#56

Interesting that this SGLT2 inhibitor reduces cardiac mTOR

The SGLT2 inhibitor ertugliflozin modifies the signature of cardiac substrate metabolism and reduces cardiac mTOR-signaling, endoplasmic reticulum stress and apoptosis

Conclusion

SGLT2 inhibition reduced left ventricular fibrosis in a murine model of cardiac hypertrophy. Mechanistically, this was associated with reduced cardiac insulin- and increased AMPK-signaling as a potential mechanism for less cardiac mTOR-activation with alleviation of downstream ER stress, UPR and apoptosis.

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#57

In proof-of-concept trial, J&J’s Invokana combo helps non-diabetics shed significant weight

The 334-patient study tested the two-med combo against phentermine alone, canagliflozin alone, and a placebo. After 26 weeks, patients using the combo had lost 7.5% of their body weight, compared with 4.1% in those taking phentermine alone, 1.9% of those only taking canagliflozin, and 0.6% of placebo patients.

Also, almost two-thirds of the patients taking both drugs reduced their body weight by at least 5%, compared with 17.5% of placebo patients.

“The findings support the potential clinical impact that canagliflozin could have on the lives of people constantly having to manage their weight,” said Dr. James List, global head of cardiovascular and metabolism at J&J’s Janssen unit. "We are committed to pursuing transformational therapies and hope to grow our understanding of how canagliflozin can be used to help more patients in the future.”

#58

SGLT2 Inhibitors vs GLP-1 Agonists: A Cardiologist and an Endocrinologist Weigh In (From Medsape.com)

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#59

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I don’t really like the sound of the risks and side effects even if rare. Also, azithromycin is not used for urogenital infections or cellulitis in the genitals (Fourier’s gangrene requires immediate surgery). I am scratching my head with Dr. Green’s Z pak thought process and I also cover why azithromycin can be potentially life-threatening dangerous given specific situations and risk factors commonly seen in this forum.

But going to research this one a bit more.

Safety of Sodium-Glucose Co-Transporter 2 Inhibitors

https://www.ajconline.org/article/S0002-9149(19)31179-8/fulltext

#60

As you know blood glucose levels increase in the elderly, I am 81 and chose to use
empagliflozin instead of increasing my dose of metformin. This is from a source referenced by the source you provided. It looks to me that empagliflozin is pretty safe. Every drug and supplement from aspirin to rapamycin has risks. One always has to weigh the risk/benefit to decide whether or not to take a certain supplement. If you are young and healthy you probably don’t need any supplements other than rapamycin if you are seeking life extension.

I really like the table.

The bold words are my emphasis.

"Conclusion

There are strong overall associations of SGLT2 inhibition with protection against major cardiovascular events, heart failure, serious decline in kidney function and all-cause death. SGLT2 inhibitors were also associated
with infections, volume depletion effects and amputation. Some associations appear to differ between compounds."

"Overall, use of SGLT2 inhibition was associated with favourable effects on major cardiovascular events, non-fatal myocardial infarction, hospitalisation for heart failure and all-cause death (Fig. 2). The I

2 statistic indicated a

high likelihood of differences between compounds beyond chance for cardiovascular death (I

2 = 80%) and a corresponding moderate likelihood of differences beyond chance for all-cause death (I

2 = 55%). There was no association of

SGLT2 inhibition detected for hospitalisation for unstable angina or stroke but for the latter there was a moderate likelihood of differences between compounds beyond chance (I

2 = 61%)."

"Effects of SGLT2 inhibitors on kidney disease outcomes

There were just two compounds with data describing effects on the renal outcomes of interest [10,47] and there were strong associations of SGLT2 inhibition with protection against progression of albuminuria and the renal composite outcome"

“Evidence of differences in protective effects was strongest for the outcome cardiovascular death, where empagliflozin appeared to provide a greater magnitude of protection. There was a corresponding, though less strong, finding for all-cause death that was probably driven by the effect on cardiovascular death”

"The association between amputation and use of SGLT2 inhibitors is a new finding that appeared to be restricted to canagliflozin.

“https://spiral.imperial.ac.uk/bitstream/10044/1/66221/2/Effects%20of%20sodium-glucose%20cotransporter%202%20inhibitors%20on%20cardiovascular%20disease%2C%20death%20and%20safety%20outcomes%20in%20type%202%20diabetes.pdf”

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#61

The studies and summary risk metrics are using diabetics, not healthy persons. I guess you’re not altering your risk calculus considering how healthy you are at 81? Could some of these side effects increase in older persons, diabetic or not? Kidney function is a huge concern, IMHO. I didn’t look for any age stratification, albeit diabetic population.

Looking at impact on glucose and hbA1c Empagliflozin @ 10mg/day, you would think diet/exercise could easily achieve these objectives? But then again, that’s why these people are T2D, lack of lifestyle control.

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I am definitely in the low glucose AUC for longevity camp. I’ve taken a good axe hack at AUC glucose with strict keto. I for sure would go hypoglycemic taking one of these meds. Some days I veer into hypoglycemic (< 3.9 mmol/L).

