#777

Yes I remember that post. It gets to the point that I was making earlier that low dose and high dose empagliflozin were tested in diabetics and if you want to take these meds as a non-diabetic and hope to affect your serum glucose you are going to need to err on the high end of the dosing range. His/her comments were targeted mainly at the point that cana is different from the other flozins which I agree with for the reasons he states.

Not sure we need to argue about this, but I think that poster’s comments are not correct. I do think his statements are attempting to make the same point I am, that one needs very high plasma glucose levels to see a significant reduction with these meds (ie Diabetes). However, I’m pretty sure a study in normal glycemic individuals would show both a reduction in plasma glucose steady state levels and peak postprandial glucose levels (not saying it will eliminate a postprandial elevation, just limit the height of the peak). Everyone agrees flozin’s lower plasma glucose levels, it doesn’t make any sense that they wouldn’t reduce the peak as well. Plenty of evidence for this with normal glycemic people doing urine dips and showing glucose in their urine, its got to come from somewhere.

#778

Well, he pointed to this study:

Which literally shows no impact on postprandial glucose with dapagliflozin in non-diabetics. “Dapagliflozin had no effect on PPG excursion”, per the abstract. Here’s the chart from the paper:

DOM-17-188-g003

The third one labeled “plasma glucose” is postprandial glucose spike. No significant difference between placebo (gray line) and dapa (green line). Canagliflozin shows a blunting, but it would have to be taken before each meal to get this effect, and only at a dose of greater than 200mg per the other study he posted. Either way, no effect of dapa.

I’m hoping/expecting the benefits of the SGTL2i drugs are independent of postprandial glucose or glucose altogether. After all, if the only thing these drugs are doing is causing us non-diabetics to excrete an extra 50g of glucose in our urine per day and there are no other beneficial tissue-specific SGLT2i effects, then we’d get all the benefits, NO potential side effects AND save a lot of money by just eating 50g less of carbs per day.

How silly are we all going to feel if it just comes down to that? :upside_down_face:

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#779

I can eat almost no carbs per day, I do it all the time. Still I end up with pretty high (~90 or 105) fasting glucose. So would Cana help burn that up all day long and lower my hba1c by a bit, or will my liver compensate and keep the sugar high?

#781

FYI: in this small trial in people with MCI but without T2D after 12 weeks they observed a small reduction in Hb A1C (-0.18) and what I think is a more significant reduction in “2-hr Glucose Area Under the Curve (- 2109.0 mg min/dL, p=0.03)”.

There are many very large trials of SGLT2 in non-diabetic people (for CKD and HF). For instance, in DAPA-CKD, “of 4,304 participants, 738 had normoglycemia, 660 had prediabetes, and 2,906 had type 2 diabetes.” They found that (see: Efficacy and Safety of Dapagliflozin by Baseline Glycemic Status: A Prespecified Analysis From the DAPA-CKD Trial 2021):

The effect of dapagliflozin on the primary outcome was consistent (P for interaction = 0.19) in normoglycemia (hazard ratio [HR] 0.62 [95% CI 0.39, 1.01]), prediabetes (HR 0.37 [0.21, 0.66]), and type 2 diabetes (HR 0.64 [0.52, 0.79]).
Our findings from a dedicated kidney outcome trial substantiate the findings from the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) study, suggesting that the kidney benefits seen with SGLT2 inhibition appear to be independent of their glucose-lowering effects, and extend these results further to those with prediabetes and normoglycemia at baseline.
Few studies have investigated SGLT2 inhibition in prediabetes. During a 13-week randomized comparison between dapagliflozin, metformin, exercise, or control intervention, Færch et al. found that dapagliflozin treatment led to improved glycemic variability, with minor reductions in HbA1c (0.1% or 1.3 mmol/mol) and fasting plasma glucose (0.1 mmol/L or 1.8 mg/dL).
In participants with normoglycemia or prediabetes, dapagliflozin reduced the risk of kidney outcomes without improving glycemic control. These data are in keeping with an analysis of the CANagliflozin cardioVascular Assessment Study (CANVAS) trial, where markers of glycemia did not explain the effect of canagliflozin on kidney outcomes. Instead, albuminuria, hemoglobin, and hematocrit were identified as important mediators, pointing to a potential reduction in fluid overload. The recognized effect of SGLT2 inhibitors on hemoglobin and hematocrit may reflect improvement in renal hypoxia and restoration in the hypoxia-inducible factor 1α/2α balance, stimulating erythropoiesis and reducing inflammation. Glucose-independent effects may include osmotic diuretic and natriuretic effects as observed in individuals with type 2 diabetes and CKD.

