my wife (60) has a RHR of low 60’s with an occasional dip into the high 50’s. She is extremely fit so I’d say your ok.
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Yes, but thinks it’s less about that for me and more about overall expertise / mindfulness practice and:
Late snacks/alcohol/stress = high overnight HR IMO
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Michael Lustgarten has a video or two on this topic and how it changes across age and how it is associated with mortality - you might want to look at that (they tend to just quite short and sweet)
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I thought this was interesting. Tofogliflozin (approved in Japan) causes less urination at night (nocturia) compared to other SGLT2i meds:
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Thanks for that, Davin8r. Tofogliflozin indeed sounds interesting. It is apparently even more selective of SGLT-2 compared to SGLT-1 than empagliflozin. It’s nice wrt. the nocturia, but ultimately what’s really of interest is how it compares to other SGLT2i in various settings, whether glucose control, CV benefits etc. I have not done a deep dive on tofogliflozin, but I did note this paper:
Tofogliflozin long-term effects on atherosclerosis progression and major clinical parameters in patients with type 2 diabetes mellitus lacking a history of cardiovascular disease: a 2-year extension study of the UTOPIA trial
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SGLT2i benefits for depression: Depression and mental health: what do you use? - #136 by adssx
For dementia: Glucose lowering meds lower dementia risk
Dapagliflozin in PD: Glucose lowering meds lower dementia risk - #5 by adssx
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Are most people getting SGLT2 inhibitors from the same Indian pharmacies you get rapamycin from? Any recommended brands?
Branded Jardiance is available from India, so that’s what I take.
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Direct Cardiac Mechanisms of the Sodium Glucose Co-Transporter 2 Inhibitor Class 2025
This review identified several key mechanisms by which SGLT2 inhibitors may benefit the heart directly, including reductions in oxidative stress, inflammation, and myocardial fibrosis. Emerging evidence suggests that these drugs modulate key pathways such as sodium-hydrogen exchange (NHE) inhibition, improvement of mitochondrial function, and promotion of ketone body utilization in cardiomyocytes.
SGLT2 inhibitors appear to confer direct cardioprotective effects. These include anti-inflammatory, anti-fibrotic, and energy efficiency improvements in the myocardium. The findings highlight new potential therapeutic mechanisms and provide a foundation for further research into the non-diabetic use of SGLT2 inhibitors in heart failure and other cardiac conditions. Understanding these direct effects could lead to optimized treatment strategies for patients with and without diabetes.
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GLT2is significantly reduced dementia risk and mortality compared to metformin in T2D patients. These findings suggest SGLT2is may offer superior neuroprotective benefits, underscoring their potential as a first-line therapy for T2D. Further randomized trials are needed to confirm these results.
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Nice find. It’s association, but still, the numbers are impressive. Are SGLT2i very good or is metformin very mediocre?
“Results
- Among 74,975 matched patients in each cohort, SGLT2i use was associated with a lower incidence of overall dementia: 2.7% vs. 6.9%: adjusted hazard ratio (aHR) 0.80 [95% CI 0.76;0.84]. Reductions were observed in vascular dementia (0.8% vs. 2.0%; aHR 0.87), Alzheimer’s dementia (1.1% vs. 3.2%; aHR, 0.76), and all-cause mortality (6.8% vs. 15.4%; aHR, 0.92). Benefits were pronounced in older adults, particularly those aged ≥80 years.”
“Benefits were pronounced in older adults, particularly those aged ≥80 years.”
Well, you expect that since dementia (and ACM) increase with age, if there are benefits, they would be more pronounced in older adults.
What would be of interest is how long does one have to be on SGLT2i to start seeing benefits and are these a steady amount per year, or are the benefits cumulative with time beyond that steady level.
Obviously, we are talking about high risk individuals with significant morbidities. How does this map out for people on these agents who don’t have these morbidities, that’s the question for those who take them for longevity/healthspan purposes.
They make a point that of course these are associations, but the RCTs are inconsistent. One wonders about the numbers of people in these RCTs, if adequately powered.
“[…] this association remains unconfirmed due to inconsistent findings across studies, particularly randomized trials.”
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Impact of sodium-glucose cotransporter-2 inhibitors on aging biomarkers and plasma ceramide levels in type 2 diabetes: beyond glycemic control
Results: SGLT2i-treated patients showed significantly lower CerC16:0, CerC22:0, and CerC24:1 levels (p < 0.01) and decreased 5MC and H2AX (p < 0.05) compared to non-SGLT2i patients. IGF-1 was significantly elevated in the SGLT2i group (p < 0.01), suggesting a possible protective effect on metabolic health. PCA distinguished control from diabetic groups but revealed overlap between SGLT2i and non-SGLT2i groups.
Conclusion: Beyond glucose control, SGLT2i may improve plasma Cer and aging markers in diabetic patients, supporting their broader therapeutic potential in aging and age-related diseases. Further large-scale studies are warranted to confirm these effects and underlying mechanisms.
Open access paper:
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Empagliflozin and dapagliflozin affect miRNA expressions on diabetic rat heart.
Empagliflozin and dapagliflozin may have different cardioprotective mechanisms.
Dapagliflozin shows protective effect on thoracic aortas.
