Canagliflozin - Another Top Longevity Drug

[desertshores]

And the winner is: Empagligozin?

[adssx]

Why? In terms of HR dapagliflozin seems the best.

[Joseph_Lavelle]

Amazing. I’ve been on dapa for a year. I’ve been trying to switch to Cana but US Customs has been an obstacle. I’ll just stay on dapa.

[Neo]

What’s do you have as (a) goal(s) for takin the flozin?

[Joseph_Lavelle]

Several goals:
(1) original goal was weight loss. didn’t happen & don’t really need it
(2) lower blood sugar. didn’t happen but may have been confounded by rapa
(3) longevity. still hoping.

[DeStrider]

@约瑟夫_拉维尔 Well, that’s a bummer. I have the same goals in taking a flozin.

[desertshores]

I am primarily interested in reducing all-cause mortality. Am I reading the table wrong?

[Davin8r]

@desertshores

am primarily interested in reducing all-cause mortality. Am I reading the table wrong?

The way I’m reading it is that the important number is the HR (Hazard Ratio, which is the ratio of the treatment group to the placebo group, the lower the better), so Dapa wins.

[adssx]

Indeed.

Still, I don’t think that you can conclude on the superiority of dapagliflozin based on these 3 trials because:

1. As pointed by @Neo somewhere else, looking at death from any cause in a short trial (2y) may be misleading as it can capture unrelated events (the HR is impressive here though). It’s better to look at the primary endpoint, but here again dapa wins,
2. Patients in these three trials all had kidney disease but the % of people with T2D varied in each group (46% for cana and 100% for cana): does this HR apply to non CKD / non T2D patients?
3. You want more trials and average them as they’re all a bit different (length, dose, demographics of participants, etc.).

So we don’t know yet which one is best. I’m considering sponsoring empa (already done), dapa and cana for the Ora Challenge to see which SGLTi is best on worms at least…

[Goran]

@adssx

which SGLTi is best on worms at least…

I don’t think worms have kidneys so I would avoid looking at any worm studies regarding SGLTi’s

[adssx]

It’s not about kidneys, SGLTi act on mTOR: Perspectives in weight control in diabetes – SGLT2 inhibitors and GLP-1–glucagon dual agonism 2023

[Neo]

@Joseph_Lavelle

Several goals:
(1) original goal was weight loss. didn’t happen & don’t really need it
(2) lower blood sugar. didn’t happen but may have been confounded by rapa
(3) longevity. still hoping.

If the goal is longevity I think you carefully have to think through if you don’t also want to access SGLT1 inhibition and not just SGLT2.

That is big enough that when I start, it will highly likely be with Cana for this reason.

As of now SGLT1 and not SGLT2 is the only one that has a decrease in mortality in a Mendelian Randomization, and Cana (and hence not SGLT2 alone but with SGLT1) is the only one we have causal mammalian longevity data for (gold standard ITP success).

There is a quite a bit of back and forth with @adssx and I discussing and debating this from a few weeks ago). Might be worth taking a look at that. For me, taking SGLT2 only - when - longevity is the goal is an extra leap of faith you have to feel good with.

Given that you also seem to be working to optimize gut health / microbiome you may also be interested in that SGLT1 seems to do that via a clear mechanism in a way that SGLT2 does not.

[Joseph_Lavelle]

Yes. I agree. But since I cannot get any Cana for now, I’ll have to live with Dapa.

[desertshores]

All cause mortality is generally considered more important when assessing overall efficacy and safety of a drug.

Of the two metrics, the all-cause mortality rate provides a more direct measure of deaths in a population. While hazard ratios represent relative risk over time, the all-cause mortality rate is an absolute measure of deaths.

All cause mortality is a more direct and unbiased measure of mortality impacts. Hazard ratios provide additional data on how risk compares over time between groups.

What’s the Risk: Differentiating Risk Ratios, Odds Ratios, and Hazard Ratios?

While hazard ratios provide valuable data on comparative event rates, all cause mortality gives a comprehensive measure of survival regardless of cause of death.

Hazard ratios may be prone to bias if they selectively focus on specific events/causes. All cause mortality provides an unbiased overall mortality measure.

