The US Food and Drug Administration (FDA) has expanded the indication of dapagliflozin (Farxiga, AstraZeneca) to include treatment of heart failure (HF) across the full spectrum of left-ventricular ejection fraction (LVEF) ― including HF with mildly reduced ejection fraction (HFmrEF) and with preserved ejection fraction (HFpEF).
The sodium-glucose cotransporter 2 (SGLT2) inhibitor was previously approved in the US for adults with heart failure with reduced ejection fraction (HFrEF).
The expanded indication is based on data from the phase 3 DELIVER trial, which showed clear clinical benefits of the SGLT2 inhibitor for patients with HF regardless of left-ventricular function, as reported previously by theheart.org | Medscape Cardiology.
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Canagliflozin still appears to be the better drug for diabetes control.
Empagliflozin is possibly better than either canagliflozin or dapagliflozin for heart problems.
It’s difficult to determine which is best overall. I guess it depends on one’s particular health issues.
“The model predicted longer survival for empagliflozin versus canagliflozin, dapagliflozin
“Conclusions”
In healthy participants, canagliflozin 300 mg provided greater 24-h UGE, a lower RTG and smaller PPG excursions than dapagliflozin 10 mg.”
https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.12418
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I am very concerned about the Klotho target protein, as it is an extremely important and critical marker for anti-aging. Of course, a few years ago, papers pointed out that FGF23 protein is the key to klotho protein. However, according to this paper, whether it is FGF23 protein or klotho protein, the effect of canagliflozin is better than that of empagliflozin.
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Excellent article, thank you.
I saw a recent post on here about Canagliflozen negatively impacting bone density in mice. Was that removed? Searching for it but nothing is coming up.
Its here: Canagliflozin Compromizes Bone Morphology and Density and Increases Fracture Risk In Mice and Humans
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@baimayangji can you elaborate on your concerns? It seems up-regulation of KL would be a good thing at least in the setting of APOE4 variant Alzheimer’s in the brain. I’m guessing likely SGLT2 inhibitors don’t cross the BBB though.
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According to the conclusion of the paper, it seems that Canagliflozen can increase the expression of klotho protein
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“Empagliflozin has an antiaging effect, which may be related to reducing Sirt1-mediated oxidative stress.”
Can’t have too many anti-aging compounds, just ask Bryan Johnson. 
I wasn’t aware that Empagliflozin upregulated Sirt1. I have a bunch in my cabinet because I stopped taking it because it didn’t seem to have much effect on my blood glucose levels.
I guess I will start taking it again.
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Not sure about side-effect/risk side of the equation, but it does seem like there may be a a lot more in addition to glucose modulation
And Prof Nir Barzilai together with a former key director at NIA ranks Cana at the very top of a ranking of gerotherapeutics potential in humans - ahead of not only metformin, but also ahead of rapa and acarbose…. See eg Table 1 here
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I still take Canagliflozin occasionally if I am having a particularly high-carb meal.
Since I exercise, use time-restricted feeding, and have a current calculated BMI of 21.6, I am not sure there would be any particular benefit for me in taking it more often.
Upregulating Sirt1 would seem more beneficial to me. I of course could be wrong.
Yes - saying I think it might impact Sirt1 (and other not just glucose-lowering longevity pathways):
www.ahajournals.org/doi/full/10.1161/CIRCHEARTFAILURE.120.007197
And
By promoting a nutrient deprivation state, SGLT2 inhibitors upregulate the energy deprivation sensors AMPK and SIRT1, inhibit the nutrient sensors mTOR and insulin/IGF1, and modulate the closely linked hypoxia-inducible factor (HIF)-2α/HIF-1α pathways.
And
In overnutrition diseases, SGLT2 inhibitors affect the autophagy via various signaling pathways, including mammalian target of rapamycin (mTOR), sirtuin 1 (SIRT1), and hypoxia-inducible factor (HIF) pathways.
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Empagliflozin improves kidney senescence induced by D-galactose by reducing sirt1-mediated oxidative stress
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have received widespread attention because of their significant protective effects on the kidney. Previous studies have shown that Sirt1, as which is an antiaging protein, is closely related to the maintenance of redox homeostasis. The goal of this study was to determine whether empagliflozin could ameliorate D-galactose-induced renal senescence in mice, and examine the possible mechanisms of Sirt1. We constructed a rapid ageing model in mice by administering D-galactose. An ageing model was constructed by treating cells with high glucose. Treadmill and Y-maze tests were used to assess exercise tolerance and learning memory ability. Pathologically stained sections were used to assess kidney injury. Tissue and cell senescence were evaluated by senescence-associated β-galactosidase staining. The expression levels of P16, SOD1, SOD2 and Sirt1 were detected by immunoblotting. D-gal-treated mice exhibited significant age-related changes, as measured by behavioural tests and ageing marker protein levels. empagliflozin alleviated these ageing manifestations. In addition, Sirt1, SOD1 and SOD2 levels were downregulated in model mice and upregulated by empagliflozin treatment. Empagliflozin had similar protective effects at the cellular level, and these effects were reduced by the Sirt1 inhibitor. Empagliflozin has an antiaging effect, which may be related to reducing Sirt1-mediated oxidative stress.
