adssx
#1125
Sodium-glucose co-transporter 2 inhibitors for all-cause and cardiovascular death in people with different stages of CKD: A systematic review and meta-analysis 2024
In people with CKD, treatment with SGLT2is compared to placebo reduced the risk of cardiovascular death by 14% (hazard ratio [HR] .86; 95%CI .79-.94), all-cause death by 15% (HR .85; 95%CI .79-.91) and MACEs by 13% (HR .87; 95%CI .81-.93). A consistent treatment effect was observed across eGFR-subgroups (≥60 mL/min/1.73 m2: HR .82, 95%CI .65-1.02; <60 mL/min/1.73 m2: HR .86, 95%CI .77-.96, p-subgroup difference = .68) and KDIGO risk-categories (low, moderate, high and very high) (p-subgroup difference = .69) for cardiovascular death; reduction in the risk of all-cause death tended to be greater in the highest KDIGO risk categories.
That’s good news!
Worldwide burden of antidiabetic drug-induced sarcopenia: An international pharmacovigilance study
Antidiabetic drugs showed significant associations with sarcopenia, with SGLT2 inhibitors exhibiting the strongest association. Notably, despite numerous reports, GLP-1 RAs, did not show a significant association.
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That’s quite bad that SGLT2I and Metformin are associated with sarcopenia. That’s very very bad unless I’m missing something here?
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adssx
#1127
It’s one paper based on about 500 cases of sarcopenia and they note: “This signal was not observed in older individuals (≥ 65 years) but was significant in the 18–64 age groups.”
So we need more data but at least it’s reassuring regarding GLP-1RAs.
2 Likes
Seems logical to me. If you’re constantly lowering glucose levels with something like SGLT2 inhibitors without giving your body enough fuel to rebuild, muscle loss could be the outcome, especially in “healthy” individuals who don’t necessarily need glucose lowering to that degree. Muscle needs glycogen to recover and grow, so if you’re not managing the refeeding process properly, sarcopenia makes sense as a risk.
That’s why I limit moderate dose empagliflozin to just 3-4 days a week around cardio, where the glucose burn is more beneficial, and I avoid it completely on weightlifting days when glucose is key for muscle recovery. Working so far…
9 Likes
tj_long
#1129
In my mind, it’s quite the opposite. In endurance training, glucose is key for recovery, while in strength training, protein is crucial. This is also reflected in the diets of endurance athletes compared to bodybuilders/strength athletes. When I was younger, I was able to build muscle quite well even though I was in ketosis for over a year, with no issues. Of course, calories need to be in a surplus.
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Interesting perspective! For me, the focus on cardio days is more about depleting ATP and activating AMPK. By lowering glucose availability with moderate-dose empagliflozin, I aim to enhance this process. When glucose is limited, the body is forced to rely more on fatty acid oxidation, which depletes ATP stores more quickly and triggers AMPK activation along with other cascades such as FOXO, H2S, and p53. This shift improves mitochondrial efficiency, and supports long-term metabolic health. So, I am not focused on 40km under 2 hours, but rather on creating hormetic stress on body in a most “convenient” way.
However, when it comes to weightlifting and muscle recovery, I prefer to keep glucose levels available to fuel glycogen replenishment and muscle protein synthesis (mTOR up, AMPK down).
5 Likes
tj_long
#1131
Yes, my previous response was written entirely from the perspective of recovery/performance. Glucose does have its benefits for muscle growth, but for me personally, its effect doesn’t seem to be significant—individual differences are possible. Glucose triggers insulin secretion, and insulin promotes an anabolic state, but for example, a high-quality whey protein induces a strong insulin response even without glucose.
But back to the topic. I asked ChatGPT about this, and according to it, one mechanism for sarcopenia could be that, based on animal studies, glucosuria can also lead to the excretion of amino acids in the urine. I didn’t get any sources, so it could be ‘hallucination’ or pure mechanistic speculation.
