#856

At 12.5 mg, you’re getting 25% more than most people who start out at 10 mg. :wink:

1 Like
#857

As canagliflozin reduced lifespan in female mice:

  1. Did clinical trials show such a gender effect for T2D, CKD, HF or any other condition?
  2. Does the remark mean females should use a lower dose?
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#858

Checking this, it looks like indeed women might benefit less from SGLT2 than men:

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#859

Effect of SGLT2 inhibitors on heart failure outcomes and cardiovascular death across the cardiometabolic disease spectrum: a systematic review and meta-analysis 2024

SGLT2 inhibitors reduced cardiovascular death by 14% in patients with heart failure (HR 0·86 [95% CI 0·79–0·93]), 15% in patients with type 2 diabetes (0·85 [0·79–0·91]), 11% in patients with chronic kidney disease (0·89 [0·82–0·96]), and 13% in patients with atherosclerotic cardiovascular disease (0·87 [0·78–0·97]).
SGLT2 inhibitors reduced heart failure events and cardiovascular death in patients with heart failure, type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease. These effects were consistent across a wide range of subgroups within these populations. This supports the eligibility of a large population with cardiorenal-metabolic diseases for treatment with SGLT2 inhibitors.

Effect of preceding drug therapy on the renal and cardiovascular outcomes of combined sodium-glucose cotransporter-2 inhibitor and glucagon-like peptide-1 receptor agonist treatment in patients with type 2 diabetes and chronic kidney disease 2024

Although the renal composite outcome did not differ between the two groups, the win ratio of the GLP-1RA-first group versus the SGLT2 inhibitor-first group was significant. These results suggest that, in GLP-1RA and SGLT2 inhibitor combination therapy, the addition of an SGLT2 inhibitor to baseline GLP-1RA treatment may lead to more favourable renal outcomes.

Protective Mechanisms of SGLTi in Ischemic Heart Disease 2024

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Empagliflozin, a sodium-glucose cotransporter inhibitor enhancing mitochondrial action and cardioprotection in metabolic syndrome 2024

This review focuses on the mitochondrial mechanisms of empagliflozin, which underlie the anti-inflammatory and recover cellular functions in MetS cardiomyocytes, including stabilizing calcium concentration, mediating metabolic reprogramming, maintaining homeostasis of mitochondrial quantity and quality, stable mitochondrial DNA copy number, and repairing damaged mitochondrial DNA.

Safety of Empagliflozin: An Individual Participant-Level Data Meta-Analysis from Four Large Trials 2024

Total trial medication exposure was 19,727 patient-years for patients who received empagliflozin (n = 10,472) and 19,447 patient-years for placebo (n = 10,461). The percentages of patients with serious AEs, fatal AEs, and AEs leading to discontinuation were similar for both groups. The incidences of serious urinary tract infection and serious pyelonephritis or urosepsis were similar for both groups but higher for women taking empagliflozin versus placebo. Serious genital infections were not increased with empagliflozin versus placebo. There was a slight increase in ketoacidosis and serious volume depletion in patients who received empagliflozin versus placebo. The occurrence of serious acute kidney injury was lower with empagliflozin versus placebo. Empagliflozin was not associated with an increased incidence of severe hypoglycemia, bone fractures, or lower limb amputations. Empagliflozin is therefore considered safe in people without diabetes, the elderly, patients with very low estimated glomerular filtration rate, low body mass index, and HF. Safety is unaltered by blood pressure, concomitant medication for hypertension, HF, and immunosuppression.

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#860

Not sure if this has been posted before. This thread is quite long…

Patients ate more and yet (most) still lost weight after 90 weeks.

Eighty-six patients with type 2 diabetes (HbA1c 7.8 ± 0.8% [62 ± 9 mmol/mol], estimated glomerular filtration rate [eGFR] 89 ± 19 mL ⋅ min−1 ⋅ 1.73 m−2) received empagliflozin (25 mg/day) for 90 weeks with frequent (n = 11) assessments of body weight, eGFR, and fasting plasma glucose (FPG).

At week 90, weight loss averaged −3.2 ± 4.2 kg (corresponding to a median calorie deficit of 51 kcal/day [interquartile range (IQR) 112]). However, the observed calorie loss through glycosuria (206 kcal/day [IQR 90]) was predicted to result in a weight loss of –11.3 ± 3.1 kg, assuming no compensatory changes in energy intake. Thus, patients lost only 29 ± 41% of the weight loss predicted by their glycosuria; the model indicated that this difference was accounted for by a 13% (IQR 12) increase in calorie intake (269 kcal/day [IQR 258]) coupled with a 2% (IQR 5) increase in daily energy expenditure (due to diet-induced thermogenesis). This increased calorie intake was inversely related to baseline BMI (partial r = −0.34, P < 0.01) and positively to baseline eGFR (partial r = 0.29, P < 0.01).

