Great info on this thread. Exactly what I was looking for. Thanks,
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Another possible mechanism behind SGLT2 benefits is increased magnesium levels. I wonder if we can get away with consuming slightly less magnesium if we take an SGLT2, saving money on a magnesium supplement.
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Unless you are consuming magnesium by Lb per day, I doubt youād save much but interesting to know SGLT2ās help increase magnesium levels.
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This database at the website āDrugs@FDA: FDA-Approved Drugsā has a wealth of information, here for empagliflozin:
Approval Date(s) and History, Letters, Labels, Reviews for NDA 204629 [empagliflozin]
I am looking for data on efficacy of doses lower than 10 mg like 6.25 mg.
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Great review: Applications of SGLT2 inhibitors beyond glycaemic control 2024
Sodiumāglucose cotransporter 2 (SGLT2) inhibitors reduce the risk of kidney disease progression in people with or without diabetes as well as the risk of acute kidney injury and hyperkalemia.
SGLT2 inhibitors reduce the risk of cardiovascular death and heart failure hospitalization among people with type 2 diabetes mellitus and have beneficial effects on key heart failure outcomes irrespective of diabetes status or left ventricular ejection fraction.
SGLT2 inhibitors modestly lower systolic and diastolic blood pressure without a significant increase in risk of hypotensive episodes and have modest benefits for weight loss.
Other benefits of SGLT2 inhibitors include improvements in liver outcomes in people with metabolic dysfunction-associated steatotic liver disease, reduced risk of symptomatic kidney stone events, improvements in anaemia outcomes and potential reductions in the risk of new-onset atrial fibrillation and new-onset diabetes.
SGLT2 inhibitors have a generally favourable adverse effect profile but are associated with increased risk of genital mycotic infections and a small increased risk of diabetic ketoacidosis; they should be used with caution in people with unstable volume status owing to the risk of hypovolemia.
Prescription of SGLT2 by clinicians and patient adherence are suboptimal despite strong evidence for the efficacy and cost-effectiveness of these therapies.
SGLT2-independent effects of canagliflozin on NHE3 and mitochondrial complex I activity inhibit proximal tubule fluid transport and albumin uptake 2024 (@Neo)
Strikingly, canagliflozin but not empagliflozin reduced fluid transport across cell monolayers, and dramatically inhibited endocytic uptake of albumin. These effects were independent of glucose and occurred at clinically relevant concentrations of drug.
Mice given a single dose of canagliflozin excreted twice as much urine over 24 h compared with empagliflozin-treated mice despite similar water intake.
Though sodium-glucose co-transporter-2 inhibitors (SGLT2i) increase the risk of mycotic genital infections (MGI) and possibly urinary tract infections (UTI), their cardiovascular benefits in patients with heart failure far outweigh those risks.
Currently, the mechanism of the protective effect of SGLT2 inhibitors on myocardial infarction is not yet understood.
Mendelian randomization analysis uncovered a causality between SGLT2 inhibition and myocardial infarction.
Based on proteome-wide mendelian randomization, APOB and CCL17 were seen as mediators in the protective effect of SGLT2 inhibition against myocardial infarction.
The impact of sodium-glucose cotransporter inhibitors on gut microbiota: a scoping review 2024
Not a great paper, but funny finding: Effect of sacubutril/valsartan and dapagliflozin on athletic performance; Can the popular cardiac medications of recent years be used as doping agents? 2024
In the study, the swimming performances of three groups of rats were evaluated by dividing them into control, sacubitril/valsartan and dapagliflozin groups. [ā¦] In the comparison of dapagliflozin and control groups, a statistical difference was observed starting from the 10th swimming session, and when the total and average swimming times were compared, the p values were <0.001 and <0.001. In triple analysis, a statistical difference was seen from the 9th swimming session until the end of the experiment. [ā¦] Our study showed a limited positive effect of sacubitril/valsartan on athletic performance. The impact of dapagliflozin on athletic performance was shown to be particularly significant.
The results show that DAPA promotes WAT ābrowningā and improves metabolic disorders. [ā¦] These findings provide a rational basis for the use of DAPA in treating obesity by promoting the browning of white adipose tissue.
SGLT-2 Inhibitors: Focus on Dapagliflozin 2024
Comparative analysis with other SGLT-2 inhibitors suggests dapagliflozinās potential superiority in preventing heart failure. Compared to empagliflozin, it has more extended effects, contributing to stable sodium diuresis, reduced blood pressure fluctuations, and potentially lower cardiovascular disease risks. However, it leads to less urinary glucose excretion compared with canagliflozin.
