#592

My local pharmacy stocks both empaglifozin (Jardiance) and dapaglifozin (Forxiga) and seems that empaglifozin is cheaper, 34 EUR (both 10 and 25 mg) vs. 39 EUR (both 5 and 10 mg) for dapaglifozin. Empaglifozin is paid by insurance and dapaglifozin has a copay of 17 EUR. No generic dapaglifozin available yet.

What is your dapaglifozin dose? I assume you don’t take it for T2D…

#593

This paper was published by Drug Design, Development and Therapy, a journal of Dove Medical Press, a publisher considered as predatory. So most likely, they publish crap. Remember that about half of the papers are a total fraud, especially those coming from India, unfortunately. Here it’s even worse as the authors are not scholars from reputable universities.

I started on 5 mg/day and then switched to 10 mg/day after 1 month. I’m not diabetic, indeed. It was first recommended to my doctor to try treating my reactive hypoglycemia. It worked very well, and my doctor (who’s not a longevity doctor at all, just a normal 70yo doctor) said: “I’m happy to prescribe it to you for the rest of your life; it’s a very good drug, it’ll protect your heart and kidneys, but you’ll have to explain to people every single time you do a blood test why there’s glucose in your urine and why you’re taking it while not being diabetic.” Then I went down the SGLTi rabbit hole, and I’m now convinced of its longevity benefits and taking it for this reason (as well). So I’m a bit of a weird case.

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#594

The paper was not itself a study but contains 56 linked footnotes for its conclusions. Have yet to find anything negative about this drug except it’s short half life

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#595

Something to be aware of if taking urine tests and SGLT2i drugs:

SGLT2 Inhibitors and False Positive Toxicology Tests

A patient with diabetes who was taking empagliflozin, an SGLT2 inhibitor, had false positive urine screening tests for ethanol in a room-temperature sample, owing to bacterial fermentation of glucose that yielded ethanol.

https://www.nejm.org/doi/full/10.1056/NEJMc2313463

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#596

Well, obviously, that person didn’t pee as often as I do. :sweat_smile:

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#597

Your daily dose of SGLT2i good news:

We already know that sotagliflozin’s maker wants to extend it to HCM: Canagliflozin - Another Top Anti-aging Drug - #497 by adssx

This paper confirms SGLTi’s potential for this indication: Impact of Sodium-Glucose Cotransporter 2 Inhibitors on Mortality in Hypertrophic Cardiomyopathy 2024

Over a 2-year follow-up period, HCM patients on SGLT2i had lower rates of all-cause mortality (OR 0.24, P < 0.01). Additionally, HCM patients on SGLT2i had lower rates of all-cause hospitalization (OR 0.69, P = 0.01) and cardiovascular symptoms (OR 0.63, P < 0.01) compared to propensity-matched HCM patients not on SGLT2i.

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Another future indication? => Dapagliflozin for Atrial Fibrillation 2024

Zelniker et al. reported that dapagliflozin reduced the risk of atrial fibrillation and atrial flutter by 19% among the 17,160 patients with type-2 diabetes who participated in the prospective multicenter randomized DECLARE-TIMI 58 trial (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58)
The mechanism for the association between SGLT-2 inhibition and the lower risk of atrial fibrillation or reduced recurrence of atrial fibrillation after catheter ablation is unclear. SGLT-2 inhibitors alter the activation of numerous genes in the heart, attenuating cardiac hypertrophy, inflammation, fibrosis, and apoptosis; activating antioxidant enzymes; decreasing the expression of hypoxia markers; and altering cardiac cell metabolism; all can affect the (re-)development of AF. As the expression of SGLT2 in the heart is negligible, it is probably not directly related to the inhibition of SGLT2 in cardiac cells. While alteration of expression and/or activity of mediators secondary to SGLT2 inhibition in the kidney or other organs or the alteration of metabolic utilization cannot be ruled out, the fact that favorable effects of SGLT2 inhibitors are seen in cardiac cells in in vitro models suggests the potential existence of yet an unidentified alternative target.
Despite the encouraging clinical results of various SGLT2 inhibitors in reducing atrial fibrillation risk, both challenges and research opportunities remain. Most existing studies are retrospective, which demonstrates the need for randomized and prospective studies to assess the impact of SGLT2 inhibitors on reducing the incidence or recurrence of atrial fibrillation in patients with or without heart failure, or type-2 diabetes. […] Thus, the jury is still out on the therapeutic effect of SGLT2 inhibitors on atrial fibrillation.
It is possible that, while SGLT2 expression is negligible in cardiac cells at baseline, de novo SGLT2 expression may exist in pathological conditions. Therefore, SGLT2 inhibitors could directly prevent atrial fibrillation–promoting mechanisms. On the contrary, if SGLT2 inhibitors have no direct effect on cardiac cells, this would further confirm that their role in ameliorating atrial arrhythmogenesis results indirectly from improved glucose metabolism and kidney function.