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Acarbose - Details On Another Top Anti-Aging Drug
#62

I wonder how big this risk truly is (of hypoglycemia) for healthy people. I thought that one of the primary effects of this class of drugs (as with acarbose) is the just flatten the curve, thus reducing the blood sugar spike we get after consuming food / carbs., but with no change in the AUC. At the same time I wouldn’t recommend SGLT2 inhibitors to anyone on a Keto diet, due to the risk of ketoacidosis as identified in posts above in this thread.

“The risk of hypoglycemia associated with SGLT2 inhibitors is low, unless co-administered with insulin or an insulin secretagogue”. From the source above by @tongMD

Also, as a circumcised male, the risk of genital infections (especially for those of us who have never had such an infection ever before) seems extremely low (and this is the highest risk side effect I believe) and easily treatable in the low chance it does happen.

SGLT2 inhibitors are associated with an increased risk of genital mycotic infection, 5,6 particularly in patients with a history of genital mycotic infection and in uncircumcised males.1, 2,3, 4Genital mycotic infections occur more frequently in females than males receiving treatment with SGLT2 inhibitors, are generally mild or moderate in severity, and respond to standard antifungal therapy.

The other risk are UTIs. Again - in healthy, non diabetic males, with no previous history of UTI, it seems like a low risk:

Data on the potential SGLT2 inhibitor-associated risk of urinary tract infection (UTI) are less consistent, and published reports have provided conflicting conclusions. Some SGLT2 inhibitor studies suggested an increased associated risk of UTI, whereas others did not.

Its unclear to me why exactly anyone would think that the risk of serious side effects with SGLT2 inhibitors is unacceptably high for healthy, younger males with a low to moderate carb diet. I don’t see the specific risk factors that are high - especially when using SGLT2 inhibitors in a pulsed dosing fashion (My default right now is 5 days out of 7, so a two day “off” period each week.

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#63

My family has a history of type II diabetes, so in spite of my healthy life style, my glucose levels have risen over the years so I have to use drugs such as metformin and empagliflozin to keep my fasting glucose level under 100 mg/dL and my hemoglobin A1c under 5.7 % of total Hgb. Supplements such as berberine have had no detectable effect on my glucose levels.

#64

Not so, look at glucose with CGM vs placebo (human data). It takes (shifts) the entire glucose curve down with dosing. There is no flattening. The AUC (using 0 mg/dL as reference) is most definitely reduced.

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Acarbose - Details On Another Top Anti-Aging Drug
#65

Interesting…

That seems to contradict what Richard Miller and his team is reporting:

CanagBloodGlu2

Admittedly - the ITP study is in mice not humans.

Though, in the study you just referenced: “Effect of empagliflozin monotherapy on postprandial glucose and 24-hour glucose variability in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, 4-week study” - the people are diabetic.

I wonder if there is any data on the blood glucose curve impact of SGLT2 inhibitors in healthy, non-diabetic populations? I will look.

#66

Ah those mice and the ITP…translation to humans is massive leap.

I didn’t find first glance, but my guess…curve will be SAME, just perhaps the delta shift might not be as much.

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#67

Yes - but what we are all betting on :smile:

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#68

Well thats’ new and pertinent information you’ve shared re risk calculus.

#69

Do you have/use a CGM? Is anyone else of low BMI, far away from T2D using this med with a CGM?

#70

Researching the issue of hypoglycemia for people using SGLT2 inhibitors a little more…

A study of 170,000 diabetic Japanese patients on SGLT2 inhibitors saw a risk of %0.13

So - in diabetic populations, around 1 in 1,000 patients.

But, the study notes:

Conclusions: …We revealed that the risk of hypoglycemia may be higher when combining SGLT2 inhibitors with sulfonylureas and/or insulin. Furthermore, we discovered a high risk of hypoglycemia in older and non-obese patients.

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#71

Yes - I reported on my results with Canagliflozin here, with CGM tracking screen shots (keep in mind that the real blood stick tests suggested the CGM was 10 to 20 points lower than the blood tests):

See: Canagliflozin for Anti-aging (part 2)

#72

Diabetics? They have massive glucose stores, would naturally assume hypoglcemia would NEVER be a risk.

Looking at the curve above, using my fasting glucose and fasted state, along with pharmacokinetics, I’d be immediately and in a sustained hypoglycemic state taking10mg.

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#73

Anyone at any age can get Fournier’s gangrene with no past medical history. All you need is a skin breach from an insect bite or minor laceration/trauma.

The genital/peritoneum area is literally one of the worst possible place you can get necrotizing fasciitis (aka “flesh-eating” bacteria) besides head and neck

It’s rare for young and healthy people, but possible.

Men are about 10x more likely to get Fournier’s gangrene and especially if you have immunosuppression (i.e. high dose rapamycin on the first day leading to neutropenia) and canagliflozin - the risk skyrockets even further.

The main association is you can see it in a male T2DM (= some immunosuppression) patient using canagliflozin. But the problem is if you show up in the urgent care/ED and “your doctor is not really a doctor” and doesn’t think of urgent surgery and just sends you home with antibiotics…

Rapamycin and Skin Abscess infection vulnerability
#74

Which SLGT2 are you taking nowadays, and any different side effects from previous?

#75

Empagliflozin - no side effects that I can notice.