(IMPORTANT) SGLT inhibitors are not a substitute for Acarbose

[Dr_Rami_Abunadar]

As a physician, It’s time that i put this myth to bed, As it has become too widespread and I haven’t seen anyone correcting it. The best case scenario is people wasting their money, Worst case is subjecting their bodies to the side and long-term effects of drugs that do not actually do what they think they do.

SGLT inhibitors (Canaglifozin, Dapagliflozin…etc) don’t affect post-prandial (Post meal) spike of glucose in healthy people. At all. Tada! (Healthy meaning their maximal glucose level doesn’t go beyond 150mg/dl after a heavy carb meal)

If you’re taking them because you want to replicate the anti-aging effect seen in the ITP trials, Then I have bad news for you. Unfortunately, this glaring misconception is the result of abstract and skim reading the scientific papers without a deep and thorough understanding.

First of all it’s important to understand why the ITP actually chose ‘Canaglifozin’.
After the promising results of Acarbose, They wanted to test the hypothesis that the reduction in glucose spike after meals that is responsible for the increased median and maximal lifespan of the mice. So they choose the SGLTI ‘Canagliflozin’. Now Cana is unique compared to the others in it’s class. While they all inhibitit SGLT2 receptiors in the kidney and help excerte glucose. Cana is the only one that also inhibits SGLT1 receptors found in the intestines. So to mimick acarbose they decided to always mix cana with the food.

Yet that’s not how Canagliflozin is consumed or works in humans. SGLT2 inhibitors like dapagliflozin or empagliflozin have zero effect on SGLT1 receptors in the gut, Meaning they have no effect on postprandial glucose in healthy people (Assuming the peak doesn’t go over 160mg/dl. those with IGT or DM are another story). Canagliflozin also has no effect, Unless it is consumed just before the meal, And it’ll work for that meal only with no effect on subsequent meals, And you’ll need to use the maximal dose (300mg) to achieve any noticeable effect and it’ll still be weaker than a dose of acarbose.

Pharmacodynamic differences between canagliflozin and dapagliflozin: results...

Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose...

So the prevailing notion that if someone doesn’t like the gases or discomfort after acarbose and they can switch to an SGLTI because it also supposedly prevents the glucose spike and extended healthspan in ITP, Is not only misguided But also categorically wrong.

It’s true that SGLT inhibitors have been shown in the literature in humans, To decrease damage to the heart and kidney, Improve HbA1c…etc (Cardiac protective effects are thought to be independent of any glucose effect) However, this does not necessarily mean this will definitively translate to anti-aging effects in healthy humans. I’d love to see an ITP study that uses Dapagliflozin in mice to see any healthspan effect and if there is a glucose spike-independent anti-aging effect of these drugs. However, until that happens, SGLTI should never be seen as a substitute for Acarbose. If someone wants to take them together then that’s another story.
Although keep in mind that SGLTI comes with rare but potentially extremely serious side effects. Which will be relevant if you’re taking them for many years, If not decades.

Of course, SGLTI are amazing drugs with certain established clinical entities with massive literature to back up their benefits, Such as:
1- established cardiovascular disease or High risk of CVD
2- Heart failure or high risk for heart failure
3- High risk of stroke
3- Diabetes, Or impaired glucose tolerance
…etc

I even predict it’ll be beneficial to those taking rapamycin and have a glucose spike larger than 160mg/dl 45-60 minutes after meals, Which Rapamycin is known to induce. Assuming they absolutely cannot tolerate or are not willing to tolerate acarbose. As the latter will always be the first choice and much more effective.

TLDR: Stick to Acarbose.

[RapAdmin]

Hi @Dr_Rami_Abunadar welcome to the forums and thank you for posting.