(since then, a recent paper showed that the benefits were probably not due to osmotic diuretic effects, so it’s still a mystery :slight_smile: )

Here’s the paper on variability: The effects of dapagliflozin, metformin or exercise on glycaemic variability in overweight or obese individuals with prediabetes (the PRE-D Trial): a multi-arm, randomised, controlled trial 2020

One hundred and twenty participants with BMI ≥25 kg/m2, 30–70 years of age, and prediabetes (HbA1c 39–47 mmol/mol [5.7–6.4%]) were randomised 1:1:1:1 to dapagliflozin (10 mg once daily), metformin (1700 mg daily), interval-based exercise (5 days/week, 30 min/session) or control (habitual lifestyle). Participants were examined at baseline and at 6, 13 and 26 weeks after randomisation. The primary outcome was the 13 week change in glycaemic variability (calculated as mean amplitude of glycaemic excursions [MAGE]) determined using a continuous glucose monitoring system (pre-specified minimal clinically important difference in MAGE ∼30%).
One hundred and twelve participants attended the examination at 13 weeks and 111 attended the follow-up visit at 26 weeks. Compared with the control group, there was a small decrease in MAGE in the dapagliflozin group (17.1% [95% CI 0.7, 30.8], p = 0.042) and a small, non-significant, reduction in the exercise group (15.3% [95% CI −1.2, 29.1], p = 0.067), whereas MAGE was unchanged in the metformin group (0.1% [95% CI −16.1, 19.4], p = 0.991)). Compared with the metformin group, MAGE was 17.2% (95% CI 0.8, 30.9; p = 0.041) lower in the dapagliflozin group and 15.4% (95% CI −1.1, 29.1; p = 0.065) lower in the exercise group after 13 weeks, with no difference between exercise and dapagliflozin (2.2% [95% CI −14.8, 22.5], p = 0.815).

So dapagliflozin improves the glycemic variability of prediabetic overweight people as much as daily interval training. What about normoglycemic non-overweight people?

This study was done after 4 days. My guess (based on my own experience + the above papers) is that the effects of SGLT2i are more systemic and take a few weeks or months to kick in.

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#782

Thanks! Is there a link to this study in your post? Or is that part of one of the other studies you mentioned?

Regarding the glycemic variability study vs exercise vs metformin, that is interesting although the authors note the effect is “small” and “clinical significance unknown”. I’m eager to get more data on any non-glucose-related effects of these meds.

#783

Yes, I replied to the original post that includes the poster: Canagliflozin - Another Top Anti-aging Drug - #750 by adssx

The vast majority of their positive effects are glucose-independent. That’s why SGLT2is are approved in CKD and HF, contrary to other antidiabetic drugs (and they might be extended to NAFLD and HCM). And that’s also why they protect more from AD and dementia than other anti-diabetic drugs. See here for some overviews: Acarbose - Details On Another Top Anti-Aging Drug - #448 by adssx

#784

Looking at those diagrams, though – don’t they all start with glycosuria? One points out increased sodium excretion as well. All the other beneficial effects appear to be downstream, don’t they? If this is the case, couldn’t we get these same downstream benefits by simply eating less sodium and sugar?

(Note I don’t want the above to be true. I take empagliflozin and I want to believe this med is useful!)

#785
  1. One of the diagrams doesn’t start with glycosuria :slight_smile:
  2. The diagrams are, of course, simplifications. And we cannot draw what we don’t know: we know that the benefits are largely glucose-independent (as other antidiabetic drugs don’t do as well and as the benefits are independent from baseline Hb A1c and Hb A1c reduction). The articles say:
    • “These benefits have been demonstrated in trials of SGLT2is, and appear, to some degree, to be independent of glycemia and substantial weight loss.”
    • “Otherwise stated, these agents have direct, glycosuria-independent, effects that decrease cellular stress and enhance cell survival.”
  3. Risk of dementia divided by 2 compared to other anti-diabetic drugs (DPP-4i): Canagliflozin - Another Top Anti-aging Drug - #723 by adssx
  4. ACM divided by 2 vs metformin: Canagliflozin - Another Top Anti-aging Drug - #705 by adssx (see also the paper explaining their potential off-target mechanisms “including the inhibition of gut microbiome–mediated uremic toxin formation”)

So no, just reducing one’s sugar intake is not equivalent to taking SGLT2.

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#786

Yes that’s true, but it’s still possible those could be downstream effects. What I’m looking for is a mechanistic explanation that ties SGLT2 inhibition to all of these effects, other than glycosuria/natriuria. We don’t have that yet, do we?

