You’ll probably get dumped on for saying that, because the study may (or may not) have failed to factor out all the confounders. But i think the MR studies back up your conclusion to a large extent. The benefit of reducing from say apob 100 to apob 70 is only about a 14% reduction in all cause mortality IF you achieve that retrospectively from birth thanks to your genetics. So achieving such a reduction for say, 10 years through a statin may only achieve a small fraction of that benefit. And there may be negative side effects which push up ACM risk. And the study couldn’t say whether the benefit continued below 70mg/dl.

In contrast there are some immediate and large ACM benefits from say improving blood glucose, or reducing inflammation.

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Is the benefit seen even for people who are not diabetic? Like going from a HbA1c of 5.8 to 4.2 for example.

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Interesting q, this would suggest a 50% reduction going from say, 7 to 5.5
It doesn’t go all the way to 4.2. But there’s a reduction if about 20% going from 5.8 to 4.5

But I’ll look for better data.

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Doesn’t this chart also suggest there may be no benefit from going fom 7.0 to 5.5?

I assume the gray area is 95% confidence interval.

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Interesting post-hoc analysis, I don’t put much weight to it either way, the better evidence is still impressive.

The JUPITER trial compared the clinical outcomes and adverse events in patients treated with rosuvastatin who attained LDL-C less than 50 mg/dl and those who did not. The study revealed reduced major cardiovascular events by 65% among those attaining LDL-C < 50 mg/dl and by 44% for the rest of the cohort. Similarly, all-cause mortality was decreased by 46% among patients achieving LDL-C < 50 mg/dl and by 20% for the remaining cohort.

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I think this may be a better study

image

https://www.researchgate.net/figure/Dose-response-relationship-of-HbA1c-levels-with-all-cause-mortality-in-subjects-without_fig1_294285062

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I think this study also has issues with the cofounding factor cancer.

Do you mean you didn’t agree with their adjustments for confounders?

Is there any mechanistic reason for why 5.2-5.3 HbA1c should be better in a healthy, metabolically optimized individual for longevity than say 4.5-5 HbA1c?

I know, it seems like you would want your glycated hemoglobin to be zero. It’s bad, right?

I think red blood cells need to eat glucose though, so maybe that has something to do with it.

The brain likes using glucose for instance, so I do think we want some reasonable glucose levels for part of our energy needs and perhaps not switch “entirely” from glucose to ketones.

But there are so many negatives from glucose, insulin and related “growth” pathways and signaling, so I’d love to hear and try to understand from anyone that believes that these U curves have the optimal at the bottom of those U curves (around 5.3 or so) if there are mechanistic rationales other than demographic (with some controls) association studies.

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Do you know of any drug that improves outcomes stratified by decrease of biomarker(s) and verified with MR for long-term effect, and consistent among drugs based on the same decrease in biomarker?
I’m just using the same standard of evidence as there exists for apoB / LDL and drugs like statins.

As Peter Attia said, if you have a blood glucose level of 0, you are dead. You need glucose in your blood, and it’s up to your body to maintain the proper amount. So, 4.5-5.6 is the optimal range based on what I’ve read. 5.0 seems to be the sweet spot.

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Deleted, for now, need to check something.

Iron and hemoglobin were inversely associated with HbA1c but not fasting glucose.

The inverse associations of HbA1c and liability to diabetes with lifespan were possibly stronger in men (-1.80 years per percentage [-2.77, -0.42]; -0.93 years per logOR [-1.23, -0.59]) than women (-0.80 [-2.69, 0.66]; -0.44 [-0.62, -0.26]).

HbA1c underestimates fasting glucose in men compared with women, possibly due to erythrocyte properties. Whether HbA1c and liability to diabetes reduce lifespan more in men than women because diagnostic and management criteria involving HbA1c mean that glycemia in men is under-treated compared to women needs urgent investigation.

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Think most, if not all, areas of medicine - not to mention longevity - will not be as well studied or as clear as cardiovascular disease.

I’m not an expert on this, but it seems that the mechanistic understanding of longevity generally points towards lower glucose (and metabolic flexibility an being able to mix/switch between glucose and fat/keyones as fuel is key). See eg the CR literature, fasting literature, that the mode of successful ITP results have to do with glucose modulating compounds, and human SGLT2i, Acarbose, and Metformin, etc, etc and related literature such as insulin and IGF-1 up generally bad for longevity.

For someone that has roller coaster glucose control with high peaks and then deep valleys it might make sense to have higher base glucose levels to not fall too low.

But such a person has probably not optimized their glucose/energy metabolism and should work on minimizing big ups and downs in glucose (and hence insulin).

For someone with great glucose control / small ups and downs, lower than 5.0 feels like good when optimizing longevity.

While we won’t have good placebo control trials in healthy individuals for glucose, this might be one place to start looking and also see what references they in turn cite:

https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(23)00085-5/fulltext

Perhaps the paper I shared with @Bicep above also.

You may also find this helpful:

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I not sure where this 5.0 is the sweet spot is coming from - other than being influenced by the all cause mortality association U curve studies?

Since you mention Dr Attia, from here he seems to think that lower is better.

Note also that the glucose level of zero is not relevant, because there are so many parts of our biology and hunger drive that will make it difficult to go too low (in a healthy, metabolically fit individual) if one is not overusing medicines.

