Essentially, you should not count on being able to take it and get anti-aging effects, it’s a giant gamble.
They suggest that unless you have an SGLT2i prescribed for some indication, taking it off label is an unquantified risk.
Bottom line, as so often, everyone must do a risk/reward analysis for their own medical situation.
I have elected to take empagliflozin 25mg/day despite having no condition for which this med is officially indicated - though I am prediabetic and even though my PCP would not prescribe it for me unless I become officially diabetic, I think in my case it’s reasonable. But even if I was not prediabetic, I would still take it. I base that on research suggesting that renal protection effects in non-impaired kidneys (healthy) are still present - I am 68, and kidney function declines with age. Getting rid of glucose I see as a win regardless, and research suggests that it may slow the progression to diabetes. That is all I am hoping for, if there is more, that’s icing on the cake. Then I have to ask what are the possible downsides or risk for these speculative benefits. Well, it seems relatively safe for a male with no history of urogenital infections. YMMV, and everyone will make their own decision, but those are my considerations.
thanks @WJ_PhD and @CronosTempi . Yeah, I’ve been taking it for more than a year now at 12.5mg daily, but I tend to like it as I haven’t been able to notice any side effects not even any muscle aches nor any effect on exercise (which metformin seems to have).
So, my dilemma was more to do with the dosing as I’m tempted to go to 25mg Empagliflozin and maybe scrap metformin (currently do 1000mg daily). I actually like metformin also especially when I take in the evening either with my dinner or before bed, but everyone is saying it effects exercise (not able to confirm nor deny as I do very light exercises and wouldn’t be able to tell either way).
@CronosTempi, do you think you experienced any side effects at that dose, which seems to be the maximum recommended for Diabetes, i.e. did it affect your exercise, or any aches etc…
Not true for me, but I may be in a specific situation insofar as I have always peed with a fairly high frequency, because I make sure to always drink a pretty high volume of liquids, so I doubt empaglifozin would necessarily increase the already high frequency.
If it hasn’t already been posted - a short 16 minute talk at ARDD2025 about 8 short term studies experimenting with SGLT2i off-label in “normal” people (younger that 60, no diabetes, no CKD, no HF ):
This can produce valuable information, as there is the core argument, that SGLT2i are simply normalizing detrimental effects of diabetes/CKD.
Overview & Aim: The presentation discusses evaluating whether FDA-approved SGLT2 inhibitors (traditionally used for diabetes, kidney disease, and heart failure) can be repurposed as gerotherapeutics to optimize healthspan and lifespan in individuals without these diseases [03:30], [10:23].
Mechanism: SGLT2 inhibitors work by inhibiting glucose reabsorption in the kidneys, causing the body to excrete glucose through urine [03:44]. This pleiotropic drug lowers blood pressure and offers systemic metabolic and cardiac benefits [04:12].
Systematic Review Findings: A massive systematic review screened over 44,000 articles, ultimately analyzing 536 human studies [07:19].
Off-Label Data: Looking strictly at 8 completed trials involving younger, conventionally “healthy” cohorts (ages 30–60) taking the drug off-label, SGLT2 inhibitors showed highly positive, statistically significant improvements across multiple organ systems—specifically cardiovascular, metabolic, renal, hepatic, and adiposity systems [08:31], [09:49].
Research Gaps: Current off-label data severely lacks insights into how SGLT2i impacts the reproductive, immune, and nervous systems [10:51].
The HEARTS Trial: To fill these gaps, a multi-disciplinary, 6-month clinical trial is being launched in Singapore [11:53]. It will evaluate the effects of 10mg of daily SGLT2i on healthy individuals (ages 35–65) with an optimal BMI, focusing on VO2 max as the primary outcome alongside digital and biological biomarkers [12:11].
“Among 12,685 patients for whom sequence data were obtained, 121 carried a cardiomyopathy variant (76 dilated cardiomyopathy, 25 hypertrophic cardiomyopathy and 25 arrhythmogenic cardiomyopathy). Over a median follow-up of 4.2 years, dapagliflozin lowered the risk of HHF more strongly in carriers (hazard ratio 0.18, 95% confidence interval 0.04–0.86) than in noncarriers (hazard ratio 0.70, 95% confidence interval 0.57–0.86; P interaction 0.03). Absolute risk reduction was 13.0% in carriers and 1.0% in noncarriers (P interaction 0.03). Most carriers (82%) had no prior HF, and in carriers without prior HF, treatment with dapagliflozin reduced the absolute risk of HHF by 12.8%, compared with a reduction of 0.6% in noncarriers (P interaction 0.01).“
That may (or may not) be ultimately true. But most people here would consider SGLT2i for generally longevity and not specifically heat failure - which is different than ASCVD.
