#1256

This is amazing. @RapAdmin we really need to add this feature! :slight_smile:

4 Likes
#1257

I don’t think many will use that function (because it’s probably subpar compared to this now, you need to feed the entire thread into a large context window like the Gemini models provide…), and if you do decisions based on summaries from large language models… that’s not good either way.

I have yet to see IMO someone make a good case for off-label use of SGLT2 inhbitors. I’d like to see it based on outcomes in RCT’s, that can be extrapolated with MR and applied for early use, like that can be done for statins.

1 Like
#1258

This is not a good case for you? => “Kidney function starts declining at age 30. SGLT2i slow down eGFR decline across the board. So if your eGFR is below 90 then SGLT2i makes sense.”?

2 Likes
#1259

Discourse AI Summarize can use whatever model you want: Discourse AI - Summarize - Site Management - Discourse Meta

1 Like
#1260

I haven’t seen anyone make the argument persuasively, combined with MR for that. You’d want to see if it’s compounding (exponential) with time as well. I would be as big of a proponent if it is like it is for statins.

#1261

If you want an MR (for male longevity only): Canagliflozin - Another Top Longevity Drug - #1067 by adssx

And there are dozens of RCTs (cited in this thread) + association studies (for instance here: Optimal Blood Pressure we Should Target? Systolic Under 110 or 100? - #392 by adssx ) for low eGFR and all-cause mortality. There’s also this MR: Kidney Function Measures and Mortality: A Mendelian Randomization Study 2024: “MR analysis suggested that a genetically predicted lower eGFRcyst was linearly associated with a higher rate of cardiovascular mortality (HR, 1.43; 95% CI, 1.18-1.75) across the entire measurement range (every 10-mL/min/1.73m2 decrement). Nonetheless, no causal associations between eGFRcyst and all-cause mortality (HR, 1.07; 95% CI, 0.98-1.17) or any types of noncardiovascular mortality were detected.” (all-cause mortality borderline significant, I’ll take it!).

And life extension in male mice for canagliflozin (ITP) and empagliflozin (non-ITP).

So the case in men with an eGFR below 90 seems strong to me (even below 100?). In females: I don’t know. In people with eGFR > 100 and perfect glycemia: I don’t know.

4 Likes
#1262

I meant MR for eGFR and SGLT2 or SLGT1 inhibition, bringing up all-cause mortality or longevity is not important at this stage.

That’s why statins and other similar drugs is so persuasive.

They lead with reducing cardiovascular events, that is compounding over time with massive decrease. This is just so much different information you brought up, and mice studies are not persuasive. That’s why I am not using these. No good, organized, arguments.

#1263

Of course SGLT2i protects eGFR. We don’t need MR for that we have hundreds of RCTs. But here is an MR: SGLT2 inhibition, high-density lipoprotein, and kidney function: a mendelian randomization study | Lipids in Health and Disease

The case seems easy to me:

  • For eGFR the higher the better (RCTs + association studies + MR)
  • eGFR declines from age 30
  • Once eGFR goes below 15 you die
  • SGLT2 prevent eGFR decline across the board (RCTs + MR + association studies)
  • Cherry on the cake: SGLT2i increases longevity in males (MR + mice studies)

What else do you need? The case seems stronger than for statins to me.

5 Likes
#1264

@adssx From the many papers you have seen about the SGLT2i’s over the years: was there any difference in outcome between females and males, that you know of - besides the ITP? And what is your thought about the root of the differences in outcome between genders in the ITP, if you don’t mind me asking?
Years down the line, I’m still wondering what may have been the reason Cana has been sown to extend lifespan in male, but not in female rodents.

#1265

Beta 0.05 = 5% increase in eGFR for every 1 SD increase in SGLT2 inhibition… lifetime… not clinically relevant?

#1266

You have to look at the normal trend with aging…

41598_2021_89442_Fig1_HTML

Distribution of estimated glomerular filtration rate and determinants of its age dependent loss

全文：Distribution of estimated glomerular filtration rate and determinants of its age dependent loss in a German population-based study | Scientific Reports

2 Likes
#1267

And what’s the trend like with genetic SGLT2 inhibition? Do they have immortal kidneys?

1 Like
#1268

All I have to go on is the @adssx paper, it should halt the decrease at whatever age you start…

  • SGLT2 prevent eGFR decline across the board (RCTs + MR + association studies)
  • Cherry on the cake: SGLT2i increases longevity in males (MR + mice studies)
1 Like
#1269

I’ll wait for a graph if someone finds it. If genetic SGLT2 inhibition gives immortal kidneys. Like genetic LDL lowering gives immortal hearts.

1 Like
#1270

I read papers for myself as a man so I might miss or forgot information related to females. But from what I remember:

  • Dapagliflozin and empagliflozin are approved for CKD, HF and T2D (canagliflozin is approved for T2D but not for HF and CKD without T2D), in men and women. I don’t think trials showed differences in outcomes by gender. Guidelines and clinical practice don’t seem to differ by gender either.
  • Women are more prone to UTI and genital infections in general. So their risk is even higher on SGLT2 (even though the OR might be the same as men, their baseline risk is higher).
  • Besides the ITP, the Mendelian randomization found that SGLT2 inhibition was causally associated with longevity in males (father’s attained age) but I don’t know if they looked at females (or if the result was negative?).
  • I think the ITP team said that the lack of benefits in female rodents might be a dose issue and they’re now trying a lower dose (60 ppm vs 180 ppm, both at 7 mo).
4 Likes
#1271

What are you saying? We have RCTs, so of course it’s clinically relevant.

That being said, I don’t know if the step is 1 SD or a per-allele increase and if 0.05 means 5% increase in eGFR. I’m not knowledgeable enough and ChatGPT (o1) tells me the paper isn’t clear on that…

#1272

I’ll be waiting for more research then.

#1273

Yes they do, look at these OR: Mendelian randomization study of sodium–glucose cotransporter 2 inhibitors in cardiac and renal diseases 2024

image
image1454×426 54 KB

MR analysis suggested that SGLT2i can provide substantial protection against a variety of CKD (Figure 3, Supplementary Table 3). Significant protection effects were observed for nephrotic syndrome (OR 0.0011, 95% confidence interval [CI] 0.000–0.237, P = 0.013), chronic glomerulonephritis (OR 0.0002, 95% CI 0.000–0.210, P = 0.017), and hypertensive nephropathy (OR 0.0003, 95% CI 0.000–0.785, P = 0.043).

2 Likes
#1274

That’s a kidney disease I know nothing about. keeping eGFR in youthful range through someone’s entire life would be more significant.

#1275

Damn check the image… :man_facepalming: