For purely iron-related discussions, I recommend we continue in one of those threads:
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The Role of Glucagon in the Acute Therapeutic Effects of SGLT2 Inhibition
And then there is this freaky paper:
Uncoupling Insulin Sensitivity From Longevity: A Sex-Dependent Effect of Hepatic Glucagon Signaling
https://onlinelibrary.wiley.com/doi/10.1111/acel.70349
“ Glucagon, a key hormone in maintaining euglycemia during fasting, also exerts broad metabolic effects, including regulation of lipid oxidation, adiposity, insulin sensitivity, and metabolic rate. However, its role in aging and longevity remains largely unexplored, a significant omission given the extensive research on dietary restriction and insulin signaling in lifespan modulation. Here, we investigated the impact of hepatic glucagon receptor (GCGR) signaling on lifespan using a liver-specific GCGR knockout (LKO) mouse model. While male LKO mice exhibited normal lifespan, female LKO mice displayed a significant reduction in survival. Strikingly, and in contrast to prevailing expectations based on metabolic improvements, this shortened lifespan in females occurred despite marked enhancements in metabolic health, including reduced body weight and adiposity, preferential glucose oxidation, elevated metabolic rate, and enhanced glucose tolerance and insulin sensitivity throughout adulthood.”
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In patients with type 2 diabetes (T2D) treated with ICDs, the arrhythmic effect of empagliflozin appears more pronounced in men than in women, according to a subanalysis of the EMPA-ICD trial published Jan. 22 in JACC: Asia.
The randomized, double-blind EMPA-ICD study evaluated 150 patients across 31 centers in Japan. The study included men and women aged ≥20 years with T2D and cardiovascular disease who were being treated with an ICD or cardiac resynchronization therapy defibrillator (CRT-D). The patients (83% men) were randomized 1:1 to receive either empagliflozin 10 mg daily or placebo between April 2019 and April 2021. Patients were evaluated for adverse events and clinical status every three months.
The primary endpoint, detected by ICDs/CRT-D over 24 weeks, was the change in the number of ventricular arrhythmias (VA), including nonsustained ventricular tachycardia, as well as sustained ventricular tachycardia and ventricular fibrillation.
Looking at the primary outcome in men, there was a significant reduction in the number of VA events in the treatment group while they increased in the placebo group (–2.10 events vs. +2.25 events; p<0.001). In contrast, in women there was a slight increase in VAs in the empagliflozin group while there was a slight decrease in placebo group (+0.55 vs. –0.08 events; p=0.35). This translated to a rate ratio in men of 0.33 for empagliflozin vs. placebo (p<0.001), a 67% reduction in arrhythmia events. In women, there was no significant difference between groups, with a rate ratio of 1.78 (p=0.35). Moreover, a significant interaction between sex and treatment was observed, suggesting a sex-specific treatment response (p=0.006).
Miyo Nakano, MD, et al., note several limitations to their analysis, including the small number of female participants, the short follow-up period and the lack of diversity within the patient population. Despite limitations, they write “these results suggest that sex-related differences in arrhythmic substrate, comorbidities and pharmacokinetic properties of SGLT2 inhibitors may influence treatment response.” Furthermore, research is needed to understand these sex-differences in treatment and pharmacokinetics to develop appropriate treatment strategies in women.
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Zydus Lifesciences announced tentative approval from the US FDA for its Dapagliflozin Tablets (5mg and 10mg). This SGLT2 inhibitor, used for type 2 diabetes, targets a significant US market segment where the reference drug (Farxiga) reported annual sales of USD 10,486.9 million. The approval signifies Zydus’s expanding product portfolio in the crucial US market and adds to its 430 US FDA approvals. Zydus Lifesciences Secures Tentative USFDA Approval for Key Diabetes Drug
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Among study subjects, 1563 (7.8%) experienced recurrent cerebrovascular events. SGLT2 inhibitor users showed lower recurrence of cerebral infarction compared to metformin users (adjusted hazard ratio=0.84, p=0.010). Among the types of cerebrovascular diseases, ischemic stroke was associated with a significantly lower risk of recurrence in SGLT2 inhibitor users than metformin users (aHR=0.70, p=0.020). In the SGLT2 inhibitor group, concurrent use of DPP4 inhibitors was associated with a reduced risk of cerebrovascular event recurrence (aHR=0.69, p=0.011).
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Is PANK1 (pantothenate kinase 1) activation the potential longevity pathway of SGLT2i? See: Fascinating information about SGLT2i and heart failure
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SGLT2i exposure was associated with significantly reduced risk of suicidality (aHR 0.75, 95% CI 0.71–0.79), all-cause mortality (aHR 0.55, 95% CI 0.52–0.57), and hospitalization (aHR 0.71, 95% CI 0.69–0.72).
I don’t have access to the full paper here but I think that they looked at all SGLT2 users with BD, so those with T2D, CKD, or HF, whereas past studies usually look at T2D only.
