I think that semaglutide + SGLT2 together can be very powerful, wrt health benefits
However, I currently use semaglutide but very intermittently (one 7mg tablet every three weeks). This is for multiple reasons:
I still observe subtle noticeable effects .
I did not want to develop tolerance by taking the high recommended dose
I feel fatigue and loss of motivation if I am on a higher or a more continuous dose — even here I try to make sure that I don’t take it immediately before a deadline for example.
With respect to SGLT2 + Semaglutide:
Combining them increased my fatigue / led to slight hypoglyceamic feeling, which is not only not fun, but also makes me want to go eat a bunch to feel better.
I now look to use SGLT2 during the trough of semaglutide, and trough of rapamycin (especially if I’m taking a larger 25mg dose of empagliflozin), and when I am having carby and sugary meals (happens mostly while traveling, where I lean into being a ‘foodie’)
I feel like I’m in a good zone with this protocol.
Another reason for my intermittent dosing is because I’m conserving my current stack lol.
I have acarbose every day before starchy meals.
And metformin occasionally with rapamycin.
Have you tried the lowest dose instead (oral semaglutide 3 mg)? And why don’t you abandon acarbose and metformin for just daily SGLT2i + semaglutide 3 mg?
Ah yeah I used to use 3mg. I might have continued but I don’t have access to it now.
I don’t see a reason to abandon acarbose.
Maybe low dose daily SGLT2i once I have access to enough. But I hesitate during peak semaglutide because of what I mentioned, and also around peak rapa, because I do want to minimize any potential UTI.
I’ve mostly used 25mg empagliflozin, which I’ve occassionally halved (e.g. if I’ve taken 25 consecutive days in a row). I’ve tried cana before, but mostly empa.
From your reading, do you know if it’s only reabsorption of glucose that is inhibited by SGLT2is or are there other compounds too? Albuminuria is suggested in the diagram, I see. I wish somebody also measured the amount of plastics and PFAS that are eliminated due to SGLT2is (if any).
I do wonder if their oppositive effects on insulin are synergestic or cancel out some effects (for e.g. on appetite supression).
From what I read, effects are additive for weight loss, synergistic for blood pressure lowering, and complementary but non additive for Hb A1C reduction:
It’s interesting that they’re additive for several health benefits, but not for diabetes (based on HbA1C), given that they’re both originally diabetes medications!
Some experts have said that we may also look back on GLP-1 drugs as one of the greatest modern advancements in the treatment of chronic conditions. They’ve already shown promise for cardiovascular, liver and kidney disease, and some are now being tested on Alzheimer’s, sleep apnea, PCOS—even addictive behaviours, like gambling. That is ahugescope.
Are these drugs going to help all of these different conditions in a meaningful way? That’s unlikely. We don’t yet have enough data to say we should put this stuff in the drinking water, but there are encouraging signs of their benefits. Right now, we have excellent data for Type 2 diabetes, heart disease and obesity. We’re gonna get some excellent data for kidney disease in the next few months, then heart failure in the summer. We’ll have to wait a year or two for Parkinson’s and Alzheimer’s.
I lost 65 lbs of scale weight and gained 1kg of lean mass while on tirzepatide (Mounjaro). I got DEXA scans. If one gets adequate protein and lifts heavy weights at least 2x a week (I was doing 3-4, progressive overload), one does not have to lose muscle. There are many similar anecdotes online. Judging by the online forum participants, most people on these drugs are obese women who don’t lift weights. Of course they lose muscle. These are the people who are letting the drug do all the work for them (not even tracking calories and macros, etc.)
Btw, tirzepatide is generally regarded by those who have tried both to be vastly superior to semaglutide in terms of effectiveness and the side effect profile. Retatrutide is even better in some respects because one tends to have more energy (less fatigue) on it. Tirz usually begins working within a couple days of the initial injection, but with sema you have to slowly increase the dose because the side effects are otherwise often intolerable. Reta usually takes 2-4 weeks to kick in, but when it does, you simply have zero appetite. I wouldn’t waste time with semaglutide.
I think the fatigue comes from allowing caloric intake to drop too low. It’s easy to not eat enough and especially not eat enough carbs when you’re trying to prioritize hitting a protein target, because after protein and fat, you might not have a lot of room left in your energy budget for carbs. I suppose the keto people wouldn’t have this issue, but I don’t function well on a keto diet and needed some carbs.
I tracked calories in Cronometer, weighing and measuring everything, and tried to not let my deficit get too low.
The other thing was to exercise daily no matter what (well, sometimes Sunday off). I mostly just alternated cardio with weights, and I didn’t slack off in terms of intensity with either.
Now with retatrutide things are a little different because the glucagon receptor agonist activity seems to provide an energy boost (a common anecdote and my experience). Retatrutide feels better than tirzepatide, I think, partially because of this. You can eat more on reta but the pounds just fall off as if they’re getting torched in a metabolic furnace.
I’ve been taking oral semaglutide (Rybelsus) for the past month, with mixed results (I know it’s not nearly as bioavailable or effective as the injectable semaglutide, much less tirzepatide or retatrutide, but at least it’s branded Rybelsus (not a compounded generic), it’s affordable, and I know what I’m getting.