We have a lot of information on SGLT2 inhibitors - and I try to add all the new research on this topic as it comes up in this thread (over 170 posts in this thread, lots of discussion and links): Canagliflozin - Another Top Anti-aging Drug

Are you saying that the hypothesis conveyed in the Peter Attia / Richard Miller podcast (and the blood glucose curve from the pubished research paper on the results) is not accurate for humans?:

The following information is sourced from the Peter Attia / Richard Miller podcast. Richard Miller suggested that when you take these canagliflozin results together with the acarbose results, you’re led to the inference that something about aging in the male mice depends a lot on staying away from really high glucose levels. However, whether that means that high glucose in the males triggers a circuit in the hypothalamus, which is bad for you or something, is just a hypothesis. It may be that it has to do with the susceptibility of the hypothalamus to inflammatory change differentially in males than in females. And this nebulous change has an impact on the cancer, or an impact on anti-cancer defenses or something. Rich Miller believes that these hypotheses are equally likely to be true, but at present, none of it gives us much of a hint as to why these drugs have a much more striking effect in the male mice

Graphical abstract of blood glucose response. [source ]

Also - I’m a little confused when you say that it doesn’t blunt post prandial glucose increases. I have read that it just lowers your blood glucose overall. Is that what you are saying? Are you saying canagliflozin only lowered the blood glucose curve in the ITP mice because it was mixed in with their food?

And, of course, I did exactly what you are saying not to do. I started on Acarbose - but quickly got sick of it because of all the gas / flatulence it caused. Then moved to Canagliflozin.

I’m a healthy male, BMI of 22 or so, never diabetic. Exercise regularly 3 to 5 times a week for 6 to 10 hours total. Mostly a fish/vegetable/berries diet, with some whole grain pasta with my kids.

I took canagliflozin for many months (taking it early in the morning, at least 1 to 2 hours prior to eating food) and wore a CGM frequently while taking the medication. My blood glucose level was very flat while taking it, while I ate all types of foods. From my post on my experience: Canagliflozin for Anti-aging (part 2)

It seems to do a really good job of managing post prandial glucose levels - typically 70 to 120 during the day - see my typical daily CGM results in screen capture attached (Note that GCM measures are typically 10 to 20 points lower than I see on my finger prick blood glucose test). I eat a fairly low carb diet anyway - but this helps when I include higher glycemic index, higher starch, higher carb foods.

I see similar results with Acarbose. I’m having trouble reconciling my experiences with these medications and what you are saying - which if I’m interpreting correctly, you suggest I shouldn’t be experiencing, is that correct?

I’m not a doctor - so I’m not an expert in this area, but I’m just reporting on my experiences with these drugs. In my experience I see both a flattening of the blood glucose curve, and a lowering of it, as measured by CGM and finger prick testing.

[desertshores]

Thank you. It’s good to know I am not completely crazy.
I am 81 and in good health. My fasting glucose levels have been increasing with age, but are still in the high normal:

Since I am retired and have nothing better to do than prick my fingers several times a day, not always but sometimes, I have monitored my blood glucose before and after a meal and found that empagliflozin has zero effect or none that is apparent, on my post-meal glucose spike. That is why I plan on adding Acarbose before high-carb meals.

[jimmy]

I am diabetic, take metformin, dapagliflozin, & acarbose. My BMI is 22. A1C 6.0. I also take rapamycin.

Dapagliflozin works very well for me with rapamycin. My blood sugars don’t go above 145 on D. Without D it can go higher than 145.

Acarbose works for me but it is more difficult to manage.

[Goran]

I think that some of these substances mentioned here works well for glucose levels, but if this is a definite cause of the longevity results in mice trials I am not so sure about. Acarbose do lower the blood sugar spikes taken with meals, but is this the main reason behind the longevity results? Acarbose also increases Butyric Acid production in the gut, and some scientists theorize that with increased Butyric acid levels the cancer frequencies go down, as cancer cells do not fancy Butyric acid, they love glucose. And Mice die from cancer sooner or later.
The Mtor story with Rapamycin is same, I am not 100% convinced that this is the only reason behind the longevity results.
Bought Rapamycin, Acarbose and other diabetic treatments works very well for the gut microbiome. I suspect there are more to these stories to be told.

[DrT]

Acarbose may also increase production of hydrogen by intestinal flora. Hydrogen gas may also have lifespan effects. This is not proven; just a hypothesis.

[rivasp12]

Very interesting stuff.

What’s your opinion of metformin/ berberine for glucose spikes?

Why do you believe that they’re cardio protective apart from the glucose effects? What’s the mechanism?

I fully agree that the potential side effects of the SGLT’s are worrisome , especially over time.

[rivasp12]

Acarbose shares some common pathways with rapamycin so the longevity mechanism isn’t totally clear.