Kidney function in “normal healthy” people declines every year by about 1% of it’s original state - starting from mid age (40/50). So by age 90 you could loose about 50% of your kidney function, despite doing most things right.
This is similar to the rationale for lowering LDL or blood pressure: it’s just a very common issue even in “normal” people. So there may be an incentive to take preventative action, such as SGLT2i. In addition there’s a mild effect on weight loss and blood pressure (which could benefit most “normal” people).
Well, if you are very old and very sick (with multiple co-morbidities), and so ill with HF that you are hospitalized, it’s good to know that SGLT2i can still massively help with ACM (all cause mortality), hospitalization and composite outcomes. Observational study.
Efficacy and Safety of SGLT2 Inhibitors in Heart Failure: Observational Evidence in Geriatric Patients-AGING-HF
“SGLT2i use was associated with lower risks of all-cause mortality (hazard ratio, 0.67 [95% CI, 0.46-0.98]; P =0.031), HF rehospitalization (hazard ratio, 0.64 [95% CI, 0.42-0.97]; P =0.037), and the composite outcome (hazard ratio, 0.60 [95% CI, 0.44-0.82]; P =0.001) at 1 year, after multivariable adjustment.”
“This review provides an analysis of the multifaceted mechanisms underlying the cardiorenal benefits of SGLT2i in HF and CKD outside of the T2D context. Eight major aspects of the protective effects of SGLT2i beyond glycemic control are explored: 1 ) the impact on renal hemodynamics and tubuloglomerular feedback; 2 ) the natriuretic effects via proximal tubule Na+/H+ exchanger NHE3 inhibition; 3 ) the modulation of neurohumoral pathways with evidence of attenuated sympathetic activity; 4 ) the impact on erythropoiesis, not only in the context of local hypoxia but also systemic inflammation and iron regulation; 5 ) the uricosuria and mitigation of the hyperuricemic environment in cardiorenal syndromes; 6 ) the multiorgan metabolic reprogramming including the potential induction of a fasting-like state, improvement in glucose and insulin tolerance, and stimulation of lipolysis and ketogenesis; 7 ) the vascular endothelial growth factor A (VEGF-A) upregulation and angiogenesis, and 8 ) the direct cardiac effects.”
As much as I hate to add another daily pill to my regimen, it’s hard to ignore SGLT-2 inhibitors.
Going to a low-dose version because weight, A1c, glucose and insulin sensitivity are already well under control through a GLP1 agonist. In addition, studies that activate the following pleitropic effects :
-Ampk activation
Ecm remodeling of kidney, heart, liver
senomorphic effects
Show that these are already activated at the minimum dose, as long as SGLT-2 receptors are sufficiently saturated to induce glucose excretion.
Curious about where egfr settles for me. After about 8 months on a GLP1/GCGR agonist, egfr rose to the mid 110s, supporting preliminary evidence that these drugs increase egfr through non-pathological hyperfiltration. SGLT-2 inhibitors initially lower it, although they stop the decline.
EGFR is just estimated. Any time you lose muscle mass or even just decrease protein intake, your eGFR will go up because the estimate is based on creatinine which is a muscle breakdown product.
Just like taking creatine will bring eGFR down. So would a hard workout before your blood draw.
Some labs are valuable to trend even while normal but trying to get meaning out of trending creatinine or eGFR is fraught when things are changing.
I say this because GLP-1s usually reduce muscle mass so would be expected to increase eGFR but not actually effect GFR. Even without weight loss, I would expect some effect only on the eGFR. Doesn’t necessarily mean your GFR didn’t go down, but you would need a better test to actually know.
That’s good to know, about egfr, thanks. I’m basing my guess on this slide from phase 3 data on Mazdutide, which demonstrated statistically significant increase in Cystatin C-based eGFR by the end of the treatment period.
Note that:
peak eGFR increases for the 16 mg dose actually maxed out around Week 24, with weight loss not yet at a plateau.
egfr increase plateaus at higher doses, while weight loss itself shows no plateau
increase in eGFR happens with a decrease in urine albumin-creatinine ratio (UACR)
All of this suggests a mechanism of increasing egfr independent of weight loss. Looking forward to the published data from Mazdutide and other GCGR agonists, hopefully some time this year.