(part in bold interesting @Neo: benefits of this class of drugs might be neither SGLT1 nor SGLT2 inhibition. For instance, this paper noted that SGLTis also seem to bind to USP30: Repurposing the inhibitors of MMP-9 and SGLT-2 against ubiquitin specific protease 30 in Parkinson's disease: computational modelling studies - PubMed )

And another paper showing the benefits of dapagliflozin post AMI: Association of SGLT2 inhibitor dapagliflozin with risks of acute kidney injury and all-cause mortality in acute myocardial infarction patients 2024

After matching, the use of DAPA in AMI patients was independently associated with a decline of AKI risk (OR 0.32; 95% CI, 0.19–0.53; P < 0.001) after hospital admission. Meanwhile, there were significant differences in mortality between the DAPA group and Ctrl group (2.5% vs. 7.6%, P = 0.012).

What a wonderful class of drugs :heart:

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#598

Not sure it’s a reliable journal, but still interesting as we don’t have many MR for SGLT2 (poke @Neo ): Diabetes mellitus, glycemic traits, SGLT2 inhibition, and risk of pulmonary arterial hypertension: A Mendelian randomization study 2024

Moreover, genetically predicted SGLT2 inhibition was causally linked to a reduced risk of PAH (OR = 1.68110-7, 95%CI = 7.05910-12-0.004, p = 0.002).

(Note: Pulmonary hypertension is not hypertension)

Also interesting: How do SGLT2 inhibitors protect the kidney? A mediation analysis of the EMPA-REG OUTCOME trial 2024

Changes in hematocrit and hemoglobin were the strongest mediators of empagliflozin’s kidney benefits in EMPA-REG OUTCOME participants with T2D and cardiovascular disease.

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#599

While I was very happy with Remogliflozin, but given the convenience and coverage of getting a far longer half life, and having found Dapagliflozin for 23 cents a pill within india (ADDII brand inside india Dartpapa 10) I just switched to it. I didn’t realize it could be found that affordably so thanks for bringing that up

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#600

Every single day we have new papers showing massive benefits for SGLTi users (among T2D, CKD, or HF => TBC if these findings extend to the general population):

Risk of Dementia in Patients with Diabetes Using Sodium-Glucose Transporter 2 Inhibitors (SGLT2i): A Systematic Review, Meta-Analysis, and Meta-Regression 2024

Pooled data from seven observational studies revealed that SGLT2i use was linked to a lower risk of dementia in people with diabetes (OR 0.45, 95% CI 0.34–0.61; p < 0.00001, I2 = 97%).
According to this research, taking SGLT2i reduces the incidence of dementia in people with diabetes by having a beneficial neuroprotective impact. Randomized controlled trials (RCTs) are still required in order to verify the findings of our research.

The impact of sodium‐glucose co‐transporter‐2 inhibitors on dementia and cardiovascular events in diabetic patients with atrial fibrillation 2024

After up to 5 years of follow‐up, SGLT2i use was associated with a significantly lower risk of incident dementia (hazard: 0.71, 95% confidence interval: 0.51– 0.98), particularly vascular dementia (HR: 0.44, 95% CI: 0.24–0.82). SGLT2i was related to reduced risks of AF‐related hospitalisation (HR: 0.72, 95% CI: 0.56–0.93), stroke (HR: 0.75, 95% CI: 0.60–0.94), and all‐cause death (HR: 0.33, 95% CI: 0.24– 0.44).

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#601

Another day, another good paper: Cardiorenal effectiveness of empagliflozin vs. glucagon-like peptide-1 receptor agonists: final-year results from the EMPRISE study 2024

Compared with GLP-1RA, empagliflozin was associated with similar risks of MI or stroke [HR: 0.99 (0.92, 1.07); RD: -0.23 (-1.25, 0.79)], and lower risks of HHF [HR: 0.50 (0.44, 0.56); RD: -2.28 (-2.98, -1.59)], MACE [HR: 0.90 (0.82, 0.99); RD: -2.54 (-4.76, -0.32)], cardiovascular mortality or HHF [HR: 0.77 (0.69, 0.86); RD: -4.11 (-5.95, -2.29)], and ESKD [0.75 (0.60, 0.94); RD: -6.77 (-11.97, -1.61)]. Absolute risk reductions were larger in older patients and in those with baseline ASCVD/HF.

