New Paper: Summary of the top FDA-approved Drugs that can be Repurposed as Gerotherapeutics / Geroprotectors

#8

Which of these are proven in clinical trials? I think it’s important to differentiate them based on level of evidence. HF and kidney damage I know.

@DrFraser this is a nice article on the history of gliflozins:

After flozins were approved as diabetes drugs, on the basis that they lower the markers of diabetes, they had to go through further trials to be sure that they did not increase the risk of heart attacks, strokes, or deaths due to cardiovascular disease. This requirement was imposed by the FDA in 2008, after a meta-analysis published in 2007 found that rosiglitazone, another diabetes drug approved on the basis of surrogate endpoints, ​increased the risk of heart attacks by 43 percent.

These trials were imposed to confirm the benefits of the drugs were not outweighed by cardiovascular side effects.

Yet something unexpected happened: the trial for empagliflozin – which, like dapagliflozin and canagliflozin, inhibits SGLT2 much more strongly than SGLT1 – showed a 14 percent reduction in major cardiovascular events, a 35 percent reduction in hospitalizations for heart failure, and a 38 percent reduction in cardiovascular deaths overall – all statistically significant.

It is more promising than rapamycin IMO.

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#9

This thread is probably helpful for that:

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#10

I think all the conditions I mentioned (on my phone so cannot double check). Especially HF and CKD, as SGLT2 are approved in most countries for that.

The canagliflozin thread posted by Neo lists most RCTs.

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#11

Of course telmisartan is the best by far (not only for cognition, also for insulin resistance and Covid infections): Angiotensin II receptor blocker (ARB) experiences? - #25 by adssx

Then amlodipine (longest acting D-CCB) and indapamide (or HCTZ).

A clinical trial of telmisartan for Parkinson’s will soon start btw. See also: Parkinson's disease - #109 by adssx

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#12

@adssx
The issue with most studies on these drugs is the use in pretty unhealthy individuals where we are looking at progression of disease in patients with heart failure or chronic kidney disease, or are at high risk of developing those issues.
Giving these agents to a healthy individual likely has markedly less (or no) benefit, would be my concern. The mouse data is interesting, but I’m not sure how this class of drug gets to the top of the list of longevity medicines. I however will go through the other thread in some detail, as I get my feed of articles from Journal Watch, and they are unlikely to put forward articles using these agent in healthy individuals.

#13
  1. They’re approved for CKD, T2D and HF and in these groups they tend to prevent the other disease. Said otherwise, if you only have T2D and no CKD or HF, SGLT2 will still protect your kidney and heart (and brain also btw). And more than other glucose-lowering drugs. So they already protect people with a healthy kidney or heart (for instance).
  2. The % of the population (at least in the US) with diabetes, pre diabetes, HF, pre HF, kidney disease or “pre CKD” or at high risk of these (because of family history, genes, age, etc.) is so high that most individuals, including “healthy” ones would fall in one of these buckets.
  3. Given the ongoing trials, we can expect SGLT2i indications to be extended to arrhythmia, atrial fibrillation, and the various liver diseases (NAFLD, etc.). This will make the case for SGLT2i even stronger.
  4. Quoting Brad Stanfield: “In terms of a so-called longevity medication, I think that SGLT2 inhibitors will be the first ones that will be prescribed and made widely available. That’s because they appear to provide significant protective effects for the kidneys. Our kidney function starts to decline from around the age of 30, so if we can use SGLT2 inhibitors to slow down or prevent that decline, that would be a powerful intervention. Of course, we’re waiting on the human data to come through, but there is a robust way of these things getting through to people.”
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#14

Do we know how large the kidney protection effects are in non kidney disease, non diabetes people is - human data wise yet?

#15

Probably the bigger challenge is whether one gets any additive effect of adding an SGLT2 inhibitor to rapamycin plus metformin plus acarbose? Are we simply hitting the same pathways, and if so, is adding another agent having any benefit.

When treating T2DM, I’ve usually gone with metformin+acarbose and a GLP-1 agonist as first line for glycemic/metabolic control. However, the SGLT2 inhibitors have some other unique benefits.

Working in the ER and seeing complex UTI’s and perineal infections in patients with use of these agents creates some concerns, but none of these were in people who were fit and healthy in any respect.

Anyway, great post, and well worth taking a serious look and think on.

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#16

I didn’t check.

Good question. But as far as I know rapa/metformin/acarbose don’t protect the kidney and liver for instance. The pathways of SGLT2 inhibitors are not known. Here are three other good reviews of SGLT2 inhibitors’ effects btw: Acarbose - Details On Another Top Anti-Aging Drug - #448 by adssx

A recent paper also showed that SGLT2i alone was as good as SGLT2i + metformin: Canagliflozin - Another Top Anti-aging Drug - #658 by adssx So SGLT2i might be better than metformin as first-line treatment.

