#642

Yes, but logically you must see some effect on blood glucose.

I’m a non- diabetic and I have trace/nil amount of urinary glucose (as measured using urinalysis reagent strip) but when I take an SGLT2 inhibitor I see a massive increase in urinary glucose of 500+ mg/dL.

If the body is excreting that amount of glucose it must surely have some effect on blood glucose

I did the urine test because I wanted to reassure myself that the meds I was sent were SGLT2 inhibitors

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#643

That’s logical but blood glucose is also affected by the liver adding glucose to the blood. I have always suspected that my liver adds more glucose than it needs to (based on my HbA1c). On the other hand, my blood sugar is always good when I am exercising hard for long periods of time. Other people bonk while I can keep going at a high level. So maybe my liver is optimized for performance vs longevity…?

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#644

Yes you’re right about the liver’s gluconeogenesis contribution to blood glucose.

Sorry, my bad, but I forgot to mention I’m on 2g of metformin a day, so I think my liver gluconeogenesis shouldn’t be contributing much to my blood glucose.

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#645

I’ve gone back and forth on this one for awhile. I’m not diabetic, but my morning fasting glucose is pretty high (105) unmedicated. hba1c was 5.2 this time, which is good for me I think it was 5.7 before. I did trial after trial on dapag and even used metformin for awhile trying to fix this. On average it does pretty well, I can’t say it always works.

I did sign up for the Cana thing and have my phone call tomorrow morning. Maybe I can learn something from them.

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#646

Like you my morning glucose level is always a little high, ~105, while my HbA1C is ~5.4%.

Because of my love/hate relationship with metformin, I stopped taking metformin for a while and tried taking Ceylon cinnamon and chromium. I had tried this in the past but it didn’t work.
After some further reading, I decided the dose and length of time I took it was too small and too short.

N=1 experiment: I am taking 3 grams of cinnamon in the morning and 3 grams+chromium in the evening before meals. After doing this for a week my fasting glucose levels are always below 100. I will stop taking the chromium in a few weeks to see if the cinnamon alone does the trick.

This is thought to work by raising insulin sensitivity.
The studies are small. No RTCs.

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#647

Yes, using cinnamon in your breakfast was one of the 10 glucose hacks from the GG video. I’m going to try that starting from tomorrow. I’m also considering an apple cider vinegar beverage before breakfast and dinner to cut down spikes. I’ll also eat my veggies first at dinner and add walnuts to my morning oatmeal.

Now, is there a good veggie to eat in the morning for breakfast? Cucumbers?

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#648

Celery sticks (with humus) to boost your NO

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#649

How about avocado? High fat high fiber low carb.

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#650

Your daily dose of recent good quality SGLTi papers:

Effect of SGLT-2 inhibitors on arrhythmia events: insight from an updated secondary analysis of > 80,000 patients (the SGLT2i—Arrhythmias and Sudden Cardiac Death) 2024

SGLT2i lowers the risks of AF and AF/AFL, and this favorable effect appeared to be particularly pronounced in patients with HFrEF, male gender, dapagliflozin, and longer follow-up (> 1 year). SGLT2i lowers the risk of SCD only in heart failure patients.

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Effects of dapagliflozin on cardiac function and short-term prognosis of patients with both acute myocardial infarction and type 2 diabetes mellitus 2024

Dapagliflozin can substantially improve the blood glucose and cardiac function of patients with both AMI and T2DM. It can lower the rate of readmission for heart failure, and provide various cardiovascular benefits besides hypoglycemic effect.

Empagliflozin ameliorates the impaired osteogenic differentiation ability of adipose-derived stem cells in diabetic osteoporosis by activating autophagy 2024

However, empagliflozin enhanced autophagy flux by promoting the formation of autophagosomes and acidification of autophagic lysosomes, resulting in an increase in LC3-II expression and a decrease in SQSTM1 expression. Furthermore, empagliflozin contributed to the reversal of osteogenesis inhibition in DOP-ASCs induced by a diabetic microenvironment.

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Vascular Endothelial Growth Factors and Risk of Cardio-renal Events: Results from the CREDENCE trial 2024

People with T2D and DKD with elevated levels of PlGF, sFLT-1, and PlGF/sFLT-1 ratio were at a higher risk for cardiorenal events. Canagliflozin did not meaningfully decrease concentrations of PlGF, sFLT-1, and VEGF-A.