Peter Attia’s calculation is that 4.6% represents estimated average glucose levels of 85 mg/dL. That does not look like a level that is too low for the liver in a person who is optimized from a metabolic perspective and easily can utilize fat and not just glucose as energy.

From below you can also see that Dr Attia seems quite happy with 4.6

Glucose control lives on a spectrum, but it conventionally gets lumped into three distinct categories: normal glucose tolerance, prediabetes, and diabetes. For example, whether your HbA1c is 4.6% or 5.6%, both are considered “normal” because they both fall under the diagnostic threshold of 5.7%. Once it hits 5.7%, so long as it does not exceed 6.4%, now you’ve got impaired glucose tolerance, also referred to as prediabetes. Once you’ve eclipsed the latter, whether your HbA1c is 6.5% or 12.5% (or even higher), you’re categorized as having type 2 diabetes. In most cases of type 2 diabetes, an individual traverses from one bucket to the next as their HbA1c slowly climbs from normal to impaired to outright diabetic. This doesn’t happen overnight, but too often it’s only confronted when the diabetes or prediabetes threshold is reached at a snapshot in time. Progressing from an HbA1c of 4.6% to 5.6% represents estimated average glucose levels climbing from 85 to 114 mg/dL.

Are continuous glucose monitors a waste of time for people without diabetes?.. 3

And here he gives his view on that lower average glucose is better* and puts that in context of success with a patient who came down to 84 mg/dL and hence at or below a predicted 4.6% HbA1c:

To recap my position and interpretation of the data available (more of which you can find in the AMA 24 show notes), lower is better than higher when it comes to average glucose, glucose variability, and glucose peaks, even in nondiabetics. In other words, there’s a lot of evidence suggesting that people with glucose in the normal range can benefit from lowering their numbers.

Let me give you an anecdote, among several I could share, to demonstrate why I find CGM useful in nondiabetics. I have a patient who came to me with normal glucose tolerance by standard metrics. He began CGM and after about two weeks it revealed an average glucose of 104 mg/dL over that time. The standard deviation in his glucose readings, which is a metric of glucose variability, was 17 mg/dL. He averaged more than five events per week in which his glucose levels exceeded 140 mg/dL. All three of these metrics are considered normal by conventional standards, but does that mean there’s no room for improvement? I like to see my patients with a mean glucose below 100 mg/dL, a glucose variability below 15 mg/dL, and, as noted above, no excursions of glucose above 140 mg/dL. After about a four-week intervention that included exercise changes and nutritional modifications his average glucose fell to 84 mg/dL, his glucose variability to 13 mg/dL, and he had zero events exceeding 140 mg/dL. If he can maintain this way of living in the long-run, it’s likely to translate into an improvement in healthspan and reduce his risk of glucose impairment.

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I think when you get into the 4.6-5.0 range, it’s more about minimizing the glucose spikes. It’s those excursions above 140 mg/dl that are considered destructive and not bouncing back and forth between 4.6-5.0. When you drop below 4.6, you open yourself up to hypoglycemia which is also damaging to your body. Having experienced hypoglycemic events, it felt like I was having a heart attack and I needed to be admitted to the hospital during one when my HBA1C went below 4.4.

So, I don’t like playing with fire and I would rather keep my HBA1C as close to 5.0 as possible. I’m not sure if you’ve experienced a hypoglycemic event, but you get dizzy, feel nauseous, start to sweat and you feel like you are going to die. It’s like motion sickness on steroids and it’s not fun. That’s what happens to me when my blood sugar gets too low.

That’s why I’ll be adopting these hacks to avoid glucose spikes:

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Thanks for color. Think I understand what you mean.

(From your pasts post I think you might fit into one of my two categories in the prior post where I agree one should have an extra buffer)

  • risks of meds pushing one too far (you were on a lot of metformin (and something else like flozin or Acar when it happened?) or (/and)
  • not totally and fully optimized metabolic fitness, believe you mention pre-diabetic specs in the past?)

What I was questioning/trying to have you clarify was that I got the sense that you were saying that 5.0 was the sweet spot in general / in the best complete longevity regime when enough zone 2, muscle, fasting, switching between glucose/fat-ketones as main fuel has optimized a person’s metabolic fitness to the best extent possible.

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Due to my past experiences - taking too much metformin (1-2 g daily) - I would end up being hypoglycemic in the late afternoon on my way home from work. I lowered my dose down to 500 mg and that worked for the most part. I guess I could have eaten a sugary/carb snack before heading home, but that seemed self-defeating.

Yes, my metabolic fitness is not fully optimized. During my last blood draw, my blood fasted HBA1C was 5.7. However, I had stopped daily metformin at that point and was just taking Acarbose. So, I can fluctuate between 4.4 (or lower) and 5.7 depending on how much metformin I am taking and the time of day. For me, I want to stay at 5.0 so I don’t have a hypoglycemic event.

I’m not sure if someone can stay perfectly at 4.5 with very little fluctuation without risking hypoglycemia. That seems like a hard tightrope to walk and I’m not sure how much of a benefit (if any) 4.5 will have over 5.0. Especially if hypoglycemic events are detrimental to health which I believe they are.

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