Canagliflozin - Another Top Anti-aging Drug

#41

96% of population diabetics, so significant vasculature damage.

Neither DPP-4 inhibitors, GLP-1RAs, nor SGLT2 inhibitors were significantly associated with a decrease in risk of all-cause dementia incidence as compared with placebo.

SGLT2 inhibitors were significantly associated with a decreased risk for vascular dementia (OR, 0.11; 95% CI, 0.02–0.66), compared with placebo. Very good OR.

“Given the relatively short follow-up period, there is likely insufficient time to observe the occurrence of dementia. Also, the long-term effect of newer GLDs on the risk of dementia remains unknown. Third, our analyses are likely underpowered because of the low numbers of dementia cases in the clinical trials, which leads to wide CIs. Fourth, we were not able to obtain information on the baseline cognitive functions of study participants in these trials.”

15-20% of all dementias are vascular.

One very strong prevailing theory is all dementia is “vascular” mediated. Would explain a lot of the risk factors, imaging, including genetics (APOE4)

Taking care of the vasculature is a primary lifestyle prevention strategy, diet and exercise.

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#42
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#43
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#44

Proximal Tubule mTORC1 Is a Central Player in the Pathophysiology of Diabetic Nephropathy and Its Correction by SGLT2 Inhibitors (2020)
https://www.cell.com/cell-reports/pdf/S2211-1247(20)30935-9.pdf

An mTOR connection, and good insight into the destructive nature of diabetes on the kidneys.

" Kogot-Levin et al. show that treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2i) attenuates the progression of diabetic kidney disease (DKD), which is the leading cause of endstage renal disease. The nutrient sensor mTORC1 is a critical node that mediates kidney dysfunction in diabetes and the protective effects of SGLT2i by regulating fibrogenesis. We suggest that renal proximal tubule cells (RPTC) mTORC1 is a critical node that mediates kidney dysfunction in diabetes and the protective effects of SGLT2i by regulating fibrogenesis". Immunostaining of kidney sections of 8-week-old diabetic Akita mice showed increased expression of the tubular injury marker cystatin-C compared with wild-type control mice . Short-term (5 days) treatment with dapagliflozin reversed the increase in cystatin-C. In summary, these findings show that mTORC1 activity is high in RPTCs compared with other regions of the kidney and is further increased in diabetes. Treatment with SGLT2i decreases mTORC1 activity in RPTCs by reducing their glucose transport and metabolism."

"mTORC1 seems to function as a double-edged sword: on one hand, it is vital for organ morphogenesis and function, and on the other hand, its sustained activation may lead to tissue dysfunction. This duality is demonstrated in the pleiotropic effects of mTORC1 in the kidney. mTORC1 is essential for glomerular development and for the integrity of the filtration barrier, as well as for the maintenance of tubular cells and transport functions. However, sustained activation of mTORC1 in RPTCs promotes tubular dysfunction and fibrosis, leading to renal failure. We believe that our findings suggest that mTORC1 is a direct regulator of fibrogenesis. Tubulointerstitial fibrosis has a robust effect on kidney function, probably explaining the strong renal-protective effects of SGLT2i even in patients with advanced kidney disease.

In diabetes, mTORC1 can be activated by nutrient overload elicited by hyperglycemia and probably by other nutrients, such as BCAA that are increased in the sera of subjects with
metabolic syndrome and obesity. RPTCs might be particularly vulnerable to the nutrient overload because of their unique role in nutrient (i.e., glucose and amino acid) transport from the kidney lumen to the blood. We suggest that the main mechanism of kidney protection by SGLT2i is in fact reduction of glucose and BCAA metabolism in the RPTCs, which is the site of action of SGLT2i, independent of the systemic metabolic effects"

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#45

Wow, really interesting. Seems like it might complement rapamycin as long as we are not shutting MTORC1 too much…

#46

Indeed. There’s that “how to measure mTOR” issue yet again, especially tissue specific. This is a glaring gap in our therapeutic dosing discovery. In the wild type mice Rapamycin cognitive study, 30% hippocampus mTOR reduction produced a very good outcome.