GRP78 contributes to the beneficial effects of SGLT2 inhibitor on proximal tubular cells in DKD 2024

Beneficial effects of SGLT2 inhibitors on kidney function are well-known; however, their molecular mechanisms are not fully understood. We focused on 78 kDa glucose-regulated protein (GRP78) and its interaction with SGLT2 and Integrin ß1 beyond the chaperone property of GRP78. In STZinduced diabetic mouse kidneys, GRP78, SGLT2, and Integrin ß1 increased in the plasma membrane fraction, while they were suppressed by canagliflozin. The altered subcellular localization of GRP78/Integrin ß1 in STZ mice promoted epithelial mesenchymal transition (EMT) and fibrosis, which were mitigated by canagliflozin. High glucose conditions reduced intracellular GRP78, increased its secretion, and caused EMT-like changes in cultured HK2 cells, which were again inhibited by canagliflozin. Urinary GRP78 increased in STZ mice, and in vitro experiments with recombinant GRP78 suggested that inflammation spread to surrounding tubular cells and canagliflozin reversed this effect. Under normal glucose culture, canagliflozin maintained SERCA activity, promoted endoplasmic reticulum (ER) robustness, reduced ER stress response impairment, and protected proximal tubular cells. In conclusion, canagliflozin restored subcellular localization of GRP78, SGLT2 and Integrin ß1 and inhibited EMT and fibrosis in DKD. In non-diabetic CKD, canagliflozin promoted ER robustness by maintaining SERCA activity and preventing ER stress response failure, and contribute to tubular protection.

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#651

Is this good or bad? VEGF can drive cancer I think?

#652

Unclear to me as well. I found these:

The effect of SGLT2 inhibitors on the endothelium and the microcirculation: from bench to bedside and beyond 2023

They also demonstrated that empagliflozin upregulates VEGF levels, thus potentiating the survival and proliferation of endothelial cells. Indeed, STAT-3 and VEGF pathways have already been reported to have a mutual relationship. In support of these findings, dapagliflozin also restored VEGF expression in HCAECs after exposure to hypoxia-reoxygenation and counteracted the extent of apoptosis.

Nice diagram btw in this paper:

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Empagliflozin Induced Ketosis, Upregulated IGF-1/Insulin Receptors and the Canonical Insulin Signaling Pathway in Neurons, and Decreased the Excitatory Neurotransmitter Glutamate in the Brain of Non-Diabetics 2022

Following the first dose, empagliflozin induced significant elevations of pIGF-1R, pIR, and common downstream mediators of the IGF and insulin signaling pathways such as pY-IRS-1 and pAKT (with the caveat of high CV for the internal control) in NEVs. These changes indicate an activation of the IGF-1 and insulin signaling pathways in neurons. No NEV biomarker differences were observed after the last empagliflozin dose compared with baseline, perhaps due to a potential adaptation to repeated dosing. Our findings on the acute elevation of proteins of the IGF-1 and insulin signaling pathways detected in NEVs are important because these NEV biomarkers have been linked to AD diagnosis [42], age-related cognitive decline [43], grey matter volume and volume of white matter hyperintensities.
Similarly, the blunted VEGF-A responses of hyperglycaemic ECs were also restored by empagliflozin, which could be attributed to the restoration of the VEGFR-2 receptor levels on the EC surface.

The Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitor Empagliflozin Reverses Hyperglycemia-Induced Monocyte and Endothelial Dysfunction Primarily through Glucose Transport-Independent but Redox-Dependent Mechanisms 2023

Mentions that empagliflozin restores VEGF levels on endothelial cells.

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#653

Can you take empagliflozin with other vasodilators or BP medicines like sartans? Or is that just too much vasodilation?

#654

I’m taking jardiance 25, nebivolol 5mg and Telmisartan 80mg, no side effects. BP is in the perfect range.

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#655

I take dapagliflozin and telmisartan. I didn’t see any counter indication. SGLT2i and sartans are super common drug classes so it would be known if there was a counter indication.

A few papers argue that SGLT2i + ARBs combined have synergistic effects. See for instance: Mechanisms underlying the blood pressure-lowering effects of empagliflozin, losartan and their combination in people with type 2 diabetes: A secondary analysis of a randomized crossover trial 2022

In people with T2D, SGLT2 inhibition in combination with an ARB had a larger blood pressure-lowering effect versus placebo than either of the drugs alone. Our data further suggest that the mechanisms underlying these blood pressure reductions at least partially differ between these agents.
This may indicate that combination therapy may induce synergistic effects on blood pressure lowering, which is in line with a recently published meta-analysis, although we were underpowered to formally test this.