[Dr_Rami_Abunadar]

Hi @RapAdmin

First, I would highly suggest reading the two papers I posted above which were conducted in healthy individuals and not diabetics. The first paper is free, The second one you can view it by using the website sci-hub. In summary, they both show that SGLTI don’t decrease post-prandial glucose spike in healthy individuals, And i emphasize healthy. By that, I mean those who do not spike above 140-150mg even after a heavy-carb meal.
These two papers were done in controlled conditions with carefully selected healthy patients, Standardized carb meals…etc with objective testing. They are a better measure of the effect of SGLTI of postprandial glucose than personal CGM, As in the latter, a lot of variables can come into play.

The reasons are a bit complex but to make it short:
In healthy individuals who don’t spike above 150mg/dl after a carb meal. Their peak is mostly a function of the rate of glucose absorption from the gut, Which for the most part SGLTI do not affect. In diabetics on the other hand, Their glucose peak (which can reach +300mg/dl in many cases, And almost always beyond the 180mg/dl renal threshold for passive glucose excretion and SGLT receptors saturation) is affected by both gut absorption AND the rate of glucose excretion from the kidney. This is why SGLTI do in fact decrease glucose peak and decrease the overall AUC of glucose in diabetics much more than in healthy individuals. And even if there was any effect on the latter, It’ll be considerably less effect than what the mice experienced in ITP.

Canaglifolzin as shown in the papers above is the only one that does blunt the glucose peak in healthy people due to it’s unique SGLT1 action in the gut. However, it only does this due to transient inhibition of the SGLT1 while it’s being absorbed. Once it’s absorbed (which is mostly within 2-3 hours). It’ll have no effect on the spike on any subsequent meal. That’s why in the second paper they saw a decrease in glucose peak if taken before the breakfast meal, But so no effect on lunch or dinner. Which is consistent with the mechanism we already know about canagliflozin.

So yes, The reason Cana consistently decreases glucose peak in mice is because it’s always mixed with food. So there is always an inhibition of SGLT1 during mice meal. As you can probably deduce, This doesn’t happen with humans. Cana is taken as a once tablet only.

[AlexKChen]

But what if you eat fruit? Acarbose doesn’t work on many fruit sugars (unless it’s mango)

[Dr_Rami_Abunadar]

I would suggest you add acarbose to all carb-containing meals, Including low-medium. Acarbose is an extremely safe drug with minimal systemic absorption. Its side effects of flatulence is directly proportional to the carb content of the meal. So with the less carb in the meal, The less likely to experience any side effects. Making it even more convenient to take acarbose.

Acarbose has actually been shown to decrease fat absorption pf meals and not just carbohydrates. It helps to decrease the chylomicron spike (triglycerides spike) after meals, And over-long periods, Those taking acarbose have lower levels of cholesterol. So it’s also useful for any meal containing fats.

Effect of acarbose on postprandial lipid metabolism in type 2 diabetes...

If rapamycin is taken with a high-fat meal (Which is what I would greatly recommend as it enhances rapamycin absorption and peak blood levels), Acarbose should be omitted, As I said above it somewhat effect fat absorption. Of course, this is just to be safe, There are actually no studies to show that acarbose interferes with the absorption of any drug. However, given how important rapamycin is. It’s better to lean on the safe side.

[Dr_Rami_Abunadar]

@jimmy

I am diabetic, take metformin, dapagliflozin, & acarbose. My BMI is 22. A1C 6.0. I also take rapamycin.

Dapagliflozin works very well for me with rapamycin. My blood sugars don’t go above 145 on D. Without D it can go higher than 145.

Acarbose works for me but it is more difficult to manage.

As i said in my post. SGLTI are fantastic drugs for those who have diabetes, or maybe even those with impaired glucose tolerance (those who spike above 140mg/dl but remain less than 180mg/dl). However, I would also recommend combining it with acarbose.

Unfortunately, those who already don’t spike beyond 140-150mg/dl. SGLTI will do little to affect the glucose peak. And Acarbose remains the primary drug.

@Goran

I think that some of these substances mentioned here works well for glucose levels, but if this is a definite cause of the longevity results in mice trials I am not so sure about. Acarbose do lower the blood sugar spikes taken with meals, but is this the main reason behind the longevity results? Acarbose also increases Butyric Acid production in the gut, and some scientists theorize that with increased Butyric acid levels the cancer frequencies go down, as cancer cells do not fancy Butyric acid, they love glucose. And Mice die from cancer sooner or later.
The Mtor story with Rapamycin is same, I am not 100% convinced that this is the only reason behind the longevity results.
Bought Rapamycin, Acarbose and other diabetic treatments works very well for the gut microbiome. I suspect there are more to these stories to be told.

