and specifically for what reasons… it could be because one company has a better sales channel for that specific indication / market segment, or because they feel its a really important market and want to invest heavily so that they have a channel for follow on drugs targeting that segment… but if we have any Pharma industry people, I’m sure they could tell us if they have some experience in this market segment. @J0hn , your thoughts? How often does the “best drug” win, in the Pharma marketshare game?

Ultimately I just tried Canagliflozin starting a few years back because it was the only one proven in the ITP studies, but when that drug didn’t work for me I moved to empagliflozin. Ultimately you just want to find a medication that works with minimal side effects for your body, so I would try a few. With the Indian suppliers its pretty easy to order different “flozins” and see what works best for you over a few month trial period. The data will continue to get better on these drugs, so we can update as we learn more.

And, as long as we’re on the topic, does anyone have a good idea why rosuvastatin has done so well?

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#487

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Atorvastatin seems to be increasing in popularity the most. In a U-shape curve! Must mean it’s fake? :wink:
It also went off patent in 2011, at the bottom of the curve.

There was the RCT that did show less side effects compared to rosuvastatin. Very promising drug.

Someone should make ‘Atorvastatin - Top Human Anti-Aging drug’ thread.

These four common medicines could help prolong your life (Viagra, atorvastatin, naproxen, oestrogen)
#488

Unfortunately I was just a ‘lowly’ lab technician in the pharmaceutical industry. The company I worked for (which I don’t wish to name) is quite large in the industry. From what I saw and heard from the trenches it’s very political and decisions were often driven by patent expiry fears…

The company was heavily into heart medication but didn’t have a statin in its portfolio so they cut a deal with a Japanese company for Crestor (Rosuvastatin), I was one of those who did the due diligence on it, to make sure we weren’t being sold ‘a pig in a poke’. I know at the time there was a big internal debate about buying a me-too drug and entering the market in n-th position, because there already so many statins on the market.
And it was the same when they partnered up to enter the SGLT2i field.

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#489

@RapAdmin I tried Rosuvastatin because it was supposed to have the least number of side-effects, it wasn’t affected by GFJ, and was just as effective as all the other statins. Due to this, I believe Rosuvastatin has become the go to statin. But, even Rosuvastatin caused me some trouble (muscle myopathy).

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#490

I read and referenced that paper above. @59vw is in my option correct in that mice is where the “only” real longevity data is (in gold standard ITP and in more than one ITP study and each time across three different sites). And those are only in Cana (too date). It also potentially a bit weird that no academic lab - outside of ITP - has done any smaller, cheaper study with other SGLTi agents given how often they do aging studies if they think it will lead to a new paper…? (Or perhaps such studies have been done but not shown longevity and hence not published?)

Please note that - as discussed elsewhere on the forum - increased health span or decreasing a or several big diseases (and even decreasing all course mortality) is not the same as increasing maximum life span. In that sense I don’t think it is correct to say ”For longevity [in] humans the whole class proved its benefits”. There is no clinical longevity data on SGLTi as far I’ve seen on this thread or elsewhere.

The only semi causal longevity data in humans I’ve seen on this thread so far is the Mendelian randomization that SGLT1 causally decreased mortality in humans.

For me @59vw point on ITP today being the only longevity data + that Cana is the only one (discussed as a real option) that has SGLT1i and not just SGLT2i have to be weighted together.

Combined with that there are the additional crucial point that SGLT1i is a different mechanism than SGLT2i (see above).

If it just were different flavors of SGLT2i I might think differently, but switching out Cana to Dapa or Empa is about also having to take a leap of faith that SGLT1i was not relevant even given that that is what the IPT and Medellian randomization data shown so far have the causal data on.

Has anyone looked if there is any other Mendelian randomization data - eg on SGLT2i - that could perhaps help guide us a bit further.

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#491

That might be a large part of what drives the uptake of SGLT2i also (same as it probably did for acarbose vs metformin in wheat diet heavy parts of the world).

Patients will ask about side effects, prescribiting doctor does not want to deal with a whiny patients about side effects - neither the patient or the doctor even know about the longevity data if they even would care about it than they in general do not.

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#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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