Chronic glycosuria elicits an adaptive increase in energy intake. Combining SGLT2 inhibition with caloric restriction is expected to be associated with major weight loss.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4542276/

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#861

Empagliflozin Extends Lifespan While Reducing Physical Activity in Drosophila Melanogaster: Insights into Non-Glycemic Pharmacological Effects 2024

We tested the hypothesis that EMPA would promote and increase longevity and physical activity ¶ by providing adult virgin female Drosophila with either DMSO (vehicle) or EMPA in the diet at concentrations of 5 μM, 25 μM, and 50 μM. EMPA treatment resulted in a significant extension of median lifespan at all concentrations: 4% (p=0.049) for 5 μM, 24% (p=0.035) for 25 μM, and 8% (p=0.025) for 50 μM, compared with DMSO.

A higher concentration is not better for female flies, but +24% at the mid-range concentration! If the paper is correct, it might confirm that SGLT1 inhibition is not necessary for longevity benefits. (poke @Neo)

Kidney protective mechanisms of SGLT2 inhibitors: evidence for a hemodynamic effect 2024

In conclusion, mechanistic physiology studies and clinical trials both support glomerular hypertension as a final common pathway for CKD progression, which is directly targeted by SGLT2 inhibitors. This effect may, in part, explain the benefits of SGLT2 inhibitors in kidney disease across diverse CKD causes, including patients with and without diabetes. Rather than inducing anxiety, observation of an eGFR dip should generally reassure clinicians and patients that SGLT2 inhibition is achieving the desired hemodynamic effect and protecting long-term kidney function.

Cardiovascular outcomes associated with SGLT2 inhibitor therapy in patients with type 2 diabetes mellitus and cancer: a systematic review and meta-analysis 2024

Nine cohort studies involving 82,654 patients were included. SGLT2 inhibitor use was associated with a significantly lower risk of all-cause mortality (RR 0.46, 95% CI 0.31–0.68, P < 0.0001; I2 = 98%) and heart failure hospitalization (RR 0.49, 95% CI 0.30–0.81, P = 0.006; I2 = 21%) compared to non-use. The mortality benefit remained significant in patients receiving anthracycline chemotherapy (RR 0.50, 95% CI 0.28–0.89, P = 0.02; I2 = 71%).
SGLT2 inhibitor therapy is associated with lower risks of all-cause mortality and heart failure hospitalization in patients with concomitant diabetes and cancer. These findings suggest that SGLT2 inhibitors may offer cardiovascular benefits in this high-risk population. Randomized controlled trials are needed to validate these findings and evaluate the safety and efficacy of SGLT2 inhibitors in specific cancer types and treatment regimens.

3 Likes
#862

Do you know more about the cancer interactions more broadly of SGLTi?

#863

Nice with data across the evolutionary spectrum. And that this was in females.

Haven’t looked at the paper but want to note that median lifespan extension is often more related to healthspan extension than longevity!

(why ITP and other aging studies generally focus on what the impact is on maximum lifespan)

1 Like
#864

Nope, sorry, but I haven’t really looked at it.

Good point. It’s just a conference abstract so I’m afraid the data about the max lifespan hasn’t been published.

1 Like
#865

I’m no expert, but just logically thinking about it, less glucose floating around the body means less available for cancer cells to feed on. Surely that reduces the chance of a cancer taking hold.

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#866

Yes, but what is interesting is that rates of new cancer and rates of deaths from cancer are divided by two among SGLT2is users compared to other anti-diabetic drugs. So it’s probably not glucose-related. SGLT2is only have a modest effect on glucose levels anyway.

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#867

Wow, that is huge. Depending on the data, that could be one of the biggest reasons to consider SGLTi in healthy individuals

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#868

With the current medications available, getting to 100-110 seems fairly realistic even for couch potatoes.

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#869

Can you share more about this!

(Found some potentially different synthesis below)

—

Meta analysis does not seem to agree with meaningful reduction

Seventy-six trials encompassing 116,375 participants were selected. Overall risk of bias was low. SGLT2 inhibitors did not reduce/increase the overall risk of cancer (RR, 1.03; 95% confidence interval [CI], 0.96–1.10) and cancer mortality (RR, 0.99; 95% CI, 0.85–1.16). SGLT2 inhibitors likely result in little to no difference in the risk of breast (RR, 1.01; 95% CI 0.77–1.32) and bladder cancers (RR, 0.93; 95% CI 0.71–1.21). Trial sequential analysis provided evidence that the sample size was sufficient to avoid missing alternative results.

