Canagliflozin - Another Top Anti-aging Drug

You take appx. 35% of glucose out of blood that will reduce it.

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What I said is still true, it’s not the way it works because other drugs that lower blood glucose does not have the same effect.

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Some good and bad findings here regarding cancer (poke @Neo): Deciphering the Causal Relationship between Sodium-glucose Cotransporter 2 Inhibition and Cancer Risks: A Comprehensive Mendelian Randomization Study 2024

For the first time we discovered that the SGLT2 inhibition may exert protection on bronchial and lung cancer and non-melanoma skin cancer from a genetic perspective. However, suggestive higher cancer risks of bladder, prostate, and corpus uteri were also noted, which warrants real-world data validation in the future.

However, this is an MR study (and okay journal and research team). Longitudinal studies and RCT found different results: Canagliflozin - Another Top Anti-aging Drug - #871 by adssx

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So what’s the verdict on the negative outcomes on prostate and bladder cancer from other studies?

One Chinese MR (above) says it’s bad. Other Western longitudinal data and RCTs say it’s neutral or good. I already know your conclusion :wink: Mine is: unclear so far, more data needed.

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Interesting Japanese preprint on the SGLT2 + GLP1RA combination: SGLT2 Inhibitor and GLP-1 Receptor Agonist Co-Treatment: Liver Function Effects in Patients with Type 2 Diabetes Mellitus 2024

SGLT2i + GLP1Ra combination treatment significantly improved liver function and prevented FIB-4 index increases among patients with FIB-4 index ≥ 1.3

Also potentially one more indication for SGLT2i? => SGLT2 inhibitors as a potential therapeutic option for pulmonary hypertension: mechanisms and clinical perspectives 2024

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Is anyone else having any problems with empagliflozin? The 25mg dose was making me dizzy in the morning, causing leg cramps and craving energy like sugar (which I don’t eat). I also take acarbose with meals every day and have no trouble there.

So I tried the 10mg daily and then every other day, but I still had minor dizzy spells on dose days and woke up with cramps in my right leg as usual. I made sure to keep my electrolytes in check and ate a full day’s worth of food.

So, I’m wondering if there would be any benefit to splitting my 10mg pills into 5mg and trying them, but I’m not sure I’d really be getting the benefits from this dose.

I do eat a low-sugar diet but also a lot of dark chocolate and berries.

Another plan could be stopping the acarbose and seeing if I get the same reaction from the empagliflozin. If I do, I’ll just stop taking it altogether.

Maybe I should just sack it off? I just don’t want to miss any potential benefits. Plus, I’ve got a load of it and want to put it to good use if possible. What do people think my options are.

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I used the empag and the dapag and the dapag got along with my body much better. I didn’t have all the symptoms you did.

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When I first started taking empagliflozin, I thought it made me feel tired, but I kept taking it and either the fatigue just resolved or it never had anything to do with the empa in the first place. I’ve been on the full 25mg QD dose for 6+ months now, zero side effects.

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One potential idea is to try canagflozin and see how that feels. Since Cana is both SGLT1i and not just SGLT2i it will not just work via the kidneys and urine, but also via your gut.

(SGLT1+2i / and Cana was also what actually was used in the NIH ITP longevity demonstrations).

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Another option is to split the pills, perhaps into quarters so you’re only dosing 5mg to 7mg or so, and try that, and dosing periodically. Or pause, and slowly restart it on a pulsed low dose level to see if you still get the effects.

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I just started empa 10mg and nothing like that so far. The first day I felt somewhat run down but I’m not convinced that was the empa doing it.

Try 6.25mg that’s the dose I’m using.

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Thanks for all responces. I’ll think I’ll try 5mg every other day first and then move up to daily if it’s working. Weird set of symptoms. Maybe I just have great blood sugar control! I do also drink 750ml of iced hibiscus tea everyday which is effective at lowering blood pressure and empag does that too, so there could a minor contraindication.

The flozins also increase fluid loss to some extent so make sure you are keeping well hydrated. Just a thought, your dizzy spells could be orthostatic and due to marginal hydration.