[adssx]

Yes but here you need to look at the HR and not the death %. Because otherwise with the same reasoning you’d conclude that the empagliflozin placebo (5.1% ACM) is better than taking the real canagliflozin (7.6%)! The placebo death rates varied in each of the above 3 studies so what matters is how much the intervention reduced mortality compared to placebo. Hence the HR. For instance for the dapa trial: 4.7%/6.8% = 0.69.

[desertshores]

We can agree to disagree. I will be taking Empagligozin because of its reduced side effects on my digestive system. (Less farts for starters: ) At least on my particular diet. I have tried both and I have a few months supply of canaglifozin that I will not be taking.

[adssx]

@desertshores

We can agree to disagree.

No we can’t, or at least, I cannot

[AnUser]

They are different studies so you can only compare the difference in risk between active and placebo. And then compare the difference of the active vs. placebo of the different studies. Because they are different populations.

If you gave a statin 1 to a low risk population 1% might die for statin vs. 2% for placebo. RR 0.5.
If you gave statin 2 to high risk population, 2% might die for statin, while 5% for placebo: RR 0.4.

Statin 1 isn’t better because 1% died, since fewer died in placebo as well. RR is better for statin 2. Baseline risk matters.

[desertshores]

It was just a polite way of saying that I am not going to argue this point with you anymore.

[adssx]

I know; mine was a joke about Nobel Prize in Economics Aumann’s theorem that states that “two rational people cannot agree to disagree”. Looks like my joke fell flat

Anyway, here’s a great paper just published in the Journal of the American Heart Association: Comparison of Effectiveness Among Different Sodium‐Glucose Cotransoporter‐2 Inhibitors According to Underlying Conditions: A Network Meta‐Analysis of Randomized Controlled Trials

(don’t look at the figures; they’re all wrong. I’ve just emailed the main author about that…)

They conclude:

The differences in reducing cardiovascular and kidney outcomes as well as safety profiles across SGLT2 inhibitors were not consistently significant, although empagliflozin might be preferred in patients without chronic kidney disease. Further investigations are needed to better understand the mechanism and clinical effectiveness of each SGLT2 inhibitor in certain populations.
This network meta‐analysis of 21 randomized controlled trials involving 96 196 patients with different backgrounds showed no consistent evidence that a particular sodium‐glucose cotransoporter‐2 inhibitor was superior to other agents, while empagliflozin showed comparatively large effects in reducing cardiovascular outcomes in patients without underlying chronic kidney disease.
Clinicians may be reassured that there was no evidence that a particular sodium‐glucose cotransoporter‐2 inhibitor was consistently more efficacious than other agents in reducing cardiovascular or renal events, although empagliflozin might potentially be preferred in patients without chronic kidney disease.

Looking a bit more in detail:

• Dapagliflozin might be better than empagliflozin for patients without diabetes: “While there were no significant differences in the studied outcomes between empagliflozin and dapagliflozin, dapagliflozin showed consistently lower HRs than empagliflozin in patients without diabetes. Because other SGLT2 inhibitors have not been evaluated in patients without diabetes, future investigations on this population are warranted. […] Because the approved doses of SGLT2 inhibitors for specific indications (eg, HF or glycemic control for patients with diabetes) vary, and the benefit of empagliflozin and dapagliflozin seemed promising regardless of diabetic status, the effects of different doses and other agents in patients without diabetes should be investigated.”
• Dapagliflozin might be the best option for patients with heart failure: “In our study, dapagliflozin showed the lowest point estimate for the primary outcome, all‐cause or cardiovascular death, and kidney disease progression in patients with HFrEF (though not statistically significant), while there was no such pattern in patients with HFpEF.”
• Canagliflozin was associated with the highest rate of amputations (but it did not reach statistical significance):
  
  
• Empagliflozin was associated with higher risks of orthostatic hypotension
• Sotagliflozin was associated with the lowest point estimate of genital infections, followed by empagliflozin. Canagliflozin and dapagliflozin had the highest rates:
  
  
• There was an “increased risk of AKI in sotagliflozin” vs dapa and empa, which “may dilute the preventive effect of SGLT2 blockade, compared with more SGLT2‐selective agents”.

Of course, the above doesn’t answer the question of which is best for “longevity” for people without T2D, CKD, or HF (or at high risk of those).

[My own conclusion: I won’t take canagliflozin. Empagliflozin and dapagliflozin seem to do a better job with fewer side effects. And there’s also more data on their neuroprotective benefits (rodent studies + longitudinal data + RCT), which is my focus.]