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This is in people with bipolar disorder. If you don’t have BD, you can ignore that study. Why? Because people with BD already suffer from increased ACM and not only from cause-specific mortality (such as suicide). So SGLT2i might be fixing something that’s causing increased ACM, but only in BD physiology. We don’t know that this applies to people without BD. If people with BD had the same mortality apart from causes such as suicide (against which apparently SGLT2i are effective) as people without BD, then this would be relevant to people without BD. But they don’t - they have higher ACM. Therefore we can’t say that this would necessarily apply to non-BD people (i.e. SGLT2i lowering ACM).
All-cause and cause-specific mortality among people with bipolar disorder: a large-scale systematic review and meta-analysis
https://www.nature.com/articles/s41380-023-02109-9
“All‐cause mortality was increased in people with BD (RR = 2.02, 95% CI: 1.89–2.16, k = 39). Specific‐cause mortality was highest for suicide (RR = 11.69, 95% CI: 9.22–14.81, k = 25). Risk of death due to unnatural causes (RR = 7.29, 95% CI: 6.41–8.28, k = 17) and natural causes (RR = 1.90, 95% CI: 1.75–2.06, k = 17) were also increased.”
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The part about suicide seems interesting to be even for people without BD who might be suicidal.
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Sure. Although it might be argued that people with BD have a different etiology of suicide than people without BD. As usual in such situations, it’s always good when such a signal (in this case lower suicide risk) is confirmed in other populations (without BD in this case), similar to how SGLT2 heart benefits were confirmed in non-diabetic people. But yes, this is nice insofar as there were some claims that SGLT2 increase depression - it seems if anything the opposite might be true (not a huge effect either way).
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It’s also good that basically SLGT2i cancels out the BD excess mortality (based on the 2.02 you sent). That’s combining two different papers using different methodologies and databases, etc. But potentially if you look at the same database and if you’d see that BD + SGLT2i has a lower ACM than no BD (and no SGLT2i) then that would be a strong signal.
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Absolutely. Note, the paper I posted is very robust, with huge data set, so we can be pretty confident in those numbers. At this point, the class effect of SGLT2i in various contexts is well established, and now what is of interest is which individual SGLT2i has the biggest impact on a given outcome and risk profile. After all, we as individuals take a specific drug, so we are interested in “is it dapaglifozin, or empagliflozin, or canagliflozin best for my vulnerability X”.
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So, we should develop rudimentary guidelines for which flozin to take. @CronosTempi @adssx want to give it a shot?
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That doesn’t make the result correct. A friend of mine who’s doing that kind of data mining studies told me that there were so many methodology details that can change the outcomes. Since then I don’t trust anything anymore 
(such as excluding or not those who study abroad!)
But in this particular case, they founs “All‐cause mortality was increased in people with BD (RR = 2.02, 95% CI: 1.89–2.16, k = 39)”. If it’s 1.89 and if the other paper is correct then potentially SGLT2i lower ACM vs non BD people. Not if it’s 2.16.
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I take dapagliflozin. I don’t think we have much data to conclude. Those who love mice might prefer canagliflozin. Those who love mechanistic reasoning and MR studies might prefer sotagliflozin (dual SGLT1 + 2 inhibitor).
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I don’t see how the Simpson’s paradox is related to what I said.
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People with BD have a certain ACM, as do people with other morbidities. It’s very hard to group them together with all SGLT2i and try to compare ACMs across all these disparate cohorts.
And also, if you look at ACM itself, what is that composed of? They try to separate cause specific to BD, such as suicide, death from unnatural causes etc., but really we should just look at deaths from “natural causes”, here given as - (RR = 1.90, 95% CI: 1.75–2.06, k = 17).
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Use of Sodium-glucose cotransporter 2 (SGLT 2) inhibitor is associated with reduced emergency room visits and hospitalizations in patients with Chronic obstructive pulmonary disease (COPD) and type 2 Diabetes Mellitus
https://www.sciencedirect.com/science/article/abs/pii/S0954611124002944
SGLT-2 Inhibitors and the Risk of Chronic Obstructive Pulmonary Disease Exacerbations and Mortality in Chronic Obstructive Pulmonary Disease Patients
The clinical effectiveness of sodium-glucose co-transporter-2 inhibitors on prognosis of patients with chronic obstructive pulmonary disease and diabetes
https://www.nature.com/articles/s41467-025-60582-y
Sodium–Glucose Cotransporter 2 Inhibitor Use and Risk of Liver-Related Events in Patients With Type 2 Diabetes: A Meta-analysis of Observational Cohort Studies
Here is a list of top 10 causes of death in the USA in 2024:
- Heart disease: 683,491
- Cancer: 619,876
- Accidents (unintentional injuries): 197,449
- Stroke (cerebrovascular diseases): 166,852
- Chronic lower respiratory diseases: 145,643
- Alzheimer’s disease: 116,022
- Diabetes: 94,445
- Nephritis, nephrotic syndrome, and nephrosis: 55,081
- Chronic liver disease and cirrhosis: 52,274
- Suicide: 48,824
Try to evaluate how many of these are impacted by SGLT2i. Question: should SGLT2i be added to the water supply?
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New paper (pay walled), mouse model, apparently shows damage and scarring of distal renal tubules due to the high concentration of glucose being excreted from the kidneys.
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