As you seem to like low-dose combinations, in George Medicines’ pipeline there’s GMRx4, “containing three existing best-in-class drugs and formulated at an ultra-low dose: metformin XR 350mg, dapagliflozin 2.5mg and sitagliptin 17.5mg”.

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#17

Appreciate the references and response.

I have a lot of patients with chronic kidney disease or heading that direction, and certainly going with an SGLT2 makes sense, for those without those factors, and for a healthy individual, it certainly has me looking a bit more at these, and at least adding it to the list.

So many patients have obesity, and I still favor the Glps in those patients as they work on every component of cardio metabolic syndrome. However as sole agents don’t get the glucose down enough.

The GLP’s should be on this list as there are clearly benefits, including longevity - perhaps the data is just lagging on these.

Your input certainly has me putting these as next agents.

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#18

There are a few problems with that table:

    1. Metformin failed at NIA ITP, also after Metformin success with humans, there were 5 previously unpublished papers that showed no benefits even in diabetics
    1. SGLT inhibitors extended lifespan in NIA ITP - but only in male mice, in female mice 0%
    1. Mehylene blue failed NIA ITP
    1. Aspirin extended lifespan at NIA ITP but only in 1 test from 3 (and only in mice)

Rapamycin is the most robust from all of this - but even then effect is not as strong as Rapamycin + Acarbose, and dose in mice is 10x higher than what people take

It seems like, based on NIA ITP, table should be:

    1. Acarbose + Rapamycin
    1. Rapamycin (high dose)
    1. 17 alfa estradiol (males only)
    1. Acarbose (males only, females only in high dose)
    1. SGLT2 inhibitors (males only)
    1. Other (glycine, Astaxanthin, NAC, taurine, etc)
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#19

I think the jury is out on longevity outside of obesity patients

  • seems very anti one of the main longevity pathways to continuously rev up insulin release into the blood 24/7 vs the normally rythm of it only going up after a meal and only as much needed depending on the type of meal and then going back down to low levels again

  • cancer risks might not have been to big for a few years of use, but what will that look like after a decade or several decades on them

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#20

There is a consistent improvement in metabolic syndrome, which increases essentially every bad health outcome. Reverse this, which these agents effectively do, and a huge percentage of the population suffers from, and we know the impact expected on longevity.
These agents do not consistently increase insulin, except in those with significant high blood sugar - which I’d argue should not be what we are primarily depending on this drug for (it should be in combination with others). They do improve insulin sensitivity, which then leads to less insulin needing to be produced.

There is reasonable literature on likely improvements in risk of neurocognitive disease. We know obesity increases malignancy - I’ve not seen any evidence to support a risk of malignancy, short or the rare cases in MEN patients. But yes, we’ve only had this class of medications, I think since 2005. We’ve seen almost 2/3rd reduction in risk of developing Parkinson’s Disease in one look at patients on a fairly weak GLP-1 agonist.
Overall, I don’t know if for the ideal body weight insulin sensitive individual whether this is helpful, but that isn’t the typical person I deal with.

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#21

Yes - we agree - huge percentage of population is above, has pre- or full diabetes, etc.

I was asking in the context of many of us on this forum who have invested in being metabolically fit, lean, etc. do we think GLP-1a would be good for longevity in such a demographic?

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#22

Interesting. I thought it increased average insulin levels in people, is that not the case? Even if it only boosts insulin when triggered by glucose that might not be good in a generally metabolically healthy individual?

#23

These agents will increase insulin secretion in the situation of having a significantly elevated glucose. However, they improve insulin sensitivity, and slow gastric emptying along with absorption of consumed calories.
How this plays out for most people is less area under the glucose curve, less need for insulin to be secreted, and thus your blood vessels seeing both less glucose and insulin.
I think there are a lot of people on these agents as part of their journey to metabolic health, where they simply can’t or won’t do it without these.
Mounjaro is as effective as a gastric bypass.
I have many patients with huge losses with low doses over time and it has enabled them to seriously improve their diet.
Some will get off them, but most … at least as of now may be on low doses long term.

#24

Think we keep talking past each other

My questions are not with regards to the average American or “most people” - a largely agree with what you have been saying about those populations.

It’s about whether in a well optimized longevity and health seeker who is lean and of great metabolic fitness, is Glp-1a still a good option for longevity (like I for instance would argue that Rapa and Acar still are)?

And would Glp-1a not increase AUC of insulin in such a group.

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#25

No it wouldn’t because you’ll have slower absorption of calories resulting in lower peak glucose and less need for insulin, and you’ll be more insulin sensitive.