Well acarbose primarily blunts the glucose spike in mice. So to test the hypothesis that the glucose spike specifically is the main culprit, The ITP chose an entirely different class of drug, Which is Canagliflozin, And it’s main common simialry to acarbose is also blunting the spike, And hold and behold. It also successfully extended lifespan, And also to a similar magnitude to acarbose. That’s one hell of a coincidence if the primary mechanism was something entirely different to the glucose spike.

So the way I see it. The glucose peak hypothesis remains to be far the most probable. And there is a heavy burden of proof to other explanations.

@rivasp12

Very interesting stuff.

What’s your opinion of metformin/ berberine for glucose spikes?

Why do you believe that they’re cardio protective apart from the glucose effects? What’s the mechanism?

There is a paper that shows metformin inhibits glucose transport in the intestines in mice. However, I don’t know if that has any relevance to humans. There are papers that show metformin reduces the postprandial glucose in diabetics, But it may be simply due it its insulin-sensitizing effect in already hyperglycemic patients. I haven’t seen any papers to suggest metformin blunts the glucose spike in healthy individuals.

I don’t know much about berberine. But I know that it acts quite similarly to metformin. I think people should stick to metformin than experiment with berberine.
I’m extremely wary of any supplements and highly discourage their use. Not enough data regarding their actual efficacy/effective dose, But also not enough data regarding their absorption/distribution/metabolism and most importantly interaction with other drugs. Not to mention the lack of regulation and purity content of these supplements.

With regards to SGLTI and heart failure, Lots of potential mechanisms are implicated. Including decreased plasma volume due to osmotic diureses resulting in decreased preload and afterload. Decreasing vascular smooth muscle tone. But the most notable explanations are due to SGLTI effect on enhancing ketone production in myocytes, And inhibition of Sodium-Hydrogen exchanger. This paper explores some of these mechanisms:
https://sci-hub.se/https://doi.org/10.1007/s10557-018-6786-x

[Pat25]

Rapadmin, I thought to remember you have replaced Canagliflozin with Empagliflozin - is that still the case? Did you get comparable CGM readings with Empagliflozin?

Do you still take Acarbose, or not at all anymore, or Metformin? Thanks!

[Pat25]

@Dr_Rami_Abunadar

Well acarbose primarily blunts the glucose spike in mice. So to test the hypothesis that the glucose spike specifically is the main culprit, The ITP chose an entirely different class of drug, Which is Canagliflozin, And it’s main common simialry to acarbose is also blunting the spike, And hold and behold. It also successfully extended lifespan, And also to a similar magnitude to acarbose. That’s one hell of a coincidence if the primary mechanism was something entirely different to the glucose spike.

So the way I see it. The glucose peak hypothesis remains to be far the most probable. And there is a heavy burden of proof to other explanations.

Thank you for your insightful posts Dr. Rami Abunadar. Do you have any thoughts/potential suggestions why Acarbose and Canagliflozing resulted in an increase in lifespan in male rodents, but not in females?

[zazim]

Yes indeed. I love these posts Dr. Rami Abunadar. I don’t take any drugs other than Metformin, but it is nice to understand what these other drugs do and do not do.

[pollux]

Dr. Abunadar: for non-diabetics, what’s the effective dosage of acarbose do you recommend? 25/50/100 mg?

[shc]

SGLT2 inhibitors may prevent diabetes

https://www.nature.com/articles/s41581-022-00541-8

[Pestodude]

What are those potential long term use side effects?

[Davin8r]

Dr. Rami,
Whenever I check urine glucose while taking empagliflozin (non-diabetic), it is very positive for glucose.
I see the data above, but I don’t understand why.
Even if the initial postprandial blood glucose peak is unaffected, why wouldn’t the area of the curve be decreased since glucose disposal should be faster due to the combined effect of disposal into the urine added with disposal into muscle, liver, etc? Any ideas? Thanks

[zazim]

This prompted me to make an appointment with an Ageless Rx physician to get a prescription for Acarbose. I have a pretty good idea of which meals cause glucose spikes. I would like to add some carbs back to my diet.