@RapAdmin This is one of the most important posts I’ve seen on this board. I agree with @DrT .
Interestingly, I’m taking a high % of those on the list, and advise them to patients. The one that is #1 on the list, SGLT2 inhibitors is not something I take or routinely advise, nor are bisphosphonates, methylene blue, aspirin or beta blockers.
The only reason some items aren’t scoring higher is due to “Not Assessed.” Also the degree of benefit is not clearly characterized.
The specificity also is an issue - for example with ACE and ARB are these agents that cross the blood brain barrier or not - same issue with Beta blockers on the last report.
On the NAC - what about NAC Ethyl Ester … The evidence on aspirin is contrary to what they cite - the evidence is most clearly stated with the USPSTF - in that most people end up with harm rather than benefit with taking this.
So targeting whatever they are looking at here might not actually be the best approach. It is however a fascinating paper and scoring system. It is arbitrary and not indicative of size of effect.
I’ve seen a few serious perineal infections with SGLT-2 inhibitors, but this is in diabetics. We don’t clearly see in this paper, was this in non-diabetics that SGLT-2 inhibitors have this great profile. Given that they result in you passing glucose into your urine – does this benefit someone who doesn’t have diabetes?
+1. Putting “ACE/ARB” as one category is weird. (I think half life is more important than BBB crossing btw.)
Yes. They also reduce heart failure, kidney damage, liver damage, arrhythmia, atrial fibrillation, and atrial flutter in non diabetics. And they decrease body weight and blood pressure a bit.
We had a good look at the evidence for metformin on this forum and it appeared that the evidence for its use by non diabetics was not strong. Indeed it appeared to be subject to selection bias.
I have a strong preference for Telmisartan as there are a host of research on this being significantly beneficial for neurocognitive decline. It has a long half life - but lisinopril does also, and crosses the BBB, but doesn’t seem to have the same benefit. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9125564/
I often discuss with patients, that if they have adequate blood pressure - let’s get you on Telmisartan … it seems like a great anti-aging and cognitive protective agent. So many people look at their blood pressure as a negative thing – instead, it is an opportunity to introduce medications that can decrease risk of death and disability.
On the SGLT2 agents, I am going to take a fresh look at these, as there are costs (not so bad if purchased off shore) that can be prohibitive for many patients. I’m biased as I’ve seen some complications, but this is in a select population that have been taking very poor care of their health. That is not the demographic that I’d be considering these agent in, in this context.
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.
@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.
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).
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.
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.
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.”
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.
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
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”.
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.
Metformin failed at NIA ITP, also after Metformin success with humans, there were 5 previously unpublished papers that showed no benefits even in diabetics
SGLT inhibitors extended lifespan in NIA ITP - but only in male mice, in female mice 0%
Mehylene blue failed NIA ITP
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
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
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.
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?
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?
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.