Canagliflozin - Another Top Anti-aging Drug

I lost 10lbs or so very quickly - 2 to 3 weeks after initiating, then no more after that. I had even more luck with metformin; about 15lbs over a few months. Apparently it works well as an appetite supressant. If those don’t work for you - I’d look into semaglutide and similar GLP1 inhibitors: Intermittent (oral) Rybelsus / Semaglutide use in healthy individuals?

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I’m sure you’ve considered chronic fatigue syndrome which worsens with physical or mental activity and shares certain traits of migraines such as headaches and light sensitivity.

@rivasp12 Thanks! Indeed, I have. In fact I was diagnosed with an autoimmune disease previously, and I have always thought the overwhelming fatigue may have an autoimmune component to it. But since it is apparently difficult to pursue a CFS/ME diagnoses where I live, I have not felt inclined to try. After years wherein I had tried to target inflammatory pathways through diet, exercise, fasting, many herbal supplements without any noticeable effects, Rapamycin really seemed to mark a change for me in terms of fatigue. But perhaps my dosing has been a bit off, and admittedly lingering depression also seems to have an impact on my energy levels.

Yes, it’s so involved since depression can give fatigue, but then again so many physical things can lead to depression.
Sometimes I just try provigil to see if it helps.

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@rivasp12 You are definitely right - it seems a bit like a vicious circle trying to find what is cause and what is effect. I’m also not sure whether my circadian rhythm may be involved. Whereas I can be exhausted during the day, I seem to feel more awake at night. In addition I was diagnosed with secondary adrenal insufficiency a few years ago, so I’ve also wondered whether my ACTH/cortisol levels may still be off during times of the day. If it would be easier to get a melatonin and day curve ACTH/cortisol level test here, I’d probably pursue that also.
Sorry, either way, all in all, I can definitely not say with certainty the Empagliflozin has anything to do with this. After all that severe fatigue had been present for years. Thank you so much for the suggestion. It sounds like a good idea to ask my GP whether he wants to prescribe Provigil - it may definitely be worth a try.

Granted, these were older patients with a prior history/risk of cardiovascular disease, low baseline eGFR-levels, but are there any other more recent studies indicating SGLT2-inhibitors may affect bone mineral density? They mention a decrease in estradiol levels in females taking Canagliflozin in this study also.

Conclusions:

Fracture risk was increased with canagliflozin treatment, driven by CANVAS patients, who were older, with a prior history/risk of cardiovascular disease, and with lower baseline estimated glomerular filtration rate and higher baseline diuretic use. The increase in fractures may be mediated by falls; however, the cause of increased fracture risk with canagliflozin is unknown.
[…]
As reported in a separate article in this issue, results from a phase 3 study in older patients aged 55 to 80 years with T2DM demonstrated that canagliflozin was associated with a small but statistically significant reduction in bone mineral density (BMD) at the total hip (but not at other skeletal sites) over 104 weeks and increases in the bone turnover markers serum collagen type 1 β-carboxy-telopeptide (β-CTX), a resorption marker, and osteocalcin, a formation marker (19). Previous studies have demonstrated a link between weight loss, decreased estradiol levels, increased bone turnover, and decreases in BMD, possibly due to decreased estrogen production (20–24); weight loss and reductions in serum estradiol levels were seen in women treated with canagliflozin (19), which may explain the increases in bone turnover and decreases in total hip BMD observed with canagliflozin treatment.

Caloric restriction promotes longevity in multiple animal models. Compounds modulating nutrient-sensing pathways have been suggested to reproduce part of the beneficial effect of caloric restriction on aging. However, none of the commonly studied caloric restriction mimetics actually produce a decrease in calories. Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) are a class of drugs which lower glucose by promoting its elimination through urine, thus inducing a net loss of calories. This effect promotes a metabolic shift at the systemic level, fostering ketones and fatty acids utilization as glucose-alternative substrates, and is accompanied by a modulation of major nutrient-sensing pathways held to drive aging, e.g., mTOR and the inflammasome, overall resembling major features of caloric restriction. In addition, preliminary experimental data suggest that SGLT-2i might also have intrinsic activities independent of their systemic effects, such as the inhibition of cellular senescence. Consistently, evidence from both preclinical and clinical studies have also suggested a marked ability of SGLT-2i to ameliorate low-grade inflammation in humans, a relevant driver of aging commonly referred to as inflammaging. Considering also the amount of data from clinical trials, observational studies, and meta-analyses suggesting a tangible effect on age-related outcomes, such as cardiovascular diseases, heart failure, kidney disease, and all-cause mortality also in patients without diabetes, here we propose a framework where at least part of the benefit provided by SGLT-2i is mediated by their ability to blunt the drivers of aging. To support this postulate, we synthesize available data relative to the effect of this class on: 1- animal models of healthspan and lifespan; 2- selected molecular pillars of aging in preclinical models; 3- biomarkers of aging and especially inflammaging in humans; and 4- COVID-19-related outcomes. The burden of evidence might prompt the design of studies testing the potential employment of this class as anti-aging drugs.

Repurposing SGLT-2 Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms

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Can sodium-glucose cotransporter 2 inhibitors ‘spin the thread of life’?

