LONGECITY

All:

 

 A recent press release is misleadingly entitled "Type 2 diabetics can live longer than people without the disease;" even the underlying paper's more cautious "Can people with type 2 diabetes live longer than those without?"(1) seems to be unjustifiably provocative based on the underlying research method. I thought I should post it proleptically, before too many people get all hot and bothered by the press release.

 

With the caveat that  I have not read the full-text paper yet myself, the following critique was authored by a Professor of Applied Statistics at the Open University in the UK ("Professor" is a much more senior position in the UK than the USA, denoting something like a department head), and seems cogent and consistent with a slightly cryptic phrase in the abstract, in which case the study is likely not worth paying much attention to:

 

Expert reaction to study looking at type 2 diabetes, metformin and lifespan

 

... "The title of this paper itself is not helpful in that anyone reading it might get the wrong idea – this study cannot actually answer the question it poses (“Can people with type 2 diabetes live longer than those without?”) for reasons discussed below, and it sounds almost as if there are grounds to advise people without diabetes to take metformin. But in fact the study isn’t saying that at all. ...

 

“the comparison in the paper runs only over the time period when the patients with diabetes were on first-line treatment with metformin, on its own (and there’s a similar comparison involving patients whose first-line treatment is with sulphonylureas). At some point after this first-line treatment starts, many of the patients with diabetes would be switched from metformin alone onto a second-line treatment, and this switch is (or should be) necessary because the diabetes or its effects have got worse. But at that point the comparison in this study simply stops.

 

“So the quote in the press release about an eight year reduction in life expectancy, in people who develop type 2 diabetes, is talking about the entire rest of a person’s life after the diagnosis, including the time when they might be on a more aggressive second-line treatment. But the comparison in the paper is looking only at the time before the treatment changes. ...

 

[MR: This is evidently what the abstract means by using a "censored followup:" they ONLY looked at deaths occurring WHILE the person was on metformin or sulfonylureas: if your disease progressed, and they added on a secnd drug to bring your glucose back under control, you were simply "censored" out of further followup. This would obviously greatly bias the resulting mortality rates (and note: it is *for sure* from the abstract that they did not actually look at life expectancy, despite the press release AND the title of the abstract: *explicitly* , they ONLY looked at *mortality rates* of people *while* they were only on one drug (or, during the matched number of years of the nondiabetic controls). This means, by definition, that people who were put on the drug most usually used for the mildest diabetes (metformin) and who remained stable and healthy on it, were being compared to more severe patients at outset (on sulfonylureas), and as soon as they got sick they vanished from the analysis! Comparing even average nondiabetic people to unusually successful diabetics is, from the get-go, comparing elite diabetics to merely average aging people. Returning to the critique:]

 

“The researchers did match the controls with patients with diabetes in certain ways, and in their statistical analysis they try to allow statistically for other differences between the people with diabetes and the controls. But the paper itself points out some issues. The researchers could not take into account certain possible confounders (other variables that might affect the comparison) because they *did not have data on them* for enough of the controls. Even without that important issue, statistical adjustment for confounders is never perfect. The difference in survival between people with diabetes on metformin, and controls without diabetes, was statistically significant but in fact rather small, and probably within the range where it could be explained by residual confounding ...

 

“Further, the paper itself also points out that people with diabetes are more likely be monitored for, and receive interventions for, problems with the heart and circulation. [Ie, because they're diabetic, they're receiving regular medical screening and coming in for prescription renewals, which gives the opportunity for high cholesterol, BP, and other risk factors to be detected and treated -- whereas members of the general, ostensibly healthy population with the same risk factors may go blissully about their business until they drop dead -MR]. This extra intervention and monitoring, and the possibility of residual confounding, between them cast huge doubt on the possibility that the better survival in the patients taking metformin, compared to controls without diabetes, was simply because they were taking metformin. ...

 

And, as a reminder: metformin has been tested now in three separate rodent lifespan studies, at high and low doses in normal, healthy mice, and also in a somewhat flawed study in normal, healthy rats, and in no case was there an increase in maximum lifespan; there was a very mild increase in average LS in the mouse studies, which might well be due correcting the residual effects of a diet of lab chow and minimal exercise.

 

-Michael

1. C. A. Bannister, S. E. Holden, S. Jenkins-Jones, C. Ll. Morgan, J. P. Halcox, G. Schernthaner, J. Mukherjee and C. J. Currie.

Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls

Diabetes, Obesity and Metabolism.

