Is it time to repurpose geroprotective diabetes medications for prevention of dementia?

#1

DiabetestMedications
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Diabetes mellitus is a well-recognized risk factor for dementia. In prospective studies, diabetes confers a greater than 80% increase in risk for all-cause dementia and Alzheimer’s disease, and greater than 180% increase in risk for vascular dementia.1 One in seven adults in the United States are estimated to have diabetes, and more than 90% of them have type 2 diabetes (T2D).2 With an aging population and increasing obesity, the incidence and prevalence of T2D is expected to continue to increase worldwide.3

Insulin resistance, which is a metabolic hallmark of T2D, has been postulated as a pathophysiologic connection between diabetes and dementia. Hyperinsulinemia, a biomarker of peripheral insulin resistance, is a risk factor for Alzheimer’s disease even in the absence of diabetes.4 At the same time, ex-vivo studies have shown evidence of brain insulin resistance in people with Alzheimer’s disease who did not have diabetes.5 While insulin signaling in the brain has an important role in neuronal and glial metabolism, synaptic neurotransmission, neuroinflammation and neurovascular coupling, it is presently unclear whether the observed associations between T2D and dementia are caused by insulin resistance in the brain or metabolic consequences of peripheral insulin resistance (as reviewed in Reference 6). T2D is also characterized by endothelial dysfunction and microvascular insufficiency, which can lead to vascular dementia even in the absence of macrovascular insults, through mechanisms involving ischemia, blood–brain barrier leakage, and disruptions in white matter integrity.7

Given the strong epidemiologic and pathophysiologic connections between diabetes and dementia, it is not surprising that glucose-lowering drugs have been of interest for the prevention of dementia. In the current issue of the Journal of the American Geriatrics Society, Tang and co-authors8 aimed to resolve inconsistencies in the existing observational data by performing a systematic review and a meta-analysis to examine the associations between the use of dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter 2 (SGLT2) inhibitors in people with T2D and the risk for incident all-cause dementia, Alzheimer’s disease and vascular dementia. Ten observational prospective studies that met the inclusion criteria for meta-analysis encompassed more than 800,000 people with T2D (44% men), with a mean baseline age of 68 years and a median duration of follow-up of 4.5 years. Included studies were predominantly deemed to be of high methodological quality, but with substantial heterogeneity. Seven studies involved DPP-4 inhibitor users who, compared to non-users, had significantly lower relative risk for all-cause dementia by 17% and vascular dementia by 41%, but without significant difference in the risk for Alzheimer’s disease. Compared to non-users, users of GLP-1RAs (five studies) and SGLT2 inhibitors (three studies) had a significantly lower risk for all-cause dementia by 28% and 38%, respectively; meta-analysis by dementia subtype was not performed due to a limited number of studies.

Full Paper:

https://agsjournals.onlinelibrary.wiley.com/doi/10.1111/jgs.18405

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#2

It’s odd that they didn’t also include acarbose or metformin in the diagram. I haven’t looked at the paper but i hope they’ve shared their perspective on DPP-4 inhibitors as well.

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#3

Metformin in elderly type 2 diabetes mellitus: dose-dependent dementia risk reduction

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#4

Anyone know what the optimal dosage is per day for Metformin?

#5

I think the best info we have to go on is the design of the TAME Metformin study - and its 1500mg slow release 1X day.

Details here (PDF of a presentation on TAME Study):

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#6

A little diatribe about why I don’t like doctors.

When I was working as an electronics design engineer, I had to be constantly studying the latest developments. If you were not current you soon would be left behind and possibly without a job.

My observation that applies to most primary care doctors, as opposed to doctors doing research, is: Most primary physicians are not keeping current with the latest in medicine. Maybe they don’t have the time or energy after seeing patients all day.

This results in the patient not being prescribed the most effective treatments and medications.
A typical example is rapamycin. I suppose by now most doctors have heard of it but are unlikely to give you a prescription.

My primary doctors have on the whole been very smart but were seldom up to date on anything medical. I have always taken a proactive approach to my health care and have frequently taken the latest studies with me to my doctor in order to get the best medications.

A typical example is metformin. My doctors never suggested that I take metformin as a prophylactic or any other medication for prevention rather than as a treatment.
The medications that I am taking are all my suggestions given by me to my doctors as a preventative measure rather than a treatment. Other than rapamycin, my doctors have been willing to prescribe the medications that I suggested. What they are not willing to do for the most part is to prescribe nonstandard tests such as Apo-B, Apo-A1. They say I don’t need it. Once again the mindset is for treatment rather than prevention.

Now that I am in my 80’s my doctors don’t give a sh*t. Won’t even prescribe a PSA test because “you will die of old age before you die of prostate cancer”.

No doctor that I have ever been to has practiced preventive medicine other than to tell patients to lose weight, stop smoking, etc.

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#7

I don’t understand doctors. If a customer was paying me (directly or indirectly) for something trivial I would gladly oblige even if I don’t agree with it.

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#8

They can be sued. Like if they write you a prescription for rapamycin and you start eating it like candy, getting sepsis and dying or losing a bunch of your limbs, they had to have had a justification for prescribing it. But I don’t know the laws very well.

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#9

I meant doing a PSA test. Prescribing medications is legally iffy, doing a hundred health tests is not.