Compared with GLP-1 receptor agonists, the SGLT-2 inhibitor-GLP-1 receptor agonist combination was associated with a 30% lower risk of major adverse cardiovascular events (7.0 v 10.3 events per 1000 person years; hazard ratio 0.70, 95% confidence interval 0.49 to 0.99) and a 57% lower risk of serious renal events (2.0 v 4.6 events per 1000 person years; hazard ratio 0.43, 0.23 to 0.80). Compared with SGLT-2 inhibitors, the GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a 29% lower risk of major adverse cardiovascular events (7.6 v 10.7 events per 1000 person years; hazard ratio 0.71, 0.52 to 0.98), whereas serious renal events generated a wide confidence interval (1.4 v 2.0 events per 1000 person years; hazard ratio 0.67, 0.32 to 1.41).
In this cohort study, the GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a lower risk of major adverse cardiovascular events and serious renal events compared with either drug class alone.
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Great post @adssx
Can anyone access this one - would be very valuable to see how much of this effect is SGLT1i driven vs by SGLT2i
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Unfortunately, empagliflozin failed to affect outcomes in a new trial of heart attack survivors. I havenāt dug into the details yet, but with a mean follow up of 18 months and all of the positive effects weāve seen in other trials, I sure would have expected to see better results.
I do wonder if the 10mg dose was too low.
https://www.medscape.com/viewarticle/empagliflozin-fails-reduce-events-after-acute-mi-2024a10006kn
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Them too, which is probably why we saw a negative result, it was under-powered for the composite heart failure + ACM? 10 mg is about as effective as 25 mg so it is unlikely that played a role.
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10mg is about as effective as 25mg for diabetes, but is it established that 10mg is as effective for heart failure and other potential cardiovascular benefits?
This is a good point. Dapagliflozin 10 mg (equivalent to empagliflozin 25 mg) succeeded where empagliflozin failed. Also, the survival curve for empagliflozin 10 mg looks good and I wonder if 6 more months could have reached significance. See more on these trials here: Canagliflozin - Another Top Anti-aging Drug - #703 by adssx
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Yes, there isnāt a large difference for outcomes.
Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes: https://www.nejm.org/doi/full/10.1056/NEJMoa1504720
A longer trial seems what the people in the medscape article, who might be the researchers, think.
It kind of looks like an exponential curve in the empa trial I linked where placebo really takes off towards the end.
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I would call this pretty significant, it seems that with empa the number drops from about 14 to 8 which is about 40% drop, not too shabby if you ask me and that is for 48 months which as someone rightly noted the benefit seems to increase as time passes, so at perhaps longer intervals the benefits might get even more significant.
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Weāre talking about different trials and statistical significance not clinical significance. The study I linked and showed a graph from was statistically significant. The point is it was very long (48 months), compared to the other one (18 months).
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Gotcha, nevertheless I do like this particular study. While I understand that 48 seems long, these classes of drugs seem to be maintenance drugs (and not one you take it for a while and it fixes the problem/ailment) you need to take for a long time, or even maybe forever. Taking that into consideration then 48 months may not seem too long. So, if it showed a 40% improvement in 48 months who knows maybe in 20 years the improvement might be 80%, but even 40% at 48 months good enough for me to continue talking it. Been taking it for last 3-4 months with no side effects and anecdotally some great result least of which seems to be lower inflammation and much harder to gain weight, or as I would like to call much harder to get fat, so this could be one of the drugs I might stick with for a long, long time. Long live Indian pharmacies.
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Provisionally accepted, not a great team, not a great journal butā¦
SGLT2 inhibition was associated with a lower risk of death due to cardiac causes (odds ratio [OR]= 0.983, [95% CI =0.972, 0.993], P = 0.0016).
Furthermore, SGLT2 inhibition was linked to a lower risk of cardiac arrest ( [OR]= 0.097, [95% CI =0.013, 0.742], P = 0.025). SGLT2 inhibition was linked to a lower risk of CHD ( [OR]= 0.957, [95% CI =0.932, 0.982], P = 0.0009).Our study identified the causal roles of SGLT2 inhibition in venous thrombolism. SGLT2 inhibition may influence death due to cardiac causes through venous thrombolism. Additionally, SGLT2 inhibition was associated with reduced risk of cardiac arrest and CHD.