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Recent good papers:

Empagliflozin rescues lifespan and liver senescence in naturally aged mice 2024

Our study revealed that empagliflozin improved survival and health in naturally aged mice. Empagliflozin extended the median survival of male mice by 5.9%. Meanwhile, empagliflozin improved learning memory and motor balance, decreased body weight, and downregulated the hepatic protein expression of P21, P16, α-SMA, and COL1A1. Empagliflozin modulates the structure of the intestinal flora, increasing the relative abundance of Lachnospiraceae, Ruminococcaceae, Lactobacillus, Blautia, and Muribaculaceae and decreasing the relative abundance of Erysipelotrichaceae, Turicibacter, and Dubosiella in naturally aged mice. Further exploration discovered that empagliflozin increased the concentration of SCFAs, decreased the levels of the inflammatory factors TNF-α, IL-6, and CXCL9, and regulated the PI3K/AKT/P21 and AMPK/SIRT1/NF-κB pathways, which may represent the underlying mechanisms involved in these beneficial hepatic effects. Taken together, the above results indicated that empagliflozin intervention could be considered a potential strategy for extending lifespan and slowing liver senescence in naturally aged mice.

Comparative cardiovascular and renal effectiveness of empagliflozin and dapagliflozin: scandinavian cohort study 2024

Use of empagliflozin and dapagliflozin was associated with similar risk of cardiovascular and renal outcomes, mortality and diabetic ketoacidosis.

Head-to-Head Comparison of Dapagliflozin vs. Empagliflozin—Cardiovascular and Safety Events 2024

Dapagliflozin has similar CV benefits at doses proven effective in cardiovascular outcome trials, i.e., dapagliflozin 10mg, but the 5 mg dose may not have similar CV effectiveness.

SGLT2i effect on atrial fibrillation: A network meta-analysis of randomized controlled trials 2024

Dapagliflozin use was associated with significant reduction in AF risk as compared to placebo in overall population and patients with diabetes, whereas the use of other gliflozins did not significantly reduce AF occurrence.

Dapagliflozin: A sodium–glucose cotransporter 2 inhibitor, attenuates angiotensin II-induced atrial fibrillation by regulating atrial electrical and structural remodeling 2024

Overall, our study identifies DAPA, a widely used SGLT2i, contributes to inhibiting Ang II-induced ox-CaMKII upregulation and electrical and structural remodeling to reduce AF susceptibility, suggesting that DAPA may be a potential therapy of treating AF.

SGLT2 Inhibitor Dapagliflozin Increases Skeletal Muscle and Brain Fatty Acid Uptake in Individuals With Type 2 Diabetes: A Randomized Double-Blind Placebo-Controlled Positron Emission Tomography Study 2024

Six weeks of treatment with dapagliflozin increases skeletal muscle and brain FA uptake, partly driven by a rise in free FA availability. This finding is in accordance with previous indirect measurements showing enhanced FA metabolism in response to SGLT2 inhibition and extends the notion of a shift toward increased FA use to muscle and brain.

Glycemic Variability after Initiation of SGLT2 Inhibitors in CKD 2024

In a pilot study, we enrolled 11 CKD patients with clinical indications for SGLT2i -7 with type 2 diabetes not on insulin, and 4 without diabetes. Participants wore DexCom G6 CGM for 10 days pre-SGLT2i and another 10 days post-SGLT2i initiation. […] Nine participants received empagliflozin 10mg, two dapagliflozin 10mg. Following SGLT2i initiation, participants with diabetes showed no significant change in mean glucose (160±54 vs 155±50 mg/dL, p=0.52), GMI (7.1±1.3 vs 7.0±1.2, p=0.52), or TIR (67±37 vs 69±39%, p=0.66). There was no change in time above range or time below range. Only 1 participant on GLP-1 receptor agonist developed asymptomatic level 1 hypoglycemia. Similarly, patients without diabetes had no change in any of the previously mentioned CGM metrics. However, glycemic variability decreased post-SGLT2i initiation, as shown by hourly CV reductions (-0.40±0.13, p=0.002). The magnitude of hourly CV reduction was more pronounced in participants without diabetes compared to those with diabetes (p-interaction=0.002). Despite higher hourly CV during daytime than nighttime, the impact of SGLT2i initiation on CV was similar across time periods without significant interaction by time of day. […] After SGLT2i initiation in CKD, while mean glycemia and TIR remained unchanged, glycemic variability diminished. This finding warrants further investigation in a larger study.

Effects of Dapagliflozin and Metformin on Vascular Function in Newly Diagnosed Type 2 Diabetes—A Randomized Controlled Trial (DMVascular Study) 2024

Initial treatment with Dapagliflozin gives a better response than Metformin for CIMT. Larger-scale longitudinal studies will clarify the potential of SGLT-2 inhibitors as initial diabetes pharmacotherapy.

