Thank you for the very reasonable response to my misgivings. What do you think about adding a micro-dose of GLP1. There is a lot of information about anti-aging benefits of this group of medications. Do you think it is reasonable to use the combination of Rapamycin, SGLT2i, and GLP1 for healthy people without ApoE4 or other serious risk factors, genetic red flags?
Well, we do know that people have used that combination with apparently additive effects, which they deemed positive, such as glucose control and weight loss. I personally remain unpersuaded. I do not find any robust evidence of longevity benefits of GLP-1RA. The extent of GLP-1 health benefits, such as they are, seem to all be the consequence of weight loss and diminished intake of calories. All the multiple benefits that I have seen are a case of āduhā - of course if you donāt overeat, your organs will benefit, duh. But show me a mechanism of benefits that do not rely on eating less and losing excess adipose tissue - because that is definitely the case for SGLT2i drugs.
Therefore adding GLP-1RA is a very individual specific consideration - if you need to lose weight and/or control overeating, and have no better way of accomplishing that, then sure, add GLP-1RA. I personally donāt need to lose weight and I donāt overeat so I am not adding it to my stack.
There is one other consideration, which might persuade me to add GLP-1RA, and that is glucose control. If all my other interventions fail to get my BG down to reasonable levels, and especially if my glucose control deteriorates as a result of rapamycin and nothing else is working, then Iād look to add a GLP-1RA, because I want to prevent metabolic derangement. If that were to happen, Iād start with semaglutide, seems the safest with the longest track record.
Bottom line, I personally, for my situation at this point see no benefit to adding GLP-1RA , but it is not unreasonable for others in a different situation to do so. But those reasons in my mind are centered around the amelioration of metabolic disregulation and not longevity or health benefits in healthy individuals. Those pleiotropic benefits in healthy individuals are persuasive to me for SGLT2i drugs and as for rapamycin itās a calculated gamble that there will be benefits.
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LukeMV
#1388
I think itās totally fine as long as you donāt have any type of health related concern where one of these could pose a risk.
Your personal decision about which medications or supplements to take for prevention of neurodegenerative diseases makes a lot of sense to me, considering your family history and APOE4 gene. You are also trying to optimize your sleep, exercising regularly and following healthy diet, which of course is even more important!
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I absolutely agree with your reasoning!
Satchel
#1391
I have been on Tirzepatide(GLP-1) for 6months-no issues. I just tried to add in 10 mg of empagliflozin and it just flattened me. No energy. Is this common? Do you try 1/2 dose? 1/4 dose?
Jjazz
#1392
I had the same experience when I added 100mg canagliflozin to my 1mg weekly retatrutide. I backed cana down to 50mg and it got a bit better. I also tried to eat more carbs and that helped too. After sticking with it for a few weeks, the fatigue was gone. Iāve since ramped my daily cana up to 150mg.
It took some time for my body to adapt, but I feel much healthier now with much more energy that I had before adding in cana.
I should also mention that being on this combination makes me MUCH more sensitive to rapamycin. I used to take 10-20 mg weekly without feeling anything. But now, even 2 mg leaves me feeling starved, energy deprived, and incredibly irritable. Iāve stopped taking it.
3 Likes
Tim
#1393
Did you make the switch in a day with no washout period? Is Dapa known for its moderate effect on uresis? I just started taking canagliflozin and my water consumption and elimination has increased dramatically.
Made the switch in one day with no problem at all. The effect on uresis is less pronounced now but still there. I estimate Iām drinking about 0.5 to 1 litre less. No idea whether this is a known effect and Iām not keeping proper records. Itās just something I noticed.
Tim
#1395
I just cut the tabs in half, at least for a break-in period.
Satchel
#1396
I started checking blood pressure and its dropped to 99/66 routinely (checked with 2 different monitors)- which I guess is why I feel wiped. Crazy diuresis as well. I have added in salt and electrolytes and hope this helps BP.
Tim
#1397
What was your BP before? I guess youāre taking a flozin. What dose and for how long? Any other BP meds?
adssx
#1398
The diuresis normally stops after a few days when the body adapts.
2 Likes
adssx
#1399
Comparative Effectiveness of SGLT2 Inhibitors and GLP-1 Receptor Agonists in Preventing Alzheimerās Disease, Vascular Dementia, and Other Dementia Types Among Patients with Type 2 Diabetes 2025
SGLT2 inhibitors were associated with a significantly lower incidence of overall dementia compared to GLP-1 receptor agonists (2.7% vs. 3.6%; HR, 0.92; 95% CI, 0.89ā0.95). The risk of VaD (HR, 0.89; 95% CI, 0.84ā0.95) and AD (HR, 0.90; 95% CI, 0.86ā0.94) was also reduced with SGLT2 inhibitors. All-cause mortality was lower in the SGLT2 group (3.6% vs. 4.6%; HR, 0.95; 95% CI, 0.92ā0.98). No significant difference was observed in other dementia subtypes (HR, 0.96; 95% CI, 0.91ā1.01).
