#682

The topic is when SGLTi could ”go big”

Once these start coming off patent I wonder if we will see a meaningful uptake in longevity circles and broader health optimizer world…

… case is building in a nice way

for that I think it’s needs to be like rapa and metformin - and accessible in the US directly at reasonable prices (and similar with Europe)

still for pioneers (and risk takers) like you and a portion of others on this forum in India may be great

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#683

Might have been already posted at some point but worth hammering this one down

Empagliflozin for Heart Failure With Preserved Left Ventricular Ejection Fraction With and Without Diabetes

In patients with heart failure and a preserved ejection fraction enrolled in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), empagliflozin significantly reduced the risk of heart failure outcomes irrespective of diabetes status at baseline.

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.059785

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#684

In patients with heart failure and a preserved ejection fraction enrolled in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), empagliflozin significantly reduced the risk of heart failure outcomes irrespective of diabetes status at baseline.

#685

I don’t know in the US but in Europe the issue isn’t price. It’s very easy (and free) to get prescribed dapa if you have T2D, HF or CKD. But for “longevity”: good luck finding one doctor prescribing it!

My dad just had a flutter ablation, there are articles showing SGLT2i potential to prevent atrial fibrillation and arrhythmias that are common post ablation. He’ll show that to his doctor but as it’s not officially approved for this indication I guess his doctor won’t prescribe it.

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#686

For the US for dapagliflozin for sure not before Oct 2025.

For other SGLT2i and other countries: :man_shrugging:

Here’s another generic manufacturer working on FDA approval for canagliflozin: Indoco Remedies gets tentative USFDA approval for Canagliflozin Tablets - Express Pharma

So hopefully by 2026 we’ll have generic cana, dapa, and empa available all around the world…

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#687

The Validation and Determination of Empagliflozin Concentration in the Presence of Grapefruit Juice Using HPLC for Pharmacokinetic Applications 2024

our results showed that the co-administration of grapefruit with empagliflozin should be cautiously monitored and avoided, in which grapefruit elevates the plasma level of empagliflozin.

:warning: Not a great journal or team but highly important if true given that many here take GFJ with rapa :warning:

Inhibition of sodium-glucose cotransporter-2 and liver-related complications in individuals with diabetes: A mendelian randomization and population-based cohort study 2024

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SGLT2 inhibitors vs. GLP-1 receptor agonists and clinical outcomes in patients with diabetes with/without atrial fibrillation 2024

For the AF cohort, SGLT2i vs. GLP-1RA was associated with a lower risk of hospitalization for heart failure (2.32 vs. 4.74 events per 100 person-years; hazard ratio (HR):0.48 [95% confidential interval (CI):0.36-0.66]), with no benefit seen for the non-AF cohort (P for homogeneity < 0.01). SGLT2i vs. GLP-1RA was associated with a lower risk of composite kidney outcomes both in the AF (0.38 vs. 0.79 events per 100 person-years; HR:0.47; [95%CI:0.23-0.96]) and non-AF cohorts (0.09 vs. 0.18 events per 100 person-years; HR:0.53; [95%CI:0.43-0.64]). There were no significant differences in the risk of major adverse cardiovascular events and all-cause mortality in those who received SGLT2i compared to GLP-1RA for the AF or non-AF cohorts.

(if someone has access to the full text I’d like to see the HRs for all-cause mortality, even if not statistically significant. They should also stratify results by BMI, I would expect GLP-1RA to reduce ACM more than SGLT2i in high BMI and less in normal BMI.)

Gut microbiota–tryptophan metabolism–GLP-1 axis participates in β-cell regeneration induced by dapagliflozin 2024

In summary, treatment with dapagliflozin in type 2 diabetic mice promotes β-cell regeneration by upregulating GLP-1 production, which is mediated via gut microbiota and tryptophan metabolism.

SGLT2 inhibitors: Beyond glycemic control 2024

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The clinical benefits of sodium–glucose cotransporter type 2 inhibitors in people with gout 2024

These medications have also been shown to lower serum urate concentrations, the causal culprit in gout risk, and are associated with a reduced risk of incident and recurrent gout, potentially owing to their purported anti-inflammatory effects. Thus, SGLT2 inhibition could simultaneously address both the symptoms of gout and its comorbidities.