(SGLT2 + GLP1RA combination, poke @DrFraser =>)

Changes in Beta-Cell Function during Dapagliflozin Therapy in Combination with Exenatide in Type 2 Diabetes Patients (T2D) 2024

Combination therapy with dapagliflozin plus exenatide leads to superior and sustained improvement in beta cell function (DI) compared to either drug alone. These data suggest that combination therapy with GLP-1 RA plus SGLT2i may enhance long-term preservation of beta-cell function in T2D patients.

Synergistic Effects of Dapagliflozin and Tirzepatide Combination Treatment on Weight Loss and Glucose Regulation in Diet-Induced Obese Animals 2024

The addition of dapagliflozin to tirzepatide resulted in further weight reduction and improvement in glycemic control compared to each drug alone.

SGLT2 Inhibitors and Parkinson’s Disease (PD) Risk in Older Populations with Type 2 Diabetes (T2D) 2024

In the Cox model (Figure), the SGLT2 inhibitor group was associated with a significantly lower risk of incident PD (HR 0.70 [95% CI 0.55-0.89]) than the DPP4 inhibitor group. The risk reduction of PD was particularly profound in non-Hispanic Black individuals (HR 0.24 [95% CI 0.07-0.86]) and insulin users (HR 0.49 [95% CI 0.32-0.77]).

Sodium–Glucose Cotransporter 2 Inhibitor Use and Risk of Dementia and Parkinson’s disease among Patients with Type 2 Diabetes—A Longitudinal, Nationwide, Population-Based Cohort Study 2024

Overall, use of SGLT2i was associated with a 22% lower risk for the composite of dementia from any cause and PD than use of other OADs (adjusted HR [aHR], 0.78 [95% CI 0.73─0.83]) with a 6-month lag period. Regarding the individual endpoints, SGLT2i use was associated with reduced risks for AD (aHR, 0.81 [95% CI 0.76─0.87]), VaD (aHR, 0.69 [95% CI 0.60─0.78]), and PD (aHR, 0.80 [95% CI 0.69─0.91]). In this nationwide population-based cohort study, SGLT2i use significantly reduced the risks for dementia and PD in patients with type 2 diabetes independent of various factors including comorbidities and bioclinical parameters.

Sotagliflozin vs. Empagliflozin or Placebo in Type 2 Diabetes on a DPP-4i +/- Metformin 2024

=> Sotagliflozin (SGLT1+2 inhibitor) is not better than empagliflozin (SGLT2i only) for HbA1c and other metabolic measurements.

Effects of empagliflozin on reproductive system in men without diabetes 2024

After one month of empagliflozin, there were no discernible changes in androgen, pituitary gonadotropin hormones, or inhibin B. Regardless of BMI category, the administration of empagliflozin, a highly selective SGLT2 inhibitor, did not alter serum androgen levels in men without diabetes. While SGLT2 is present in the testes, its inhibition does not seem to affect testosterone production in Leydig cells nor inhibin B secretion by the Sertoli cells.

(SGTL2i and cancer @Neo =>)

Sodium–glucose cotransporter 2 inhibitors and the cancer patient: from diabetes to cardioprotection and beyond 2024

This review will cover biological foundations and clinical evidence for SGLT2i modulating myocardial function and metabolism, with a focus on their possible use as cardioprotective agents in the cardio-oncology settings. Furthermore, we will explore recently emerged SGLT2i effects on hematopoiesis and immune system, carrying the potential of attenuating tumor growth and chemotherapy-induced cytopenias.

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Despite my initial concerns on these agents with potential of soft tissue perineal infections - which are very rare - the benefits are clear in so many domains. They are among the first I Rx right now for longevity and neurocognitive decline risk mitigation.
Great update. Thanks for this.

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Impact of SGLT2 Inhibitors on Atrial Fibrillation Recurrence after Catheter Ablation in Type 2 Diabetes Mellitus: A Meta-Analysis of Reconstructed Kaplan–Meier Curves with Trial Sequential Analysis 2024

Direct meta-analysis showed that SGLT2i, compared with all antidiabetic medications (HR 0.57, 95% CI [0.44, 0.73], I2) and DPP4i (HR 0.41, 95% CI [0.24, 0.70], I2), was associated with a lower risk of AF recurrence.
SGLT2i are associated with a reduced risk of AF recurrence after CA in patients with T2DM. These results suggest that SGLT2i is promising in improving clinical outcomes for this population.