3 Likes
LukeMV
#1132
My educated guess is if we lift weights, it’ll probably offset any minimal risk of sarcopenia, bone loss, etc
6 Likes
jnorm
#1133
You could also just up your calorie intake while on SGLT2i, although how much of the benefits are then lost? Maybe still there are benefits, as the anti-fibrotic effects (at least for heart) are present in the absence of diabetes:
Methods: The EMPATROPISM clinical trial (NCT 03485222) investigated the efficacy and safety of EMPA in non-diabetic HFrEF patients. 84 patients were randomized to EMPA 10mg daily for 6 months or placebo on top of optimal medical treatment, and were evaluated with cardiac magnetic resonance (CMR). IMF was assessed by CMR using extracellular volume (ECV) by T1 mapping. Aortic stiffness was quantified by pulse wave velocity (PWV) by CMR. The primary endpoint was change in LVEDV. Prespecified secondary endpoints were changes in ECV (ΔECV) and PWV (ΔPWV) at 6 months between both arms
Results: 80 patients completed the follow up period. There were no differences at baseline in LVEDV (220±75 vs 209±68mL for EMPA vs placebo, p=0.5) or LVEF (36±8 vs 37±8%, p=0.7). There were no differences at baseline in both groups in either ECV or PWV (Table). In the primary endpoint, EMPA-treated patients showed decrease in LVEDV and increase in LVEF (ΔLVEDV -25±25 vs -1±25mL, p<0.001; and ΔLVEF 6±4 vs 0±4%, p<0.001 for EMPA vs placebo). EMPA-treated patients exhibited a reduction in ECV (ΔECV -1.25±1.5 vs 0.3±1.4% for EMPA vs placebo, p<0.001), which demonstrates IMF regression with SGLT2i. EMPA-treated patients exhibited a reduction in PWV (ΔECV -0.6±1 vs 0.6±1.4 m/s for EMPA vs control, p<0.001), which indicates amelioration of aortic stiffness with SGLT2i
Conclusions: In HFrEF patients without diabetes, treatment with empagliflozin ameliorates IMF and aortic stiffness. This may explain the benefits of SGLT2i in HFrEF even in the absence of diabetes [ref]
Also some evidence that these effects are SGLT2-independent
3 Likes
mccoy
#1134
That’s my experience as well. Every time I try to moderate carbs, I go catabolic. No matter the amount of protein (although I could never go much above the quantity of 1.6 g/kg/d).
1 Like
tj_long
#1136
Are you compensating for the lower amount of carbs by increasing fat in your diet? Simply increasing protein probably won’t work - At least that’s been my experience.
Similarly, if I do endurance training for several weeks with too few carbs, I start to experience symptoms of overtraining. Maybe people are just different.
1 Like
mccoy
#1137
tj_long, yes, I tried to keep the regime isocaloric with plenty of fats, using cronometer as a daily tracker. Probably the energy intake drifted downward when I ceased using cronometer.
Here is where the individual genetic makeup probably makes the difference.
I’m not usually hungry, and sometimes, I eat less than usual. Periods with some caloric deficit might have sent a strong inhibitory signal via the AMPK cascade.
Also, I have an hypothesis supported by a single blood draw, which I’ll have to repeat.
That analysis showed very low fasting insulin and pretty low IGF-1, so it may be that I need carbs to keep these signals above the threshold needed to switch up mTOR to phosphorylate the downstream anabolic targets.
Even if carbs are substituted by fats, this takes the energy signal (AMPK) theoretically constant, but it may dim the Insulin-IGF1/PI3K/AKT signal. Which signal prevails probably depends on a host of individual factors too complex to clarify.
All the above, of course, keeping constant the mechanical signal given by resistance exercise.
Last but not least, let’s remember that the typical buildup diet of bodybuilders, also advised by Brad schoenfeld in his book, is based on carbs and protein, with not so much fats.
So, I presume it is not impossible to gain muscle mass on a low carb diet, only it’s not so easy and it depends probably on individuals.
@Rapan
Empa and Cana both meet primary end-points for other diseases. I agree, for specific indications (not aging itself) essentially treating diseases- Empa looks better on paper, that’s a fact.
Cana research on autoimmune though limited is not hypothetical, that’s not how that research should be interrupted. These are not rodent studies they are human and it’s not like talking about metformin and aging which you can describe as hypothetical… At this point, like 70% or drugs, physicians can use drugs off-label such as cana for rheumatic diseases and adaptive related autoimmunity. I had my rheumatologist prescribe it 18 months ago- harmless at least and helpful at best as it doesn’t cause hypoglycemia and the risks are low compared to other molecules for rheumatic diseases. Works great for my lupus, easy to test, either it lowers T-cells or it doesn’t, it’s quite standard and very measurable.
Do you have a background in medicine? Why did you describe it as hypothetical, do you mean not proven clinically? What are you reading to describe it as hypothetical?