I don’t know what proportion of people on this board are truly at ideal body weight with minimal visceral fat? I’d think only some, there are probably a lot on the board who would benefit from weight loss…

But yes the argument for these is unclear in the rare individual who has naturally sorted out ideal weight and excellent insulin sensitivity.

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#26

Thanks Dr Fraser.

@adssx and @AlexKChen see above, the picture might be less bad re insulin levels in healthy people on GLP-1a than we had wondered elsewhere

(personally I’d still want to know more long term data about cancer risk if taking this for longevity/other things like dementia at this point if not overweight)

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#27

I know the researchers leading the GLP-1 RA RCTs for PD (exenatide, lixisenatide, and liraglutide): they’re also super excited about SGLT2’s potential for PD. Mayo Clinic just started a small trial of dapagliflozin for PD and LBD: ClinicalTrials.gov And a trial of empagliflozin might start soon after some showed it could reverse PD in animal models: Empagliflozin repurposing in Parkinson’s disease; modulation of oxidative stress, neuroinflammation, AMPK/SIRT-1/PGC-1α, and wnt/β-catenin pathways 2023

I also find it interesting that GLP-1 RA and SGLTi might rely on similar mechanisms on GIP levels via opposite ways: Sotagliflozin effects differ from empagliflozin only at breakfast

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.
"[T]he 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,” they conclude.

There aren’t many studies comparing GLP1RA to SGLTi as they’re both super recent (2004 for GLP1-RA with the approval of exenatide and 2013 for flozins). But those I found show that SGLTi are as good if not significantly better than GLP1 for dementia prevention:

We also have one RCT (n= 119) by a good team showing improved cognition with empagliflozin: Effects of SGLT2 inhibition via empagliflozin on cognitive and physical impairment in frail diabetic elders with chronic kidney disease 2024 For GLP1-RA, we have way more RCTs, but “Results tends to show an improvement in some brain markers (e.g. hippocampal connections, cerebral glucose metabolism, hippocampal activation on functional magnetic resonance imaging), but without being able to demonstrate a strong correlation to cognitive scores.” (GLP-1 receptor agonists effect on cognitive function in patients with and without type 2 diabetes 2023)

Still, there’s a lot of intra-class variability. For instance for GLP1-RAs, researchers look at which ones have the highest uptake in the brain. And for SGLTi, “When stratified by different SGLT2 inhibitors, dapagliflozin exhibited the lowest risk (aHR 0.67 [95% CI 0.53–0.84]), followed by empagliflozin (aHR 0.78 [95% CI 0.69–0.89]), whereas canagliflozin showed no association (aHR 0.96 [95% CI 0.80–1.16]).” (Association of Sodium–Glucose Cotransporter 2 Inhibitors With Time to Dementia: A Population-Based Cohort Study 2022)

SGLT inhibitors also cause weight loss: Emerging Role of SGLT-2 Inhibitors for the Treatment of Obesity 2019

For approved SGLT2 inhibitors there is on average some 1.5–2 kg weight loss (placebo-adjusted), for GLP1-RAs 2–4 kg, and for the combination 3–5 kg

It’s not massive, but for non-overweight people it’s good. I’ve been on dapagliflozin for 3 months and my body fat percentage (measured by DEXA) went from 16.6% (6mo ago) to 14.9% (yesterday). It’s probably not only dapagliflozin, but it’s still interesting. My weight stayed more or less constant.

Avgerinos et al found that in non-diabetics empagliflozin shifted metabolism towards a low-insulin, high-glucagon state which elevated fatty acids, and β-hydroxybutyrate levels: Empagliflozin Induced Ketosis, Upregulated IGF-1/Insulin Receptors and the Canonical Insulin Signaling Pathway in Neurons, and Decreased the Excitatory Neurotransmitter Glutamate in the Brain of Non-Diabetics 2022

I couldn’t find papers on this, but I think that in non-diabetic patients, GLP-1 RAs still promote insulin secretion in response to food intake. Since their body’s insulin production and glucose regulation are already in balance, the effect is to merely enhance the natural glucose-dependent insulin response.

(FWIW, I had reactive hypoglycemia; with my endocrinologist, we tried diet, acarbose, and metformin to no avail, then I suggested to try GLP1-RA after reading papers about their potential for reactive hypo. He objected that SGLTi might be better precisely because they don’t stimulate insulin secretion, quite the contrary. After 3 months of dapagliflozin, I don’t have reactive hypoglycemia anymore, and there are now many ongoing trials of SGLTi for reactive hypoglycemia.)

My conclusion:

  • SGLT inhibitors decrease insulin secretion
  • GLP-1RAs increase insulin secretion in diabetic people and at best, they’re neutral in non-diabetic
  • So in terms of insulin secretion, SGLTi are better than GLP1 in people with and without diabetes.
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Intermittent (oral) Rybelsus / Semaglutide use in healthy individuals?