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.
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.
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
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.
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?
Good coverage on Canagliflozin and the presenter’s experiences with using both Canagliflozin and Acarbose:
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.
Another new SGLT2 inhibitor drug approved by the FDA…
TheracosBio has secured US Food and Drug Administration approval for its SGLT2 blocker Brenzavvy (bexagliflozin).
The product has been developed as a treatment for type 2 diabetes in adults, as an adjunct to diet and exercise.
The company will compete with existing well-established products in this class, including Jardiance (empagliflozin), Farxiga (dapagliflozin), Inovokana (canagliflozin) and Suglat (ipragliflozin).
https://www.thepharmaletter.com/in-brief/brief-us-approval-for-theracosbio-s-sglt-inhibitor
Yeah it’s unclear why in male mice there are much stronger effects than the smaller effects on females and very important to figure out the root causes if possible.
There are some clues, if you read up Miller’s ITP related research on 17aE2 where he suggested MEK1/ERK pathway
Recent article on SGLT2 inhibitors:
I think I may have a UTI associated with my Canagliflozin use, some of the signs and symptoms are there including kidney (I think?) pain on my right side. I had amoxicillin on hand so I took one, I’ll go get checked if it doesn’t resolve soon. Can’t figure out what else it would be
I have a supply of empagliflozin but have been hesitant to start taking it for this very reason. Perhaps I am being a little overly cautious
Hope whatever it is resolves soon.
It could also be this
Signs and symptoms of acute kidney injury may include decreased urine or swelling in the legs or feet.