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#10

You need to buy the additional blood tests at a private clinic and pay out of your own pocket if they won’t prescribe it. Unfortunately the options for what you can order without a doctors referral aren’t great in some countries.

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#11

At the 21:00 mark, the speaker mentions a drug, Biumetanide? that reduced Alzheimer’s and Dementia by 70% in humans and 100% in mice. @adssx

Thoughts?

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#12

I didn’t know about bumetanide, thanks. There’s only one ongoing trial, at Stanford, results expected next year: ClinicalTrials.gov

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#13

It’s a bit more complicated. I however absolutely sympathize and agree with many of the points.
So if you are insured, one of the obligations I have is to responsibly order tests that have a good reason - as, if I don’t, the insurance is likely to deny it, may even ask me why I’m not following guidelines - and it drives up the cost of healthcare for all in that pool of insured if all the doctors are ordering things that aren’t sensible.

So the way around this, is that if you want something done - yes, if you are paying fully for it, and the doctor has no obligation to practice cost effective medicine - then yes - should be fine, so long as there is no risk to the test.

For example, I have patients frequently present to the ER with abdominal pain, with no medical reason to need a CT scan (but thinking they “need” one). In my medical experience, if there is no reason to do the test, I won’t be doing it. There is cost, radiation and IV dye exposure and the patient isn’t an expert in sorting out what is appropriate medicine for their acute issue.

If someone wants things like ultrasounds, bloods, urines … and they are truly paying for it - no one else is on the hook - absolutely have at it. This however is rarely the situation. It is the situation in my private practice, but not when I work in the ER.

The prostate test is an annoying example - the likelihood of someone in their 80’s who gets prostate cancer dying from this is very low. Getting harmed from useless additional tests and procedures, is pretty likely. However, I think you have the right to know and hopefully get excellent expert advice on how to manage this if it were to occur. It also should never be an age issue - it should be a numbers of quality years estimated remaining. If I have someone who is only going to live another 2 years, doing bowel, breast, prostate cancer screening is silly - but if they might make it 15 years - seems pretty sensible to me.

I’m less worried about a bad patient outcome and suit with the things I prescribe, and there is a lot of shared decision making, consents, etc - probably more worried about a state medical board deciding to make an example out of someone if they decide they don’t like proactive care and use of drugs, despite evidence, off label.

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#14

At less than $16.00 for 30 x 2mg tables, an already “approved FDA drug”{I do not care if a compound is approved or not] you are going to wait?

Roizen coves this in his other video posted and in his book.

“If you wait until you are ready, it is almost certainly too late.”
~ Seth Godin

“I am not the waiting type.”
~Joseph

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#15

I think we all need to take care of ourselves as if we will live to 100. So an 80 yo with prostate cancer needs to cure it or else he won’t make it to 100. Assuming he’s taken good care of himself, the prostate cancer should be taken care of or that will become the limiting factor in his lifespan.

Of course, there are a lot of 80 yo people who haven’t taken care of themselves and will be done in by something else before the prostate cancer kills them. Frankly, that’s a shame. Everyone should be able to make it to 100 if they are proactive.

It seems that the system is not to worry until something breaks. But by then, it may be too late. Be proactive.

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#16

If the results are coming out next year, I can wait. I don’t think I’m that close to dementia yet.

Maybe others here would disagree with my assessment. :wink:

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#17

It’s not a benign drug is the issue. It is a loop diuretic, I use it for patients with heart failure most commonly.
Potassium needs monitoring and often needs supplementing, it can make your kidney function go off badly, you can get hypovolemic, have issues with postural hypotension, alkalosis, oto toxicity, pancreatitis, hepatic encephalopathy, immune reactions include lupus like illness - stevens-Johnson syndrome, increased Uric acid, hyponatremia, elevated blood sugar, photosensitivity …. On and on.

As much as many drugs that have a lot of listed side effects have most people have none … this one - and yes it is dose dependent have a very significant rate of having multiple of those actually occur (usually on the electrolyte side of things).

So grabbing this off the internet without having a thorough understanding of what would need to be done to safely monitor wouldn’t be the best move.

There are other candidates - and also - are we simply adding a drug and no benefit and potential harms at the point rapamycin seems to do a pretty good job, from what we know, in decreasing this same outcome. I like Rapa’s safety profile better, and then add a bit of telmisartan, an sglt2-i, PDE5, GLP/GIP agent … That’s my pick of approach.

Anyway, anyone thinking of taking this, understand what a physician does to monitor safety, and make sure this is done so you don’t end up in a serious way with adverse effects. It certainly can and is used safely - but not without monitoring.

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Experimental and real-world evidence supporting the computational repurposing of bumetanide for *APOE4*-related Alzheimer’s disease
#18

For those looking, same review some doctor’s use

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Experimental and real-world evidence supporting the computational repurposing of bumetanide for *APOE4*-related Alzheimer’s disease
#19

I have had a similar experience --doctors not being proactive, not knowing what they should. I do get that they are slammed and don’t have much time to do anything except look at the official guidelines. And to be fair, when I have pushed (politely) and provided evidence, they have been more or less willing to test or prescribe. It is totally on us to stay fully informed and ask for what we want.

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#20
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