Gout: One more indication for SGLT2i?! :heart_eyes:

Exploring the Efficacy of Sotagliflozin on Heart and Kidney Health in Diabetic Patients: A Comprehensive Meta-Analysis 2024

Patients taking sotagliflozin had a drastic decline in the number of deaths due to stroke and non-fatal myocardial infarction. Yet, there is no difference between the groups in terms of changes in mortality due to other causes or the glomerular filtration rate (GFR). Sotagliflozin demonstrated effectiveness in reducing the mortality rate related to heart failure and cardiovascular events when the dose was increased from 200 mg to 400 mg. Despite this, evidence is still needed to prove the renal protective action.

If I understand correctly, empagliflozin and dapagliflozin (SGLT2 inhibitors only) are approved for CKD while sotagliflozin and canagliflozin (dual SGLT1+2 inhibitors) are not (they’re approved for T2D + CKD and/or HF + CKD) and the above paper confirms that sotagliflozin’s renoprotective effect isn’t clear yet. So could SGLT1 inhibition be detrimental for kidneys?

Dapagliflozin in patients with heart failure and previous myocardial infarction: A participant-level pooled analysis of DAPA-HF and DELIVER 2024

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Safety and Effectiveness of Sodium-Glucose Co-transporter 2 Inhibitors on Glycemic Control in Patients with Type 2 Diabetes Mellitus Fasting during Ramadan: A Review 2024

Overall, the gathered evidence suggests that SGLT2 inhibitors constitute a safe and effective treatment option for most T2DM patients fasting during Ramadan.

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#688

lol​:joy::joy::joy:, seems like everything expires early in India.

#689

@adssx ”reactive hypoglycemia”. Is this caused by excessive insulin production?

I have had this happen in the context of athletic activity where if I ate carbs an hour before exercise (to “top off my glycogen stores”) I would get low blood sugar once I started exercising due to the double whammy of insulin and exercise induced uptake of glucose into muscles. I “solved” it by not eating carbs 3 hours before exercising.

How do SGLT2 inhibitors help with this issue?

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#690

Since SGLTi’s blunt the insulin response to a glucose load (by dumping some of the glucose into the urine), seems like this would reduce risk of reactive hypoglycemia.

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#691

In general, I don’t know. In my case, it’s not due to excessive insulin production so we didn’t really find the cause :man_shrugging:

Not sure it’s known, here’s a recent paper in the specific case of post-bariatric surgery reactive hypo: Use of SGLT2 inhibitors after bariatric/metabolic surgery: Risk/benefit balance 2023

On the other hand, SGLT2is may exert a favorable effect to reduce the risk of postprandial hypoglycemia, a complication reported among patients who have been treated with bariatric/metabolic surgery. An increased hepatic glucose production and a reduced production of interleukin-1β have been proposed as possible underlying mechanisms for this protective effect.

In general, SGLT2i shift metabolism towards a low-insulin, high-glucagon state: Sodium, Glucose and Dysregulated Glucagon Secretion: The Potential of Sodium Glucose Transporters 2022

Diabetes is defined by hyperglycaemia due to progressive insulin resistance and compromised insulin release. In parallel, alpha cells develop dysregulation of glucagon secretion. Diabetic patients have insufficient glucagon secretion during hypoglycaemia and a lack of inhibition of glucagon secretion at higher blood glucose levels resulting in postprandial hyperglucagonaemia, which contributes to the development of hyperglycaemia. […] While SGLT2 inhibitors aim at increasing glycosuria to decrease blood glucose levels, these inhibitors also increase circulating glucagon concentrations. Here, we review recent advances in our understanding of how SGLTs are involved in the regulation of glucagon secretion. […] In both type 1 and insulin dependent type 2 diabetic patients the role of glucagon, namely the response to hypoglycaemia is absent

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#692

@Davin8r this makes sense but I never understood the time course of the two actions. How long for blood glucose to impact insulin secretion (2 phases, I think) vs how long for kidneys to excrete the extra blood sugar? Perhaps the pancreas is faster than the kidney. Certainly SGLT2 helps with chronically elevated blood sugar and related insulin.

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#693

why no one speak about phlorizin from apple ? :stuck_out_tongue: it is a dual SGLT2 and 1 inhibitor

#694

Can you get it without all the sugar from the apple?