SGLTis beat GLP1RAs? TBC…

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#602

I too am considering switching from Remogliflozin.

I’m going to do a 24 hour urinary glucose output study using Remogliflozin, Empagliflozin and Canagliflozin. I will probably time it for when I next do a CGM.

The only problem is i’m in the preliminary stages of a divorce :disappointed:

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#603

Small presentation on SGLT2i by Peter Attia and his squire

The longer AMA behind a paywall Peter says there is no statistical difference in UTI’s between placebo and SGLT2i’s but there is a difference in genital infections. The absolute risk increase is 4-5 % points, a 4.23 relative risk increase (RR 300% increase). Basically for every 22 people that takes these drugs, one of them will get a genital infection! But they are not life threatening infections and are easy to treat.

Citing this study:

In total, 77 RCTs involving 50,820 participants were eligible. The meta-analyses of randomized controlled trials (RCTs) showed no significant difference in UTIs between SGLT2 inhibitors versus control (2,526/29,086 vs. 1,278/14,940; risk ratio (RR) 1.05, 95% confidence interval (CI) 0.98 to 1.12; moderate quality evidence), but suggested increased risk of genital infections with SGLT2 inhibitors (1,521/24,017 vs. 216/12,552; RR 3.30, 95% CI 2.74 to 3.99; moderate quality evidence).

https://www.nature.com/articles/s41598-017-02733-w

So it’s something to think about and I wonder how to think about this if stacking with rapamycin, an immunosupressant.

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#604

The 4.23 relative risk increase might be for all SGLTi. It’s lower for empagliflozin (HR 2.86):

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(source: Comparison of Effectiveness Among Different Sodium‐Glucose Cotransoporter‐2 Inhibitors According to Underlying Conditions: A Network Meta‐Analysis of Randomized Controlled Trials 2024)

Absolute risk is especially high among females and people with prior genital infection (but similar relative HRs):

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(Risk factors for genital infections in people initiating SGLT2 inhibitors and their impact on discontinuation 2020)

So if I understand correctly, another way to look at the risk: men without prior genital infection who take SGLTi have the same risk of genital infection as women without prior genital infection who don’t take SGLTi. So… it looks OK?

Yes, concomitant use with rapa is something to think about (and I have no idea what to think about it…).

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#605

Fyi for those in US in case you want to help create some momentum, here is a note I received today for Ageless Rx:

Thank you for your message and interest!

We have started the recruitment process and you are invited to participate in an exclusive 2-week study that examines the efficacy and tolerability of Canagliflozin on glucose biomarkers. We are offering 20 interested patients access to 1-week of Canagliflozin Rx, Urine Test Kits, and a Continuous Glucose Monitor, and will provide you with your urine glucose and average glucose biomarker results.

What does it mean to participate?

Participation in this study is free! You will receive a 1x Continuous Glucose Monitor, 4x Urine Test Kits, and 1x week of Canagliflozin Rx. During the study, we ask that you measure blood pressure readings, answer online surveys, complete urine test kits, wear a continuous glucose monitor, and document your macronutrients during the study. Don’t worry– we’ll provide you with everything you need, right to your door.

What is Canagliflozin?

Canagliflozin, commonly known as Invokana, is an FDA-approved medication used in the treatment of type 2 diabetes. It belongs to the class of sodium-glucose co-transporter 2 (SGLT2) inhibitors. The drug works by inhibiting glucose reabsorption in the kidneys, promoting its excretion through urine, thereby lowering blood sugar levels. Similar to rapamycin, canagliflozin performed favorably at extending lifespan in mice in the Interventions Testing Program (ITP). Read more about that here.

In our study, we aim to explore the efficacy and tolerability of canagliflozin in healthy individuals when administered intermittently.

How can I get started?

Act fast! This study will only enroll 20 individuals (but will pave the way for future projects).

–Click Here to Take The Next Step–

*Please note that individuals based in these states will not be available to participate in this study: AL, AR, KY, LA, MS, NC, ND, NY, and SC.

Thank you for your time.