Four abstracts from the American Thoracic Society International Conference, authored by different teams, suggest that SGLT2i might also protect the lungs!
- SGLT2 Inhibitor Attenuates Pulmonary Arterial Remodeling Through PPARĪ³ Activation
- SGLT2 Inhibitors and Pulmonary Arterial Hypertension: A Retrospective Study
- Implications of Sodium-glucose Cotransporter 2 (SGLT-2) Inhibitor Use in the Incidence of Asthma and Chronic Obstructive Pulmonary Disease (COPD) Amongst Patients With Type 2 Diabetes Mellitus: āWhen subjected to further logistic regression analysis, we found a decreased incidence of asthma (OR-0.117, CI:0.01-0.92) and COPD (OR-0.264, CI:0.09-0.73) in patients on SGLT-2i compared to those without. Conclusion: We observed a decreased incidence of obstructive airway diseases like asthma and COPD in T2DM patients on SGLT2i. The Diabetes-asthma association has been well established and the pathogenesis of this association has been attributed to the chronic proinflammatory state which would also explain the association with COPD as well. SGLT-2i have been shown to inhibit NLRP3 inflammasome activation, thereby leading to a decrease in proinflammatory cytokine levels.ā
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Association of Sodium-glucose Cotransporter 2 (SGLT-2) Inhibitor Use and Chronic
Obstructive Pulmonary Disease (COPD) Outcomes Amongst Patients With Type 2 Diabetes
Mellitus: āFurther logistic regression analysis showed similar findings of decreased rates of ED visits (OR-0.065, CI:0.118-0.354), number of hospitalizations (OR-0.169, CI:0.055-0.52), and COPD exacerbations (OR-0.224, CI:0.068-0.735) in patients on SGLT- 2i compared to those without. Conclusion: SGLT-2i use was associated with a decreased incidence of COPD outcomes such as ED visits, number of hospitalizations and COPD exacerbations, thereby demonstrating a protective effect of SGLT-2i use in COPD. The rationale behind these results could be explained by the literature evidence of reduced proinflammatory markers and increased anti-inflammatory markers seen with SGLT-2i use in T2DM patients via inhibition of NLRP3 inflammasome activation in multiple tissues including heart, liver, kidney and lungs.ā
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Any bit of evidence helps. Thanks for posting what you find. Truly, longevity protocols should probably include an SGLT2I.
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Venous thrombolism was associated with death due to cardiac causes ([OR]= 1.031, [95% CI =1.005, 1.057], P = 0.0199). Mediation analysis showed evidence of indirect effect of SGLT2 inhibition on death due to cardiac causes through venous thrombolism(Ī² = -0.0015ļ¼[95% CI = -0.0032 -0.0002], P=0.042), with a mediated proportion of 8.9% (95% CI=1.2%, 18.7%) of the total.
Our study identified the causal roles of SGLT2 inhibition in venous thrombolism. SGLT2 inhibition may influence death due to cardiac causes through venous thrombolism. Additionally, SGLT2 inhibition was associated with reduced risk of cardiac arrest and CHD.
Since the studies are in diabetics itās tough to know if itās just that effect or would help in healthy, non diabetics?
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I agree. Still. The first paper is in cells and mice and the second one is on SGLT2i users without saying for which use so there could be people without T2D (but still CKD or HF), so itās reasonable to conjecture that SGLT2i might protect the lungs of non diabetic people as well. Needs more studies of course.
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Comment on this: SGLT2 inhibitors: not every drug has the same effect
Despite these limitations, this manuscript provides crucial information about the effects of SGLT2i in PT and highlights the need for further investigation of the potential molecular mechanisms of gliflozins. Recent basic, clinical, and population studies revealed multiple conditions where SGLT2i (and/or dual SGLT1/2 inhibitors) have beneficial effects, and there may be scenarios where one SGLT inhibitor has improved efficacy over another due to potential off-target effects.
Preprint by a good team that confirms off-target mechanisms: Sodium-glucose co-transporter 2 Inhibitors Act Independently of SGLT2 to Confer Benefit for Heart Failure with Reduced Ejection Fraction in Mice 2024
In a mouse heart failure model, SGLT2i treatment, but not generalized SGLT2 knockout, resulted in improved systolic function and reduced pathologic cardiac remodeling. SGLT2i treatment of the SGLT2 knockout mice sustained the cardiac benefits, demonstrating an off-target role for these drugs. This benefit is independent of metabolic changes, including ketosis. The mechanism of action and target of SGLT2i in HF remain elusive.
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