In recent years, randomised clinical trials have demonstrated that SGLT2i reduce cardiovascular-renal events and all-cause mortality in people with and without diabetes. The cardio-renal benefits observed are independent of glucose lowering effect and multiple mechanisms have been proposed for these results. SGLT2i can exert anti-ageing effects on the vasculature and other body organs through several signalling pathways including the activation of the nuclear factor erythroid-2-related factor 2 and the induction of antioxidant enzymes. We speculate that the pro-longevity effects of the SGLT2i are mediated by soluble Klotho, an anti-ageing kidney-derived hormone and an emerging therapeutic target for cardio-renal diseases.

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I did order empagliflozin from India. It could take a month to get here, but fun to give it a try and see if I can stand it. Thanks for posting on these “other” drugs.

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Canagliglozin extends life span and leads to less weight gain in C57BL6 male mice

bioRxiv. posted 20 November 2022, 10.1101/2022.11.20.517248

SGLT2 inhibitors are widely prescribed drugs for type 2 diabetes and heart failure. It seems that their beneficial health effects are multifaceted and not only limited to the amelioration of glycemic profile. It is suggested that SGLT2 inhibitors-induced glycosuria causes a metabolic shift that mimics the fasting response. It is also known that calorie restriction leads to enhanced longevity in mice. Thus, we hypothesized that long-term treatment of mice with SGLT2 inhibitors might extend their life span. To this end male C57BL6 mice at the age of 4 months were put on a normal chow diet or on a diet supplemented with 200 mg/kg canagliflozin. The canagliflozin-treated mice showed lower body weight gain over time and increased life span. The median survival of control mice was 107.5 weeks, while that of the canagliflozin-treated group was 112.5 weeks (p=0.011). No difference was seen in the presence or severity of cataracts. This study showed for the first time an enhanced median survival of canagliflozin-treated male mice with a homogeneous genetic background (C57BL6). Further analyses are in progress to elucidate the metabolic adaptations and mechanisms underlying this effect.

http://biorxiv.org/content/early/2022/11/20/2022.11.20.517248

“Empagliflozin reduced major adverse CV event (MACE) by 14%, CV death by 38%, and hospitalization for heart failure (HHF) by 35% vs placebo,”

“canagliflozin reduced MACE by 14% and HHF by 33%.”

“Empagliflozin dominated canagliflozin, yielding more quality-adjusted life years”

“Conclusions Empagliflozin was projected to dominate canagliflozin and be highly cost-effective compared with dapagliflozin and SoC using US healthcare costs.”

Probably no need to pay the higher price for Canagliflozin.

It appears empagliflozin may be a little safer than Canagliflozin.

https://www.ingentaconnect.com/content/ben/chamc/2015/00000013/00000002/art00009

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only in type 2 diabetes. Show me a study showing benefits of empagliflozin in one without diabetes (there’s another thread on this!!)

I recall that Dr. Abunadar said on this forum that Canagliflozin also inhibit SGLT1 while 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. Canagliflozin if consumed just before the meal works on SGLT1.

I was referring to the all-cause mortality risk in patients in non-diabetics.
And I never lend any credence to one doctor’s opinion.
At this point, there are not any studies that I can find that include the long-term effect of empagliflozin on all-cause mortality for healthy people, but there are currently some studies that will include these people.
So, it doesn’t take anymore leap of faith than it does for rapamycin to reduce ACM.

"Protection from HF in non-diabetics was confirmed for empagliflozin in the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) trial. A meta-analysis of DAPA-HF and EMPEROR-Reduced confirmed reductions in all-cause and CV death and the combined risk of CV death or worsening HF, as well as in the composite renal endpoint {hazard ratio [HR] 0.62 [95% confidence interval (CI) 0.43–0.90]} without differences based on the presence of diabetes or baseline estimated glomerular filtration rate (eGFR).

"In patients with heart failure and a preserved ejection fraction enrolled in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), empagliflozin significantly reduced the risk of heart failure outcomes irrespective of diabetes status at baseline.

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Canagliflozin had an anti-ageing effect in spite of hemoglobin A1C being unaffected. Does it mean that there is another mechanism to anti-ageing besides blood sugar control?
My question about Acarbose is a practical one. If Acarbose in combination with Rapamycin have more robust anti-ageing effect than each of them taking separately, should one take Acarbose with every meal, even the meal not containing starch?

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Good news on another… flozin drug

https://www.nature.com/articles/s41591-022-02102-9

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Good coverage on Canagliflozin and the presenter’s experiences with using both Canagliflozin and Acarbose:

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SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease

Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in humans with type 2 diabetes (T2D); however, the underlying mechanism remains unclear. Activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome and subsequent interleukin (IL)-1β release induces atherosclerosis and heart failure. Here we show the effect of SGLT2 inhibitor empagliflozin on NLRP3 inflammasome activity. Patients with T2D and high cardiovascular risk receive SGLT2 inhibitor or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor’s glucose-lowering capacity is similar to sulfonylurea, it shows a greater reduction in IL-1β secretion compared to sulfonylurea accompanied by increased serum β-hydroxybutyrate (BHB) and decreased serum insulin. Ex vivo experiments with macrophages verify the inhibitory effects of high BHB and low insulin levels on NLRP3 inflammasome activation. In conclusion, SGLT2 inhibitor attenuates NLRP3 inflammasome activation, which might help to explain its cardioprotective effects.

https://www.nature.com/articles/s41467-020-15983-6

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