6 Likes
adssx
#1400
Weird Egyptian paper (in mice with asthma!): Empagliflozin inhibits autophagy and mitigates airway inflammation and remodelling in mice with ovalbumin-induced allergic asthma
Animals were treated with empagliflozin (10 mg/kg; orally) and/or rapamycin (an autophagy inducer; 4 mg/kg; intraperitoneally) before every challenge.
However, the therapeutic potential of empagliflozin was inhibited when rapamycin was co-administered. In conclusion, this study demonstrates that empagliflozin has immunomodulatory, anti-inflammatory, and anti-remodelling properties in ovalbumin-induced allergic asthma and suggests that autophagic flux inhibition may play a role in empagliflozinās anti-asthmatic effects.
2 Likes
dicarlo2
#1401
HRs while significant, donāt seem that impressive, especially compared to the HRs for various kidney diseases. Seems like SGLT2-inhibitors are a nice addition to the prevention toolkit, but not primary prevention level of efficacy. Ie probably worth taking for prevention, but donāt expect that itās going to make a huge difference.
adssx
#1402
Itās the HR compared to GLP-1RAs! Compared to metformin or standard of care, the HR is about 0.5 in other papers. Itās massive.
6 Likes
RapAdmin
#1403
Not sure if this has been posted already (let me know ) and not sure if to post this here or in the Cardiovascular Health threadā¦
Sotagliflozin, a drug recently approved by the Food and Drug Administration to treat type 2 diabetes and kidney disease with additional cardiovascular risk factors, can significantly reduce heart attack and stroke among these patients, according to results from an international clinical trial led by a Mount Sinai researcher.
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adssx
#1404
Hereās the paper published yesterday: Effect of sotagliflozin on major adverse cardiovascular events: a prespecified secondary analysis of the SCORED randomised trial
Sodiumāglucose co-transporter (SGLT)-2 inhibitors have shown consistent benefit in improving heart failure-related outcomes but not ischaemic cardiovascular events such as myocardial infarction or stroke. We assessed if the dual SGLT1/2 inhibitor sotagliflozin improves ischaemic outcomes.
We did a prespecified secondary analysis of the SCORED trial, which was a double-blind, placebo-controlled, randomised clinical trial enrolling patients (aged ā„18 years) with type 2 diabetes, chronic kidney disease (estimated glomerular filtration rate [eGFR] 25ā60 mL/min per 1Ā·73 m2), and additional cardiovascular risk factors.
Patients in the sotagliflozin group had a significantly lower rate of total MACE than those in the placebo group (4Ā·8 events per 100 person-years vs 6Ā·3 events per 100 person-years; hazard ratio [HR] 0Ā·77 [95% CI 0Ā·65ā0Ā·91]; p=0Ā·0020). Interaction analyses suggested a consistent effect of sotagliflozin on total MACE among stratified subgroups without evidence of heterogeneity. Additionally, sotagliflozin significantly reduced the rate of myocardial infarction (1Ā·8 events per 100 person-years vs 2Ā·7 events per 100 person-years; HR 0Ā·68 [0Ā·52ā0Ā·89]; p=0Ā·0041) and stroke (1Ā·2 events per 100 person-years vs 1Ā·8 events per 100 person-years; HR 0Ā·66 [0Ā·48ā0Ā·91]; p=0Ā·012) compared with placebo.
Sotagliflozin reduced MACE, with independent reductions in myocardial infarction and stroke, among patients with type 2 diabetes, chronic kidney disease, and additional cardiovascular risk. The ischaemic benefit on both myocardial infarction and stroke has not been previously observed with other SGLT inhibitors and warrants investigation of combined SGLT1 and SGLT2 inhibition as a possible underlying mechanism.
Comment in the Lancet: Sodiumāglucose co-transporter inhibitorsāwho would have guessed?
āPrediction is very difficult, especially about the futureā; whether it is the Nobel laureate Niels Bohr or others who have spoken on this matter, this is definitely true and a demanding reality in medical research.1 For the pharmaceutical industry, predicting the effectiveness of drugs is a major concern, and finding a blockbuster drug is challenging but highly warranted. Few people had predicted the broad effects of the sodiumāglucose co-transporter (SGLT) inhibitor class when initially developing a diabetes drug that increased glucose excretion in urine. In the early phases of developement, SGLT inhibitors received little interest and attention even among diabetologists, as increased glucose in urine was considered to give unpleasant side-effects. Fortunately, several pharmaceutical companies developed and investigated their SGLT inhibitor compounds, including cardiovascular safety profiles. Today, the well known era of the SGLT inhibitor class, with extension of their diabetes indication to the prevention and treatment of heart failure and kidney disease even in patients without diabetes, is remarkable.
Canagliflozin is also an SGLT1 inhibitor but way less than sotagliflozin:
Spotlight on ertugliflozin and its potential in the treatment of type 2 diabetes: evidence to date
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adssx
#1405
Before everyone jumps to sotagliflozin: this paper did not find differences between sotagliflozin and other SGLT2 inhibitors other than an āincreased risk of AKI in sotagliflozinā vs dapa and empa, which āmay dilute the preventive effect of SGLT2 blockade, compared with more SGLT2āselective agentsā.
acute kidney injury (AKI)
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