Paywalled article:
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Thank you for those studies, the “Geroscience Repurposing” review article is fantastic. Here it is again for anyone who didn’t see it.
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Introduction Relationships between glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors and impact on kidney and cardiovascular outcomes are uncertain.
Conclusions The glycemic effects of canagliflozin are attenuated at lower eGFR but effects on kidney and cardiac end points are preserved. Non-glycemic effects may be primarily responsible for the kidney and cardioprotective benefits of canagliflozin.22
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TheracosBio launches lowest cost SGLT2 inhibitor Brenzavvy
US drug developer TheracosBio today announced that Brenzavvy (bexagliflozin), an approved oral sodium-glucose cotransporter 2 (SGLT2) inhibitor, is now available by prescription through the Mark Cuban Cost Plus Drug Company, a pharmacy benefit manager (PBM).
One 30-day supply of Brenzavvy is available for $47.85 plus shipping and handling, which TheracosBio says is the lowest price for any SGLT2 inhibitor on the market. In comparison, all other brand-name SGLT2 inhibitors on the market are priced at rates in the hundreds of dollars per month, with some 30-day prescriptions approaching $600 per month. TheracosBio’s business model is specifically designed to deliver effective medications for prevalent diseases while translating cost savings to patients.
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SGLT2 Inhibitors in Aging-Related Cardiovascular Disease: A Review of Potential Mechanisms
Population aging combined with higher susceptibility to cardiovascular diseases in older adults is increasing the incidence of conditions such as atherosclerosis, myocardial infarction, heart failure, myocardial hypertrophy, myocardial fibrosis, arrhythmia, and hypertension. sodium–glucose cotransporter 2 inhibitors (SGLT2i) were originally developed as a novel oral drug for patients with type 2 diabetes mellitus. Unexpectedly, recent studies have shown that, beyond their effect on hyperglycemia, SGLT2i also have a variety of beneficial effects on cardiovascular disease. Experimental models of cardiovascular disease have shown that SGLT2i ameliorate the process of aging-related cardiovascular disease by inhibiting inflammation, reducing oxidative stress, and reversing endothelial dysfunction. In this review, we discuss the role of SGLT2i in aging-related cardiovascular disease and propose the use of SGLT2i to prevent and treat these conditions in older adults.
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I’m in the Empagliflozin camp. I tried it for several months and it was quite effective at keeping my fasting blood sugar low. After I ran out I didn’t re-order. Since I don’t have type 2 diabetes, I am just trying different ways to keep my blood sugar lower than it is. The next combo that I am trying is linagliptin and acarbose. If that isn’t sufficient, I will add Empagliflozin.
Also:
“In conclusion, linagliptin and empagliflozin may be promising MARK4 inhibitors, which can further be exploited as potential lead molecules against MARK4-directed neurodegenerative diseases.”
“MARK4 is involved in several malignancies, including, diabetes mellitus, cancer and neurodegeneration. Repurposing approved drugs provides an alternative approach to developing safe and effective therapeutics against rapidly emerging diseases.”
“reductions from baseline in HbA1c were significantly greater with empagliflozin 10 mg/linagliptin 5 mg compared with the individual components but were not significantly different with empagliflozin 25 mg/linagliptin 5 mg compared with the individual components”
Generative AI is experimental. Info quality may vary.
"Empagliflozin is cheaper and more cost-effective than canagliflozin. Empagliflozin costs less and has higher quality-adjusted life years (QALYs) than canagliflozin.
Empagliflozin also has a lower incremental cost-effectiveness ratio (ICER) than dapagliflozin.
However, dapagliflozin-SoC is the most cost-effective strategy.
Empagliflozin is more effective than canagliflozin in reducing the risk of hospitalization for heart failure or cardiovascular mortality in patients with Type 2 diabetes.
https://pubs.acs.org/doi/full/10.1021/acsomega.2c06634
Cost-effectiveness of empagliflozin versus canagliflozin, dapagliflozin, or standard of care in patients with type 2 diabetes and established cardiovascular disease - PMC(cost,versus%20dapagliflozin%20and%20SoC%2C%20respectively.
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So far it looks like dapa > empa > cana wrt high efficacy for broad-spectrum protection and lower adverse events in the review studies I’ve seen. Curious if anyone has seen something different.
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