Are Sodium-Glucose Cotransporter-2 Inhibitors the Cherry on Top of Cardio-Oncology Care? 2024

There is an abundance of data from translational and observational clinical studies supporting a potential beneficial role of SGLT2-i in mitigating the cardiotoxic effects of cancer patients receiving anthracyclines. These findings underscore the need for more robust clinical trials to investigate the effect on cardiovascular outcomes of the prophylactic SGLT2-i treatment in patients undergoing cancer treatment.

Empagliflozin attenuates epithelial to mesenchymal transition through senescence in peritoneal dialysis 2024

Epithelial to mesenchymal transition (EMT) is considered as one of the senescence processes; reportedly, anti-senescence therapies effectively reduce EMT. Some models have shown anti-senescence effects with the use of sodium-glucose cotransporter-2 (SGLT2) inhibitor. Therefore, our study investigated the anti-senescence effects of empagliflozin as a SGLT2 inhibitor in a peritoneal fibrosis model and their impact on EMT inhibition.
Reactive oxygen species production, DNA damage, senescence, and EMT markers were increased by glucose treatment; however, co-treatment with glucose and empagliflozin attenuated these changes.

GLP-1RAs as good as SGLT2i in protecting kidneys (one question remains: what about their combination?): [No Differences in Kidney Function Decline Between People With Type 2 Diabetes Starting a Sodium-Glucose Cotransporter 2 Inhibitor or a Glucagon-like Peptide-1 Receptor Agonist: A Real-world Retrospective Comparative Observational Study]
(https://www.sciencedirect.com/science/article/pii/S0149291824000882) 2024

Heterogeneous treatment effects of sodium-glucose cotransporter 2 inhibitors on risk of dementia in people with type 2 diabetes: A population-based cohort study 2024

Among 35,458 individuals with T2D, 1.8% in the SGLT2 inhibitor group and 4.7% in the sulfonylurea group developed all-cause dementia over a 3.2-year follow-up, yielding a lower risk for SGLT2 inhibitors (RD, –2.5%; 95% CI, –3.0% to –2.1%). Hispanic ethnicity and chronic kidney disease were identified as the two important variables to define four subgroups in which RD ranged from –4.3% (–5.5 to –3.2) to –0.9% (–1.9 to 0.2).

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" Strikingly, canagliflozin but not empagliflozin reduced fluid transport across cell monolayers"

^How is this important for differentiating cana’s MoA? Does it account for cana increasing glucose excretion more than empa?

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A rare negative (or non-conclusive) result for SGLT2i: Association between SGLT2 Inhibitors and Risk of Dementia and Parkinson’s Disease: A Meta-Analysis of 12 Randomized Controlled Trials 2024

A total of 12 RCTs with 74, 442 patients (40,784 in the SGLT2i group and 33,658 in the control group) were included in the analysis. The mean age of patients in SGLT2i and control was 65.3 and 65.2 years respectively. Pooled analysis showed that there is no significant association between SGLT2i and the risk of dementia (OR, 1.37 (95%CI: 0.70-2.69), P=0.36), dementia Alzheimer’s type (OR, 1.99 (95%CI: 0.59-6.71), P=0.27), vascular dementia (OR, O.40 (95%CI: 0.09-1.85), P=0.24), and Parkinson’s Disease (OR, 0.63 (95%CI: 0.25-1.61), P=0.33) was comparable between SGLT2i and control groups.
The mean follow-up duration was 2.9 years.
While previous meta-analyses of largely observational studies suggested that SGLT2i could reduce the risk of dementia, our meta-analysis of RCTs finds no significant association between SGLT2i use and risk of dementia and Parkinson’s Disease. However, with wide confidence intervals, clinically relevant harm or benefit of SGLT2i on these outcomes cannot be excluded.

Good journal. Team from India + Pakistan + US.

My two cents:

  • As they say, the CIs are wide, and harm or benefit still cannot be excluded
  • It might be that for neuroprotection, starting at 65 years old is too late.
  • For PD, (all?) observational studies and animal models saw benefits of SGLT2i: are these trends the results of confounders? Are these effects just symptomatic and not disease-modifying?
  • TBC…
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