You’re probably aware of the off label use also. Open Evidence says mirabegron activates brown adipose tissue and increases resting energy exposure, but it says vibegron has not been shown to do the same. Maybe it just hasn’t been studied, though.
The administration of 200 mg per day of oral mirabegron for 12 weeks to 12 healthy men was associated with higher BAT activity (measured via 18F-fluorodeoxyglucose positron emission tomography combined with computed tomography) and the elevation of the resting metabolic rate by 203 ± 40 kcal/day, compared to individuals receiving the placebo.
But nothing is free:
It was reported that high doses of mirabegron (especially 200 mg per day), much higher than those approved by the FDA for bladder overactivity (50 mg per day), may be associated with cardiovascular side effects such as headaches, tachycardia, and elevated blood pressure (mostly only systolic blood pressure)
Risking cardio health with high dose beta-3 agonists would seem unwise since there are so many other options for fat loss these days, but I get it that some who have more issues than I do with losing body fat might need a multi-pronged approach. Personally, I’d be happy with being able to take an SGLT2i and not have to get up to pee at night (while also keeping hematocrit under control).
No, it’s too dangerous, and why I put the block quote there about the risk. The BP increase is substantial. But at therapeutic doses, it still beiges white adipose tissue! And there’s speculation that there may still be a small, cumulative metabolic effect over time.
Dapagliflozin and empagliflozin showed similar cardiorenal and safety outcomes.
However, analysis among patients without stable prior ACEI/ARB exposure revealed a higher risk of all-cause mortality with empagliflozin. Dapagliflozin was more often prescribed by cardiologists, while endocrinologists and nephrologists favored empagliflozin.
After propensity score via overlap weights and in the ITT analysis, the SGLT2i group showed significantly lower incidence (per person-year) compared to the DPP4i group for several safety outcomes: UTI (20·67‰ vs. 25·57‰, hazard ratio [HR]: 0·81, 95% confident interval [CI]: 0·79–0·83), fracture or falls (16·59‰ vs. 18·06‰, HR: 0·92, 95% CI: 0·90–0·94), AKI (0·94‰ vs. 2·04‰, HR: 0·46, 95% CI: 0·41–0·50), bullous pemphigoid (0·05‰ vs. 0·10‰, HR: 0·50, 95% CI: 0·33–0·76), and all-cause mortality (13·64‰ vs. 23·73‰, HR: 0·57, 95% CI: 0·56–0·59). Conversely, the risk of genital infection was significantly higher in the SGLT2i group (2·50‰ vs. 1·54‰, HR: 1·62, 95% CI: 1·52–1·73). These findings remained consistent in the PP analysis and across most subgroups.
SGLT2i therapy was associated with a lower incidence of IDA in T2DM patients compared to DPP-4i therapy. These findings suggest a potential hematologic benefit of SGLT2 inhibitors, warranting further investigation in randomised controlled trials.
In summary, treatment with dapagliflozin in type 2 diabetic mice promotes β-cell regeneration by upregulating GLP-1 production, which is mediated via gut microbiota and tryptophan metabolism.
In that case, shouldn’t all patients using certain statins be immediately put on an SGLT2i (dapagliflozin)? Because [CAUTION: Chinese!]:
Statins aggravate insulin resistance through reduced blood glucagon-like peptide-1 levels in a microbiota-dependent manner
Very true, except it can be higher than the 52-54 range as long as there are no genetic risk factors like Factor V (which a blood test can check for) and elevated platelets (also hypertension, high fibrinogen, high WBC).
From Vera AI: The average adult male living at the world’s highest permanent settlements** (Andean highlanders, La Rinconada) typically has Hb ~19–21 g/dL and Hct ~58–65%
Those people do not have any more thrombosis than the sea level population (unless they have high platelets or genetic clotting risks).
But yes, SGLT2’s do indeed raise hematocrit and hemoglobin.