Kindly,

The AgelessRx Project Team

There email is: research@agelessrx.com

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#606
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#607

I don’t know what to conclude of these papers by the same team:

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#608

Sodium-glucose cotransporter-2 inhibitors and their potential role in dementia onset and cognitive function in patients with diabetes mellitus: a systematic review and meta-analysis 2024

The use of SGLT-2 inhibitors significantly lowers dementia risk compared to SGLT-2i non-users (Hazard ratio: 0.68, 95 % CI: 0.50–0.92). Furthermore, our findings indicated a positive effect of SGLT-2 inhibitor use on cognitive function score improvement, as demonstrated by the standardized mean difference of 0.88 (95 % CI: 0.32–1.44), particularly among populations with mild cognitive impairment or dementia.

Antihypertensive Effect of Sodium-Glucose Cotransporter 2 Inhibitors and Glucagon-like Peptide 1 Receptor Agonists 2024

Current data show that SGLT2 inhibitors have a stronger antihypertensive effect than GLP-1 receptor agonists, which is mainly related to their renal effect. Briefly, SGLT2 inhibitors increase the response to diuretics and decrease the meal-related antinatriuretic pressure by lowering post-prandial hyperglycemia and hyperinsulinemia and prevent proximal sodium reabsorption. SGLT2 inhibitors can be used as second-line therapy in patients with diabetes mellitus or heart disease and concomitant hypertension.
SGLT2 inhibitors have an evident beneficial effect on BP. The BP-lowering effect seems to be continuous and chronic, rather than acute. SGLT2 inhibitors should be highly considered as second- or third-line therapy in hypertensive patients with DM and especially in those with proteinuria. GLP-1 agonists have modest chronic effect on BP reduction (≈2 mmHg for SBP), and antihypertensive action has not been consistently reported in studies that use ambulatory BP monitoring. The importance of SGLT2 inhibitors should be particularly investigated in drug-resistant hypertension. Future clinical investigations should provide direct comparisons with other antihypertensive medications.

SGLTi are already approved for HF but now researchers are looking at HF prevention: Empagliflozin to elderly and obese patients with increased risk of developing heart failure: Study protocol for the Empire Prevent trial program 2024

@Neo this article is for you: Mechanistic Modeling of Empagliflozin: Predicting Pharmacokinetics, Urinary Glucose Excretion, and Investigating Compensatory Role of SGLT1 in Renal Glucose Reabsorption 2024

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#609

According to a 2021 study, empagliflozin is less costly and more effective than canagliflozin and dapagliflozin over shorter durations.

“Empagliflozin was dominant (less costly, more effective) over both canagliflozin and dapagliflozin over the shorter durations. Empagliflozin remained cost-effective relative to SoC over 10 years”

“Patients receiving empagliflozin were predicted to survive longer due to lower rates of CV death versus canagliflozin”

This article compares all three.:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098979/#:~:text=Empagliflozin%20was%20dominant%20(less%20costly%2C%20more%20effective),canagliflozin%20and%20dapagliflozin%20over%20the%20shorter%20durations.

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#610

Two caveats:

  1. “in patients with type 2 diabetes and established cardiovascular disease”
  2. In the US (where empagliflozin, dapagliflozin, and canagliflozin cost 10 times more than in Europe)
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#611

Ah, and also:

  • “The authors would like to thank Samuel Mettam, formerly of Boehringer Ingelheim, for his contribution to the empagliflozin versus dapagliflozin cost-effectiveness analysis.”
  • “Funding: Sponsorship for this study and article processing charges were funded by Boehringer Ingelheim Pharma GmbH & Co KG of Ingelheim am Rhein, Germany. […] Editorial assistance in the preparation of this article was provided by Janet Dooley of Evidera’s Editorial and Design Services team. Support for this assistance was funded by Boehringer Ingelheim Pharmaceuticals, Inc.”
  • “Competing interests: OSR, SBB, and KF are employees of Evidera, which provides consulting and other research services to the biopharmaceutical industry. ARK and LC were employees of Evidera during the conduct of this study and development of this article, but are now employed elsewhere. In their salaried positions, Evidera employees work with a variety of companies and organizations, and are precluded from receiving any payment or honoraria directly from these organisations for services rendered. Evidera received funding from Boehringer Ingelheim Pharma GmbH & Co KG. EP and AU are current employees of Boehringer Ingelheim Pharma GmbH & Co. KG of Ingelheim am Rhein, Germany. PKG was an employee of Boehringer Ingelheim Pharmaceuticals, Inc. in Ridgefield, Connecticut, USA during the conduct of this study and development of this article, but he is now employed elsewhere.”

Boehringer Ingelheim is, of course, the company behind empagliflozin.

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