#787

Considering the beneficial effects the flozins have on kidney function, maybe the longevity effects are related to that?

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#788

No, we don’t have one. Mechanistic explanations are useless scientistic hubris. We don’t even know how paracetamol works.

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#789

Oh c’mon now. We have plenty of nice mechanistic data for all kinds of drugs. Look at rapamycin and mTOR! By knowing how things work, it opens up possibilities for other targets in the pathway(s) which may be even safer and/or more effective.

#790

Yes but, according to Brian Kennedy, 10–20% of current drugs have the wrong target: https://www.youtube.com/watch?v=RQeylLfMpoo

And I think that this doesn’t include drugs with additional unknown targets. Mechanistic theories are interesting, but in some situations, such as for SGLT2i, they’re useless.

That’s why Eric Schmidt funded EveBio to map all FDA-approved drugs and targets. They’ve told me they’ve already found some crazy results. The data will be published in open data later this year.

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#791

You’d still need clinical trials for those targets in the same pathways either way for it to be comparable. If you believe sodium or sugar restriction would have the same benefit, you can look up if such clinical trials exist.

#792

Of course you would. This doesn’t diminish the importance of mechanistic pathways.

#793

I’m not claiming they’re always necessary, but useless? I guess we’ll have to agree to disagree on this one.

#794

Two smart people cannot agree to disagree so I won’t :slight_smile: I said it’s useless here because we know that we don’t know. So expecting a mechanistic explanation is a waste of time. Of course, it would be nice to have one.

#795

Oh, I don’t expect one. I just want one :grin:

1 Like
#796

Haha ne too :slightly_smiling_face:

USP30 might be one other target: Canagliflozin - Another Top Anti-aging Drug - #597 by adssx
In addition to the gut microbiome effect mentioned in the previous paper.

#797

Just published, another paper suggesting that the cardioprotective effects of dapagliflozin are independent of the glucose reduction: ELUCIDATE Trial: A Single‐Center Randomized Controlled Study

They compared dapagliflozin with “standard of care” (SOC, I assume, metformin and other non-SGLT2 antidiabetic drugs?) “in patients with type 2 diabetes free from cardiovascular disease”. Differences in HbA1c and insulin resistance (HOMA-IR) were nonsignificant (although close, p=0.09, over just 6 months). On the other hand, dapagliflozin, compared with SOC significantly:

  • Decreased weight (–1.5 kg)
  • Decreased BMI (–0.62)
  • Decreased SBP (–7.63 mmHg, poke @Davin8r, I was wrong; it looks like it decreases SBP even in normotensive non-obese people, at least with T2D: “The overall study population tended to be overweight, with a mean body mass index of 26.38±4.39 kg/m2 and a mean waist circumference of 92.53±11.13 cm. The baseline mean systolic and diastolic blood pressure was 130.24±13.89 and 76.36±11.09 mm Hg, respectively.”)
  • Increased hematocrit
  • Increased blood urea nitrogen

Dapagliflozin also produced beneficial effects on cardiac geometry and diverse mechanical properties via cardiac structural and functional remodeling: greater reduction in left ventricular (LV) dimension and LV mass index, LV global longitudinal strain increment and improved LV systolic and early diastolic strain rates.

They offer some potential mechanisms (and discard others):

These findings suggest that the favorable effects of SGLT2i on cardiac geometry may extend from patients with clinically evident HF to a population with preclinical diabetic cardiomyopathy.
While SGLT2 is believed to provide additional energy substrates that fuel the failing heart by facilitating a ketogenetic environment, it may also enhance cardiac energy use, resulting in a metabolic shift from glucose oxidation toward more effective fatty acid oxidation and improved mitochondrial function. Additional electromechanical cardiac benefits from SGLT2is may be mediated through improved cardiomyocytes ion channel transporters (eg, sodium‐hydrogen exchanger 1, Ca2+ handling, or late‐INa) function. Indeed, we observed significant improvement in GLS and systolic strain rate with a paralleled increment of diastolic strain rate after 24 weeks of dapagliflozin add‐on therapy compared with the conventional antidiabetic regimen.
Accumulating evidence suggests that SGLT2is may mediate cardioprotective benefits through anti‐inflammatory and antifibrotic effects. In our study, we hypothesized that 24 weeks of dapagliflozin add‐on therapy mitigated cardiac fibrosis by reducing proinflammatory mediators compared with the SOC group. However, we found no change in transforming growth factor‐β, tumor necrosis factor receptor 1, fatty acid–binding protein 4, growth differentiation factor 15, or hsCRP levels.

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