Right, but the key difference is that adaptations to high altitude are different than what occurs with elevated hematocrit from testosterone (and/or SGLTIs). The adaptations from high altitude implement a coordinated physiologic response that reduces the risk of thrombosis, whereas such adaptations do not occur with testosterone therapy. This explains it pretty well:
Oh I know they’re different. I’m just pointing out I don’t think there is a big concern with elevated hematocrit and hemoglobin regardless without the other aforementioned risk factors. There certainly isn’t with SGLT2’s. In fact, I would imagine the risk would be greatly reduced on an SGLT2.
I really do wish that were the case, but it seems there is a big concern:
“Recent multi-institutional cohort studies have demonstrated that elevated hematocrit (≥52%) in men on testosterone therapy is independently associated with a higher risk of major adverse cardiovascular events and venous thromboembolism, even in the absence of other risk factors. For example, men who developed polycythemia while on testosterone had a significantly higher incidence of MACE/VTE compared to those who maintained normal hematocrit, with an odds ratio of 1.35 (95% CI 1.13–1.61) in the first year of therapy.[3] This risk appears to be independent of baseline thrombophilia or other traditional risk factors.”
You would think they would be adequately powered: “23 RCTs with 155,443 participants included in the meta-analysis”. But:
According to the results, compared with placebo, no significantly altered dementia risks were observed in patients receiving DPP-4i (RR = 1.19, 95%CI, 0.61 to 2.32), SGLT-2i (RR = 0.45, 95%CI, 0.67 to 3.12), GLP-1RA (RR = 1.08, 95%CI, 0.57 to 2.05), TZD (RR = 0.73, 95%CI, 0.09 to 32.74), or sulfonylurea (RR = 1.75, 95%CI, 0.66 to 4.63). With respect to the risks of Alzheimer’s disease, vascular dementia, and dementia with Lewy bodies, no significant associations were observed when intercomparing all anti-diabetic agents and placebo as well. …
Why are these figures different from those in Table S6 and S7?
Then, those are short RCTs for diabetes so it’s not surprising not to find anything statistically significant. Still, SGLT2 are on the “good side of null” and combined with MR and longitudinal studies, that’s enough for me: Canagliflozin - Another Top Longevity Drug - #1742 by adssx
A small RCT of dapagliflozin in AD also found cognitive improvement (posted here previously).
Defective MQC critically contributes to CRS-3-related myocardial dysfunction. The study proposes that DAPA therapy may normalize DUSP1-dependent MQC and consequently alleviate the cardiac depression associated with CRS-3.
Second study says: Results: A total of 5,842 men who received TT and developed polycythemia were matched and compared to 5,842 men who did not develop polycythemia. Men with polycythemia had a higher risk of MACE/VTE (number of outcomes: 301, 5.15%) than men who had normal hematocrit (226, 3.87%) while on TT (OR 1.35, 95% CI 1.13-1.61, p <0.001).
While I suppose you’re right, that’s still a pretty small risk and 5.15% compared to 3.87% doesn’t seem like much, given the large number of people.
Nattokinase I believe is the best safe insurance policy we could take to mitigate any increased risk. I have a high hematocrit so I take plenty of that (8000FU + a bag of fermented natto daily), just in case.
It’s a 33% increased relative risk, bringing it up to more than 1 in 20, so with my cardio history (calcium score and high Lpa), I need to be careful. I’m anxious to see what my hematocrit is today after stopping empagliflozin, changing TRT to daily microdose, increasing cardio, increasing to max dose irbesartan and staying well-hydrated
I also take nattokinase every night (10,000 FU). I’m not convinced it’s helpful because the research quality is shaky at best, but risk of harm seems low and it’s cheap.
Odd. I don’t think I have kidney damage, as none of my other numbers say so. T2DM, same, A1c 5.7, FBG 98. Maybe I was slightly dehydrated for the test (approx. 18 hours with no liquids).
If you only tried it for one day, that’s just not a good test: it could have been some other, random thing. Try five days at a low dose, five days off, and five days on again.
You and @Pender could also try canagliflozin, which is a dual SGLT1/2 inhibitor, so you absorb less glucose in the GI rather than only losing it out the urine.
They don’t work for me because I have essentially zero fat over top of my triceps muscle, so the needle goes into my muscle, hurts like hell the entire time the CGM is on, and gives sketchy readings.