Article first published online: 31 JUL 2014 | DOI: 10.1111/dom.12354

http://onlinelibrary....12354/abstract

 

Edited by Michael, 09 August 2014 - 11:52 PM.

Thanks for posting the analysis. I guess there is hope still

 

I thought Metformin reduced cancer occurrence. Would have thought that would in effect increase lifespan. Do you know of other studies that do show increased life expectancy? In mostly healthy people? I imagine a lot of people on metformin are in pretty bad health and wouldn't be a good analog to those who are  reasonable weight and eat low carb.

Thanks for posting the analysis. I guess there is hope still

Yes, but not in metformin, I don't think .
 

I thought Metformin reduced cancer occurrence. Would have thought that would in effect increase lifespan.

The question that one has to ask is 'compared to whom?' Metformin-treated diabetic patients have lower cancer rates than other diabetic patients treated with different drugs; rather than a cancer-protective effect of metformin, this seems likely to be the result of the cancer-promoting effects of most other diabetes drugs, either by increasing insulin levels, which (sulfonylureas, insulin, meglitinides) or other mechanisms (thiazolidinediones).

 

Metformin also reduces cancer rates in mice with horrendous oncogenic mutations. Whooptee-doo.

 

It did not lower cancer rates in any of the studies with normal, healthy rat or mouse controls.
 

Do you know of other studies that do show increased life expectancy? In mostly healthy people?

 

Healthy people have not been taking metformin long enough (let alone in suffficient numbers or with sufficient consistency) to have any data on that. And who is going to fund a clinical trial (or authorize one) lasting a couple of decades in healthy people, or even dig up the tiny proportion of people who, within the last decade or so, have started taking metformin (most of them buying it black market and thus possibly fake or contaminated) and track them for a similar period relative to controls? And the latter group are massively different from the rest of the population: most of them are life extensionists popping tons of supplements (and all of them different supplements), getting exercise, eating very unusually good diets, well-educated, good incomes, etc. Disentangling that statistically is going to be nigh-on impossible, even if you could scrounge up the study population (which I doubt -- it's hard enough to do these studies as it is).
 

Bad news for the FDA trial, if the study fail, it will be bad for the anti-aging trance.

Trial is still "ongoing". I see this "Estimated Primary Completion Date:December 2015 (Final data collection date for primary outcome measure)"...here we are end of December 2016. 

 

https://clinicaltria...ord/NCT02432287

 

Perhaps it does not mean the trial will be rapped up Dec 2015? Or???

 

 

Metformin activates AMPK

 

https://www.ncbi.nlm...cles/PMC209533/   "metformin activates AMPK in hepatocytes" and "AMPK activation is required for metformin’s inhibitory effect on glucose production by hepatocytes."

 

Metformin suppresses LPS, aka endotoxin

 

https://www.ncbi.nlm...pubmed/24973221 " Metformin suppresses lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages via activating transcription factor-3 (ATF-3) induction."

 

Metformin -> Active AMPK -> ATF-3,  (Active AMPK + ATF-3) -> inhibits macrophage Tumor Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6) in a concentration-dependent manner. (These inflammatory cytokines, signaling molecules, are normally produced when macrophages encounter cell wall remnants from gram-negative bacteria, LPS/endotoxin).

 

"The three most common inflammatory cytokines that are responsible for chronic inflammatory diseases are Tumor Necrosis Factor (TNF-α), Interleukin-1beta (IL-1b) and Interleukin-6 (IL-6)."  "The transcription factor nuclear factor NF-kappaB is also heavily spoken about, and these four proteins are what people most likely refer to when they talk about chronic inflammation" https://selfhacked.c...rleukin-6-il-6/

Metformin reduces all cause mortality:https://www.ncbi.nlm...ubmed/28802803/

 

Not a big fan of meta-analysis, but another positive mark for metformin. Considering all the health-positive research results, the almost non-existent side effects, and low cost, I am disappointed it is not an OTC supplement yet.

 

 

Considering all the health-positive research results, the almost non-existent side effects, ..

 

Except the initial vomiting and diarrhea in my case. After getting used to it without these side-effects still a precipitous fall in serum B9, B12 and CoQ10. Along with rise in homocysteine..
 

Considering all the health-positive research results, the almost non-existent side effects, ..

Except the initial vomiting and diarrhea in my case. After getting used to it without these side-effects still a precipitous fall in serum B9, B12 and CoQ10. Along with rise in homocysteine..

Easy things to supplement with, and certainly worth it. I've been taking Metformin for four years with no side effect, and normal homocysteine ( 6).