2 Likes
What is in question for me is Cana’s effect on mitochondrial complex 1 which hosts most of it’s cancer benefits, unlike Empagliflozin. Complex 1 is a primary target for some cancers, Empagliflozin does not target this pathway.
Beyond, it’s effects on at modulating adaptive related autoimmunity deserves more discussion. Though I agree, not 100% actionable for first line in rheumatic diseases; hydroquinone is the go to, but there are some cases it cannot be used with some that are susceptible to the side effects- there are not many safe choices beyond that. I was one of them, hydroquinone affected my eye sight.
I brought this up not for a very simple paragraph on personal views on a quick google search, but to have a scientific debate and gain perspective from each other on very complex topics. At glance it might seen easy to interrupt but like anything there’s a lot to know.
Intention is not to necessarily discuss actionable recommendations but to dissect the incomplete data. Cana, after all was the drug used in the ITP and besides SGLT2, it has other direct targets that are unique than others within this class of drugs.
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For what it’s worth, my story: I take remogliflozin (not available in the US, but available in India; an SGLT2 inhibitor) as well as metformin. Remogliflozin requires a twice-daily dosing schedule and I like that as I eat twice daily and so I can dose so that I get peak blood levels at about the time that my blood sugar will spike. I don’t snack. I also exercise heavily daily (9000 steps on the backside of a dam) and so I burn lots of calories and have to replace them. I also watch my diet carefully, so eat nothing with added sugars (most everything at the grocery store!) or foods with inherently high sugar content (fruits). So I eat lots of meat, eggs, bacon, cheeses, no-added-sugar peanut butter, keto-friendly bread, etc.) Still I have such robust gluconeogenesis (my liver converting fats to glucose) that my blood sugar will run too high without treatment. Metformin is insufficient, hence the remogliflozin. I never suspected high ketones (and never checked) because I also use a CGM on and off and my BS just does not drop low enough to induce ketoacidosis, and my glucose actually rises when I “do my steps”. Regarding lactic acidosis, I have a lactate meter and I use it occasionally to check my lactate while doing my steps. I do “double steps” (so cover the 111 steps up on the dam by doing 56 double steps) X 4 consecutive sets to get my HR up to ~90% of my heart rate max (just for grins and hopefully slow my mental decline). I can get my lactate into the low 20’s with that, but within just 2 minutes of descending the steps, my lactate will drop precipitously to near normal. That is, my daily exercise pattern has induced my mitochondria to utilize lactate as a fuel source. So I don’t worry about a clinical lactic acidosis despite easily being able to drive my lactate so high, so quickly. For clarity, I am 73 yrs old. I spend ~10.5 hrs/wk doing my steps at the dam and when last tested, I achieved a very high METS. That is, I am not fat and pretty, but old and in good shape.
1 Like
mccoy
#1141
It’s surprising that you have high BS (how high?) with little or no carbs and constant exercise + metformin.
If you suspect an overwhelming gluconeogenesis, then you might try and moderate protein. I don’t know if fats can contribute to glycaemia significantly (by which mechanism?)
My identical twin brother has the same problem. I tried a friend’s CGM at his insistence and was surprised after a dinner of ribs (with BBQ sauce that of course as I soon later learned had brown sugar as its main ingredient) that my BS rose to nearly 300! So I bought a half dozen Dexcom G7 CGMs, gave one to my brother, and low and behold, he had the same problem. Upon learning this, we have independently modified our diets. He too exercises lots. As we have remarked to each other numerous times, “I can’t eat anything without raising my BS”. His doc did not want to put him on any meds, including no metformin despite him having a normal BMI, exercises more than 99% of those in his age group, and religiously follows a diet of low carbs. Crazy. So I supply him with meds. Our BSs now match on the same meds.
2 Likes
Pat25
#1143
Edit: redundancy. Poster already explained concern about other molecules.
adssx
#1144
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: Guardians against Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Heart Diseases 2024
Based on the existing evidence, the effects of SGLT2 inhibitors may potentially involve the restoration of mitochondrial biogenesis and alleviation of ER stress. Such consequences are achieved by enhancing adenosine triphosphate (ATP) production, preserving mitochondrial membrane potential, improving the activity of electron transport chain complexes, maintaining mitochondrial dynamics, mitigating oxidative stress and apoptosis, influencing cellular calcium and sodium handling, and targeting the unfolded protein response (UPR) through three signaling pathways including inositol requiring enzyme 1α (IRE1α), protein kinase R like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6).
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