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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Thanks for this color @DeStrider def shows how important it is to optimize for the individual.

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Alcohol usage reduces hba1c

Agree, and given how much people drink on average at population that biases the association studies…

I mentioned it earlier today here;

Please be careful about using the word “color”. After reading through this whole thread, and particularly your post here - Cardiovascular Health - #91 by Neo
…and the trainwreck that followed, I said to myself, I hope Neo never says that again! I hope @DeStrider won’t derail in the same way (but you never know :wink:)

Regarding colchicine, it is an anti-inflammatory, and if you already know your c-reactive protein level is low, then I’m not sure colchicine is going to do anything extra for you. I’d also like to see the cardioprotective effects of colchicine compared to those of aspirin, another anti-inflammatory agent that is very safe (probably more so than colchicine). Right now I’m sticking with the low-dose aspirin…

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The effects of apple cider vinegar on cardiometabolic risk factors: A systematic review and meta-analysis of clinical trials

Sahar Dadkhah Tehrani et al. Curr Med Chem. 2023.

Abstract

Background: Cardiometabolic syndrome (CMS) is a set of metabolic abnormalities that are risk factors for cardiovascular disease (CVD). Apple cider vinegar (ACV) has been used in several studies as a natural agent to improve CMS risk factors. The present study aimed to perform a systematic review and meta-analysis of the effects of ACV consumption on lipid and glycemic parameters.

Methods: PubMed, Scopus, and ISI Web of Science databases were systematically searched to find clinical trials evaluating the effects of ACV consumption on CMS risk factors.

Results: Overall, 25 clinical trials (33 arms) comprising 1320 adults were entered in this study. ACV consumption could significantly improve the levels of FBG (-21.20 mg/dl; 95% CI: -32.31 to -2.21; I2: 95.8%), HbA1c (-0.91mg/dl; 95% CI: -1.62 to -0.21; I2: 98.9%), and TC (-6.72 mg/dl; 95% CI: -12.91 to -0.53; I2:50.8%). No significant results were observed for BMI, HOMA-IR, serum insulin, TG, LDL-C, and HDL-C. Subgroup analysis showed a significant decrease in FBG, HbA1c, TC, and TG in diabetic patients. In this type of analysis, ACV consumption significantly reduced FBG levels when administered for both duration subgroups (≥12 and <12 weeks). Moreover, in the subgroup analysis based on duration, TG concentration was significantly decreased following ACV consumption for ≥ 12 weeks.

Conclusion: This meta-analysis showed that consumption of ACV has a favorable effect in decreasing some CMS risk factors including FBG, HbA1c, and TC.

Abstract & Full Text Excerpts

Full Text (Paywall)

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I totally agree. And it means we don’t need to obsess about suppressing the mean average blood sugar (hba1c) to the max. We can focus on a wider/easier target range for hba1c plus avoiding big spikes using the hacks you linked.

I love these hacks. They totally worked when I self-tested using continuous blood sugar monitoring. I’ve been using them for a couple of years and was amazed at how quickly they normalize. Most of them are just part of my unconscious behaviour now. They’re also great for kids. E.g. Giving my kids vegetables (crudités of raw carrot, red pepper etc) before the meal starts guarantees they’ll eat them because they’re so hungry. Giving my kids vegetables with the meal guarantees an argument. We spend quite a bit of time in France and there, vegetables first are part of the culture the standard school lunch menu. And it means that by the time they reach pudding, the blood sugar spike risk is massively reduced.

My other fave is doing some squats immediately after eating something very sugary. It really works to avoid the spike and it’s so easy to do.

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I’d hope that anyone doing a cohort study on this will have factored out the obvious confounders: people with eating disorders like anorexia, people with excessive use of antidiabetic drugs, people with hemolytic anemia or hemorrhage.

If so, a possible explanation would be that any diet and life style which achieves a very low hba1c might be more prone to repeated hypoglycemic episodes which are having a negative effect. Or maybe a lower hba1c correlates with more spiking of blood glucose because the system is less able to deal with blood glucose when it does occur.

I would argue that the true curve is almost certainly u-shaped (hba1c of zero has to be bad for surely?) its just a question of where the low point is.

5.3 seems a reasonable target given that most people are well above that.

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GliSODin, a vegetal sod with gliadin, as preventative agent vs. atherosclerosis, as confirmed with carotid ultrasound-B imaging

M Cloarec et al. Eur Ann Allergy Clin Immunol. 2007 Feb.

Abstract

Prevention of cardiovascular disease should target high-risk subjects based on genetic/familial factors, blood chemistry, blood pressure, body mass index (BMI), and a history of/or current cigarette smoking. We selected active adults (n=76) aged 30-60 and investigated these risk factors, in order to recommend preventive measures. Another interesting variable is the preclinical status or atheroma of the arterial (carotid) wall or lumen. We also investigated the presence of oxidative stress in, and the anti-oxidant status of these subjects. We studied the anti-oxidative efficacy of superoxide dismutase (SOD) and variations of malondialdehyde (MDA). Supplementation with GliSODin, a vegetal SOD associated with gliadin, was effective in controlling the thickness of the carotid artery intima and media layers as measured uby ultrasonography-B. We could demonstrate the preventive efficacy of GliSODin at a preclinical stage in subjects with risk factors of cardiovascular disease.

PubMed Abstract

Additional information from a citing study:

”A research study on individuals at risk for developing atherosclerosis demonstrated a striking difference between the control and the protected SOD–supplemented group when examining carotid thickness. Individuals receiving SOD–gliadin daily (500 U SOD activity) or placebo for a period of 2 y were subjected to B-scan ultrasonography to measure the intima media thickness (IMT), a standard detection method for atherosclerotic lesions. Decreased carotid IMT measurements were seen in patients after 365 d of treatment with SOD–gliadin. Moreover, the supplemented group registered an increase in SOD and CAT levels in the blood compared with the placebo group. Additionally, lipid peroxidation, used as a measurement of oxidative stress, was reduced after SOD–gliadin intake. Together, these data suggest a potential role for SOD–gliadin supplementation in the prevention of atherosclerotic lesions, possibly through its general antioxidant action.”

Reference
Romao S. Therapeutic value of oral supplementation with melon superoxide dismutase and wheat gliadin combination. Nutrition. 2015 Mar;31(3):430-6. doi: 10.1016/j.nut.2014.10.006. Epub 2014 Nov 5. Erratum in: Nutrition. 2015 Sep;31(9):1187. PMID: 25701330.

Interesting but I don’t know how I’d work vinegar into my diet. I don’t eat salads. =)

A while back I saw a study that sauerkraut reduces inflammation, and I tried it for a while but it didn’t really go with anything I usually eat (no I don’t eat hot dogs).

Anti-Inflammatory and Immunomodulatory Properties of Fermented Plant Foods - PMC (nih.gov)

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I add apple cider vinegar to my water bottle. It makes water taste better. I also take a spoon of ACV with little water before I eat my mostly carbs breakfast. I also add ACV in soups and of course to salads. Why don’t you eat salads?

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