One should read this post by Josh Mittledorf. He summarizes the evidence as of 2012. I don't think there is much question that Metformin extends life ( modestly) , and can extend health span for those with underlying health issues.
https://joshmitteldo...nti-aging-drug/

Ive got metformin with glyburide 500/5mg formula. Instant release. Im not diabetic and want them to decrease aging. So far I tried one right after id finished preparing lunch. Got hit with diaphoresis,tremors, lightheaded and practically ate several pounds of food before the hypoglycemic symptoms subsided.

The question is how many mg at a time are people using. Obviously, 500mg at once was way too much for me.

I use Metformin as a non Diabetic at 500 mg, twice per day. I will only take a dose if I have a lot of food in my stomach, including protein. Otherwise, I get loose stools, and stomach issues. Due to that, I often only take 1 dose per day.

 

 

 

Valijon, I have not seen recommendations to take Glyburide for anti aging. There is a risk of Hypoglycemia especially if taken without eating. The following is from the "Black Box" warning which in some cases is only added after a product has been on the market, when problems occur , and when new information via research is discovered. There are also warnings about Cardiovascular issues from a long term study which looked at another medication of the same class as Glyburide.

 

Search Google for Glyburide insert and you will have different references to look at. They are pdf files, so I can not provide a link.Good luck.

 

"Hypoglycemia: All sulfonylureas including MICRONASE are capable of producing
severe hypoglycemia. Proper patient selection and dosage and instructions are important
to avoid hypoglycemic episodes. Renal or hepatic insufficiency may cause elevated drug
levels of glyburide and the latter may also diminish gluconeogenic capacity, both of

which increase the risk of serious hypoglycemic reactions. Elderly, debilitated or
malnourished patients, and those with adrenal or pituitary insufficiency, are particularly
susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be
difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking
drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe
or prolonged exercise, when alcohol is ingested, or when more than one glucose lowering
drug is used. The risk of hypoglycemia may be increased with combination therapy."

 

"UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of
tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2­
1/2 times that of patients treated with diet alone. A significant increase in total mortality
was not observed, but the use of tolbutamide was discontinued based on the increase in
cardiovascular mortality, thus limiting the opportunity for the study to show an increase in
overall mortality. Despite controversy regarding the interpretation of these results, the
findings of the UGDP study provide an adequate basis for this warning. The patient should
be informed of the potential risks and advantages of Diaßeta and of alternative modes of
therapy.


 

 
 
 
   

 

Edited by Heisok, 30 November 2017 - 10:25 PM.

Thank you for the information. I see the only way to go then is metformin alone.

So metformin increase lifespan that's right ? we don't have to pay attention to this subject ?

Metformin will inhibit mTOR which will induce autophagy which increases life span. The negative is it will decrease IGF levels so it’s kind of a double edge sword in a way depending on your goals.

So metformin increase lifespan that's right ?

No.
 

we don't have to pay attention to this subject ?

That depends on if you care whether it extends lifespan in otherwise-healthy aging people or not.
 

Metformin will inhibit mTOR which will induce autophagy which increases life span.

 
... or so you'd think. But, again: this has been tested rigorously several times, and metforming does not increase lifespan (though it can reduce the shortening of lifespan induced by diabetes and some animal cancer models). This is all documented earlier in the thread; please go back and read before objecting or asking questions.

Edited by Michael, 30 May 2018 - 05:06 PM.

There is an emerging evidence of metformin increasing incidence of neurodegenerative diseases

https://www.ncbi.nlm...pubmed/28583443

I recall another epidemiological study on this, but cant found it now.

 

 

 

https://www.ncbi.nlm...pubmed/28954880

And related thread: https://www.longecit...use-alzheimers/
Edited by tintinet, 03 June 2018 - 08:59 PM.

https://www.ncbi.nlm...pubmed/28954880
 

 

"After accounting for confounding by indication, metformin was associated with a lower risk of subsequent dementia than sulfonylurea use in veterans <75 years of age." Fine — but that's not an argument for its use in nondiabetics, of course.

There is an emerging evidence of metformin increasing incidence of neurodegenerative diseases
https://www.ncbi.nlm...pubmed/28583443
I recall another epidemiological study on this, but cant found it now.

Well that’s just terrible. I wonder what effect metformin actually had on the Diseases. As in was lowering glucose levels to much the blaming factor, decreasing mTOR the factor,etc.
Edited by John250, 04 June 2018 - 04:07 PM.