The meta-analysis cited above:

Efficacy and safety of combination therapy with sodium–glucose cotransporter 2 inhibitors and renin–angiotensin system blockers in patients with type 2 diabetes: a systematic review and meta-analysis 2021

Compared with ACEI/ARB alone, the combination therapy with SGLT2 inhibitors and ACEIs/ARBs in T2DM was effective and well-tolerated and could achieve additional effects including better control of blood pressure, improvement of renal outcomes, alleviation of long-term renal function and a decrease in blood glucose and body weight. The combination therapy showed an increased risk of hypoglycaemia.

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#656

Another more recent paper: Renoprotective potential of concomittant medications with SGLT2 inhibitors and renin-angiotensin system inhibitors in diabetic nephropathy without albuminuria: a retrospective cohort study 2023

In conclusion, SGLT2 inhibitors also have safeguarding effects in the stage of diabetic nephropathy without albuminuria, and the combined use of a SGLT2 inhibitor and a RAS inhibitor appears to be more effective than the single use of each.

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#657

Does it matter if -flozins are enterically or film coated? the abovementioned Invonka is film-coated…
also looking at Shreeji_impex now…

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#658

Enterically or film coated: no idea…

A few good articles:

Systemic and organ-specific anti-inflammatory effects of sodium-glucose cotransporter-2 inhibitors 2024

Evidence from animal models and human studies clearly demonstrate that sodium-glucose cotransporter-2 (SGLT2) inhibitors have systemic and tissue-specific anti-inflammatory effects that may be independent of glycemic control and weight loss.
SGLT2 inhibitors may achieve their anti-inflammatory effects through various mechanisms, including reduction of reactive oxygen species, inflammasome activation, intracellular sodium and calcium levels, circulating uric acid, and mitochondrial dysfunction.
The direct and indirect mitigation of inflammatory pathways by SGLT2 inhibitors may partially explain their cardiac and renoprotective effects. However, this remains to be formally demonstrated in human studies.

Comparison between sodium-glucose cotransporter 2 inhibitors and dipeptidyl peptidase 4 inhibitors on the risk of incident cancer in patients with diabetes mellitus: A real-world evidence study 2024

After controlling for relevant variables, the SGLT-2i cohort (aHR = 0.90, 95% CI = 0.87–0.93) had a significantly lower risk of developing cancer than the DPP-4i cohort, particularly when the SGLT-2i was dapagliflozin (aHR = 0.91, 95% CI = 0.87–0.95) or empagliflozin (aHR = 0.90, 95% CI = 0.86–0.94). Regarding cancer type, the SGLT-2i cohort’s risk of cancer was significantly lower than that of the DPP-4i cohort for leukaemia, oesophageal, colorectal, liver, pancreatic, lung, skin and bladder cancer.

Effects of SGLT2 Inhibitors with and without Metformin in High-Risk, Treatment-Naïve Patients with Diabetes 2024

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In high-risk, treatment-naïve diabetic patients, initiating SGLT2i therapy alone or in combination with metformin resulted in comparable cardiovascular and renal outcomes. These findings suggest that metformin might not be mandatory as a first-line treatment for achieving cardiovascular benefits in such patients.

Efficacy of empagliflozin as adjunctive therapy to citalopram in major depressive disorder: a randomized double-blind, placebo-controlled clinical trial 2024

Compared to the control group, patients treated with empagliflozin using repeated-measures ANOVA showed greater improvement in reducing the severity of depression symptoms over time (p value = 0.0001).

(I’ve been feeling way better in terms of mood since I started taking dapagliflozin, n=1 but the above findings confirm my intuition…)

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New Paper: Summary of the top FDA-approved Drugs that can be Repurposed as Gerotherapeutics / Geroprotectors
#659

They are film-coated. I believe this is mostly to do in order to discourage half/quarter dosing by doctors.

#660

They are film coated and it’s just to make it easier to swallow.

#661

I don’t view this argument as the sole reason behind the instructions not to halve the medication. It seems there may be an ulterior motive at play. The leaflet’s statement about not halving the pills, along with the peculiar shapes of some flozin medications, could be intentional efforts to discourage halving and ensure full dosage consumption. Studies have indeed shown that flozins can be effective at half doses or even every other day, potentially leading to significant cost savings for national insurers. However, if manufacturers allowed pill halving, it could result in reduced profits, especially since both doses are priced the same. Additionally, the fact that empaglifozin’s lower dose isn’t exactly half of the larger dose further supports this notion.

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