#695

Yes, just take an extract such as this one : https://fr.iherb.com/pr/life-extension-applewise-600-mg-30-vegetarian-capsules/87136

However, note that it is a O-glucoside that is hydrolyzed by β-glucosidase in the intestine, means poorly stable as it is… I dont know what is the % that can remains stable in the kidney to perform the inhibition on SGLT2, because its IC50 is VERY good (nM range, such as canagliflozin)

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#696

Exploring the association between weight loss-inducing medications and multiple sclerosis: insights from the FDA adverse event reporting system database 2024

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The following medications were not included in the analysis due to an inadequate number of reports (i.e. ⩽5): tirzepatide, orlistat, canagliflozin, and dapagliflozin.
Our findings suggest a potential consideration for repurposing anti-diabetic weight loss-inducing drugs including semaglutide, dulaglutide, and liraglutide (glucagon-like peptide-1 receptor agonists), empagliflozin (sodium-glucose cotransporter-2 inhibitor), and metformin (biguanide), for MS. This warrants validation through rigorous methodologies and prospective studies.

If you look at the excluded drugs in Table 1, tirzepatide and dapagliflozin look even more promising.

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#697

Is that based on # MS events / # other events?

#698

That’s how I did the maths, assuming that “No. reports of events other than MS” is somewhat proportional to the use of the drug. In any case, we need more data on this. There’s an ongoing trial of metformin for MS: https://www.mssociety.org.uk/research/explore-our-research/emerging-research-and-treatments/explore-treatments-in-trials/metformin Two weeks ago I met with the charity behind this trial and suggested to test next GLP-1RAs and SGLT2is but they didn’t seem super interested (not sure they were aware of what SGLT2i were…). I’ve just sent them the paper, wait and see. :roll_eyes:

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#699

Good review: SGLT2 Inhibitors – The New Standard of Care for Cardiovascular, Renal and Metabolic Protection in Type 2 Diabetes: A Narrative Review

Considering the wealth of data supporting these medicines, the Improving Diabetes Steering Committee (IDSC) expects SGLT2i therapies to take a more prominent role in future guidelines, potentially as a key component of standard care for newly diagnosed individuals with T2DM.
The expansive evidence-base indicates that the proven advantages of SGLT2is in slowing or preventing the onset of serious CVRM complications and maintaining durable health outcomes should outweigh (or place into context) manageable issues (e.g. mycotic genital infections) and perceived potential risk of rare adverse events that may have previously delayed or deterred prescribing of these medicines for the right individuals.
Putting the evidence in to practice, the IDSC supports the implementation of a rapid sequential approach to T2DM management comprising early combination therapy with metformin and an SGLT2i agent for most people with T2DM, rather than gradual stepwise intensification of treatment over an extended period. Using this method, metformin should be initiated and titrated to an appropriate dose during the first month, with the SGLT2i agent added (unless contraindicated) after 4 weeks (supported by a telephone appointment, where possible) or by a review after 12 weeks (at latest). For high-risk individuals (high CV risk, CVD or kidney disease), an SGLT2i should be started at diagnosis, with or without other diabetes therapies, in line with ADA/EASD and KDIGO guidelines

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What's the Deal with Renewed Interest in Metformin?
#700

Open Access Paper:

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.124.069568

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#701

Methods: This was a collaborative trial-level meta-analysis from the SGLT2i meta-analysis cardio-renal trialists consortium, which includes all phase 3, placebo-controlled, outcomes trials of SGLT2i across three patient populations (diabetes at high risk for atherosclerotic cardiovascular disease [ASCVD], heart failure [HF], or chronic kidney disease [CKD]). The outcomes of interest were MACE (composite of CV death, myocardial infarction [MI], or stroke), individual components of MACE (inclusive of fatal and non-fatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i vs. placebo were meta-analyzed across trials and examined across key subgroups (established ASCVD, prior MI, diabetes, prior HF, albuminuria, CKD stages and risk groups).

Results: A total of 78,607 patients across 11 trials were included: 42,568 (54.2%), 20,725 (26.4%), and 15,314 (19.5%) were included from trials of patients with diabetes at high risk for ASCVD, HF, or CKD, respectively. SGLT2i reduced the rate of MACE by 9% (HR 0.91 [95% CI 0.87-0.96], p<0.0001) with a consistent effect across all three patient populations (I 2=0%) and across all key subgroups. This effect was primarily driven by a reduction in CV death (HR 0.86 [0.81-0.92], p<0.0001), with no significant effect for MI in the overall population (HR 0.95 [0.87-1.04], p=0.29), and no effect on stroke (HR 0.99 [0.91-1.07], p=0.77). The benefit for CV death was driven primarily by reductions in HF death and sudden cardiac death (HR 0.68 [0.46-1.02] and HR 0.86 [0.78-0.95], respectively) and was generally consistent across subgroups, with the possible exception of being more apparent in those with albuminuria (Pint=0.02).

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