#47

Like all of these, pulsed dosing is probably best…

perhaps a good strategy would be to take the SGLT2 inhibitor for 5 of the 7 days, starting at the same time as the rapamycin dose, thus leaving day 6 and 7 with minimal mTORC1 inhibition…

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#48

Maybe but a total guess. That’s the frustration, flying blind. No idea how you can scientifically define “best” as it relates to our objective, longevity.

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#49

The agony of the early adopters… :wink:

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#50

More good news:

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13653

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#51

Great paper on normal (non diabetic) wild type mice, but sadly, “tumorigenesis was inhibited or decelerated by this drug, though only in males”

“In the current study, we show that Cana reduced hypothalamic gliosis in both sexes, which may contribute to improved whole-body metabolism. Cana treatment was associated with reduced pS6 in the hippocampus of 30-month-old male mice, implicating reduced mTOR signaling. Previous studies have shown that Cana’s effects on metabolic health were associated with suppressed mTOR signaling, as shown by reduced hepatic pS6 signaling accompanied by increasing AMPK activity in young animals”

Yet agin… > lower glucose > lower insulin signalling > lower brain mTOR > longevity/cognitive

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#52

Something to be aware of for people who may be going in for surgery…

Seems like SGLT2 inhibitors don’t mix well with anesthesia due to increased risk of ketoacidosis , note it seems it may also be an issue with concomitant use of SGLT2 inhibitors during prolonged fasting (so, it sounds best to avoid SGLT2 inhibitors during fasting, or if you are on a Keto Diet) … from a new academic conference its seems.

Details/discussion below:

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Continuous Ketone Monitor (SiBio)
#53

Empagliflozin attenuates cardiac microvascular ischemia/reperfusion injury through improving mitochondrial homeostasis

Empagliflozin has been reported to protect endothelial cell function, regardless of diabetes status. However, the role of empagliflozin in microvascular protection during myocardial ischemia reperfusion injury (I/R) has not been fully understood.

Conclusions

These results demonstrated that empagliflozin can protect the microvasculature by inhibiting the DNA-PKcs/Fis1/mitochondrial fission pathway during myocardial I/R injury.

Full Paper:

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#54

“We’ve had a few normoglycaemic ketoaxidotic patients here.”

A “few” in just one reporting center?

Ketoacidosis associated with low-carbohydrate diet in a non-diabetic lactating woman: a case report

Introduction: Non-diabetic ketoacidosis is a rare condition which can be caused by starvation. Lack of glucose can force the body into ketogenesis causing a metabolic acidosis. As previously reported in the literature, ketoacidosis might, on rare occasions, be caused by a diet with low carbohydrate content. However, to the best of our knowledge this is the first reported case in the literature of ketoacidosis, in a non-diabetic patient, associated with a combination of low carbohydrate, high fat diet and lactation.

Case presentation: A healthy non-diabetic, 32-year old white woman started a low carbohydrate, high fat diet when she was breastfeeding her son of 10 months of age. After 10 days she was admitted to our hospital with nausea and vomiting and a serum pH of 7.20 and base excess of −19. Clinical signs and blood samples were compatible with ketoacidosis. She was given fluids intravenously and insulin. No anamnestic or clinical signs of diabetes were found. She recovered quickly and was discharged 3 days later.

Conclusions: Ketogenic diets like low carbohydrate, high fat may induce ketoacidosis. Lactation might further aggravate the condition and can perhaps even be the trigger into ketoacidosis. Health services should be aware of the risks associated with ketogenic diets, and be able to recognize this serious condition when it is presented.

A lactating woman has a high demand of substrate to produce milk. A LCHF diet limits the amount of substrate and results in a negative energy balance. This kind of diet should thus be avoided during lactation.

Our case shows that medical services should be aware of the fact that a strict LCHF diet often leads to ketosis and in rare cases even into ketoacidosis which is a dangerous condition that must be immediately diagnosed and treated in order to reduce morbidity.

#55

does SGLT2 inhibitors prevent the re-absorption of fructose?

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#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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