SGLT2 inhibitors showed neutral cancer risk in T2DM patients but may reduce gastrointestinal cancer versus metformin, guiding tailored therapy based on patient risk profiles.
SGLT2i-treated patients showed significantly lower CerC16:0, CerC22:0, and CerC24:1 levels (p < 0.01) and decreased 5MC and H2AX (p < 0.05) compared to non-SGLT2i patients. IGF-1 was significantly elevated in the SGLT2i group (p < 0.01), suggesting a possible protective effect on metabolic health. PCA distinguished control from diabetic groups but revealed overlap between SGLT2i and non-SGLT2i groups.
Beyond glucose control, SGLT2i may improve plasma Cer and aging markers in diabetic patients, supporting their broader therapeutic potential in aging and age-related diseases. Further large-scale studies are warranted to confirm these effects and underlying mechanisms.
SGLT2i continuously prevents cardiac hypertrophy by reducing ferroptosis via AMPK up-regulation 2025
Unexpectedly, mechanistic studies revealed that antagonism of AMPK aggravated oxidative stress and ferroptosis, reduced GPX4 (glutathione peroxidase 4) level, and partially abolished the anti-hypertrophic and anti-ferroptosis effects of SGLT2i in H9C2 cells. Taken together, the regulatory role between AMPK and ferroptosis was revealed for the first time in cardiac hypertrophy. SGLT2i counteracts ferroptosis by activating AMPK, providing a sustained protection against cardiac hypertrophy. This positions SGLT2i as a potential therapeutic agent for the treatment of cardiac hypertrophy. Besides, in addition to the downregulation of AMPK in hypertrophic heart tissue, its levels are also reduced in plasma, suggesting its potential to serve as a diagnostic marker for the early detection of ferroptosis and cardiac hypertrophy.
(poke @John_Hemming, on AMPK activation)
SGLT2-i and DPP4-i enhance ketone metabolism in the brain.
SGLT2-i and DPP4-i suppress neuroinflammation and promote M2 microglial polarization.
SGLT2-i and DPP4-i inhibit NLRP3 inflammasome activation through distinct pathways.
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Beautiful collection of papers, thank you Antoine!
I really hope we can dig into the disparate effects of SGLTi, because we all take different ones, and many papers that find effects lump them all together which severely limits the actionability of such findings.
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Have we seen this in other studies?
Have people seen their IGF-1 go up after starting?
(Not sure we want it to go up and do the extent flozins are CR mimetics I would have thought IGF-1 to go down if anything and not up)
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Fully agreed. I really wish I had measured my serum IGF-1 level before I started taking empagliflozin, but alas, I did not, as I was not aware that there was any impact of SGLTi on IGF-1 levels. I did however measure my level recently after 5 months of daily 12.5mg empagliflozin. It showed as 132 ng/mL, (reference interval 68-247). I wish I had a before and after reading, but regrettably, I don’t. FWIW, Dr. Fuhrman pegs optimal levels as between 80 and 150:
So whatever empaglifozin might or might not be doing to my IGF-1 levels, it doesn’t appear that at 12mg/day for five months takes me far out of the (presumably) reasonable range at age 66. YMMV.
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SGLTi in general seem very safe, even in people with chronic conditions. UTI incidence is slightly elevated in people with diabetes, but not seemingly in other conditions.
Update on the Efficacy and Safety of Sodium–Glucose Co-Transporter 2 Inhibitors in Patients with Chronic Diseases: A Systematic Review and Meta-Analysis
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A new open access paper:
Dapagliflozin ameliorates intestinal stem cell aging by regulating the MAPK signaling pathway in Drosophila
Introduction: Intestinal stem cells (ISCs) possess the ability to self-renew and differentiate, which is essential for maintaining intestinal tissue homeostasis. However, their functionality significantly declines with age, leading to diminished tissue regeneration and an increased risk of age-associated diseases.
Methods: This study investigates the effects of Dapagliflozin (DAPA), a novel insulin sensitizer and SGLT2 inhibitor, on aging ISCs using the Drosophila melanogaster model. Our findings demonstrate that DAPA can inhibit the MAPK signaling pathway, as confirmed by network pharmacology analysis and molecular docking experiments.
Results: DAPA ameliorates ISC aging, improves intestinal function (including enhanced fecal excretion, restored intestinal barrier integrity and acid-base balance), and enhances healthspan. These results highlight the potential of DAPA as an anti-aging therapeutic agent.
Discussion: This study provides new evidence for the application of DAPA as an anti-aging treatment.
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I have been taking a half dose of dapagliflozin (5mg) and had my serum uric acid come back at 2.1 (LabCorp reference range: 3.8-8.4 mg/dL) in spite of 180mg of bempedoic acid daily. Openevidence says this is not a concern if it’s due to an SGLT2i, and my eGFR-cys is 118, so my renal function is fine. Has anyone successfully raised uric acid that is too low? I rarely drink alcohol and don’t wish to start, but I am considering a pro-gout diet if necessary.
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Some people find that eating more fish, like sardines, can raise your uric acid. I was on 12.5mg/day of empagliflozin (just bumped it up to 25mg/day), and LabCorp measured me at 3, which was also flagged as “low”. I’m fine with 3. The 2.1 is a little aggressive. Perhaps sardines.
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