Anyway, at both the 7mg dose and 14mg, I’m getting significant sleep disruption per both subjective experience and per my Oura Ring Gen 3, which shows decreased sleep duration/quality, increased heart rate (about 10 BPM) and significantly decreased heart rate variability (HRV). The 7mg dose is more tolerable but also less effective suppressing my appetite. I increased to the 14 mg dose for a week, and the appetite suppression was far better, but the sleep disruption/fatigue was too much to handle, so I’ve gone back down to 7mg for the time being.
I’ve lost 10 pounds, all of which should be fat given that I’m still doing near-daily resistance training and maintaining protein intake via whey isolate powder, but I think I’ve plateaued with the weight loss on the 7mg dose. I’m going to try a few things to see if I can get HRV and heart rate back under control as well as daytime fatigue (which for me seems much more related to the sleep disruption than caloric deficit since I feel markedly better after a mid-day nap, but I’d prefer not to have to take naps). If I can make a dent in those parameters, I’ll try the 14mg dose again and see how it goes.
No idea. That’s why I wanted to test one month or two then measure insulin (and therefore HOMA-IR).
Yes, I’ve used many CGMs over the past 12 months. I could share screenshots but I think it’s useless because you need to know what I ate on that day to understand whether a peak/pattern is “normal” or not.
I take 50 mg acarbose whenever I have a more carb heavy meal (mostly when dining out). I tried to take it 2x daily but it didn’t improve things that much.
That’s a good point, and tirz and reta also tend to cause a heart rate increase (especially reta) and sleep disruption at least in the beginning. This is very commonly reported on the forums. And I also had a drop in HRV.
I only experienced the sleep issues from tirz for about 2 weeks before adjusting to it, but the first few days were really bad. I wonder if you would adjust to the 14 after a while.
The nice thing about injections is that they’re easy to adjust, of course. The jump from 2.5mg/wk to 5mg a week of tirz was brutal given that it was a doubling, so I just reduced it down to 3.5 for a few weeks. I also didn’t stick to once per week, adjusting that as hunger warranted. I suppose one can play with frequency with pills or injections though.
More generally, it’s worth mentioning that these medications certainly make weight loss possible, but I don’t think they make it as easy as people may think because the side effects really can be difficult to ensure for months on end. I was somewhat nauseous most days, but usually just a little bit. Enough to be uncomfortable but not incapacitated. It wasn’t fun and if I had to do it over again, I think I would have tried taking breaks.
The average given by the CGM (5.4 mmol/L = 97 mg/dL) is equivalent to Hb A1c of 5.0% (source). My latest Hb A1c from early March was 5.1%. So, CGM and blood test are in agreement.
The peak is OK. But I’m “yo-yo-ing” a lot, and when this happens, I feel terrible. That’s why Hb A1c isn’t a great KPI; the same average can correspond to different patterns:
Using the last 7 days of my latest CGM data, with dapagliflozin 10 mg daily + acarbose 50 mg just before “big” meals + “good carb” diet (no white rice but whole grain quinoa OK for instance):
≥ 130 mg/dL (7.2 mmol/L): 5 times/week
≥ 140 mg/dL (7.8 mmol/L): 3 times/week
≥ 150 mg/dL (8.3 mmol/L): 1 time/week
Latest HOMA-IR from early March: 1.4 (glucose: 4.6 mmol/L & insulin: 39.8 pmol/L).
High level it seems like you have definitely improved your glucose dynamics a lot.
(Depending how how you sleep/where you were the CGM the nigh time drops might just be about sleeping on the arm where you are wearing the CGM).
Based on the data you shared I’d probably be more focus on the insulin part of the equation than the glucose. You might still benefit from some more glucose optimization, but ideally not if the cost comes at increased insulin.
Wish we had continuous insulin measurements… I could see how someone having big problems with glucose (more than you have on the SGLT2i + Acar) might lower their insulin peaks via knocking down the glucose more when on GLP1-RAs. Might be the case for you too, but would def try and get as many insulin datapoints before and after the GLP1-RA experiment if you decide to do it.
Would also try and see if there is data in non-obese/non-bariatric surgery/non-diabetes humans and mice about the direction of insulin on GLP-1 meds.
Btw, what are your IGF-1 levels? If they are not as low as you’d like from a longevity phenotype you might be want to be a bit more concerned about risking to increase your insulin levels.
(the issue I don’t think we know enough about is also to what extent the GLP-1 impacted insulin levels are increased 24/7 and not just associated with the postprandial pattern of going up, but then down again).
Lastly, have you explored doing some of the non-medical things to lower glucose (more fiber, order of eating different foods, some movement after meals, using vinegar and things like cinnamon going into meals, finding ways to destress / lower cortisol levels, etc, etc, etc)?
I didn’t know that it could cause hypos. Do you have sources on this by any chance?
Besides the longevity risk–benefit assessment, I want to stop my post-(big) meal symptoms and improve my quality of life. If the cost is increased insulin, I might be OK with it.
Yes, I couldn’t find such data. The results of semaglutide for CKD will be published soon, so hopefully, the full results should show insulin levels before and after among non-obese and non-diabetic people.
I think I’ve never measured it. What should I read about this?
I do ~ 80% of these things (I’m also a Zoe client). It helps, but not enough.