Specific cancers (MR studies):

For genetic evidence, genetically proxied SGLT2 inhibition reduced the risk of overall (odds ratio=0.56, 95%CI=0.38 to 0.82), advanced (OR=0.52, 95%CI=0.27 to 0.99) and early-onset (OR=0.27, 95%CI=0.11 to 0.72) prostate cancer.

In primary analysis, SGLT2 inhibition was associated with reduced risk of bladder cancer (OR: 0.98, 95% CI: 0.97-0.99) per unit lowering of HbA1c level. A protective association was also observed for prostate cancer with odds ratio = 0.31 (95% CI = 0.21-0.47). However, we did not discover a causal relationship between SGLT2 inhibition and kidney cancer (OR: 1.00, 95% CI: 0.99-1.00).

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#870

Here divided by 5: Canagliflozin - Another Top Anti-aging Drug - #334 by adssx

Here cancer‐related mortality divided by 2: Canagliflozin - Another Top Anti-aging Drug - #390 by adssx

Here divided by 2: Canagliflozin - Another Top Anti-aging Drug - #861 by adssx

Also, even more here for dapagliflozin: Effects of novel SGLT2 inhibitors on cancer incidence in hyperglycemic patients: a meta-analysis of randomized clinical trials 2022

Our meta-analysis showed that SGLT-2 inhibitors were significantly associated with an overall reduced risk of cancer as compared to placebo (RR = 0.35, CI 0.33–0.37, P = 0.00) with a particular effectiveness for dapagliflozin and ertuglifozin (RR = 0.06, CI 0.06–0.07 and RR = 0.22, CI 0.18–0.26, respectively). Network Medicine approaches may advance the possible repurposing of these drugs in patients with concomitant diabetes and cancer.

All the above in diabetic patients. Might not translate to normoglycemic people.

6 Likes
#871

Here’s a more recent meta-analysis of clinical trials: Sodium-glucose cotransporter 2 inhibitors and cancer: a systematic review and meta-analysis 2024

Compared to the placebo SGLT2 inhibitors did not significantly increase the overall incidence of cancer (RR 1.01; 95% CI 0.94–1.08; p = 0.82).
However, dapagliflozin did significantly reduce the risk of bladder cancer by 47% (RR 0.53; 95% CI 0.35–0.81; p = 0.003).
Dapagliflozin reduced the risk of respiratory cancer by 26% (RR 0.74; 95% CI 0.55–1.00; p = 0.05). SGLT2 inhibitors (particularly mediated by dapagliflozin and ertugliflozin but not statistically significant) were associated with a greater risk of renal cancer than the placebo (RR 1.39; 95% CI 1.04–1.87; p = 0.03).

Trials last about 1y. So, I think it’s normal not to see effects. The finding for renal cancer might be concerning but cohort studies do not corroborate it: Sodium–Glucose Cotransporter 2 Inhibitors and Risk of Bladder and Renal Cancer: Scandinavian Cohort Study 2022

Use of SGLT2 inhibitors, as compared with GLP-1 receptor agonists, was not associated with a statistically significant increase in risk of bladder cancer (adjusted HR 0.88 [95% CI 0.59–1.31]) or renal cancer (adjusted HR 1.09 [95% CI 0.73–1.63]) (Table 1). In additional analyses, the adjusted HR did not increase with time since cohort entry (Table 1). In several sensitivity analyses, including those with adjustment for additional variables such as smoking and glycated hemoglobin, the findings did not differ materially from those of the main analyses (Table 1).

Given that MR studies did not find much and that dapagliflozin seems to be an outlier (in both clinical trials and longitudinal studies), the potential positive effects might be off-target and might not be class effects.

5 Likes
#872

The SGLT1 vs 2 debate is still on: The SGLT2 inhibitor canagliflozin, but not dapagliflozin or empagliflozin, ameliorates vascular calcification in a mouse model of nephrocalcinosis 2024

One more potential mechanism: The effect of dapagliflozin on anemia in patients with CKD 2024

The use of dapagliflozin for eight months resulted in a significant elevation in hemoglobin levels in patients with CKD. Further studies can explore of better understanding of the effect and confirm the mechanisms that explain this finding. Elevation of hemoglobin with SGLT2is may be closely linked to the reduction of cardiovascular mortality and heart failure.

Association between sodium–glucose cotransporter-2 (SGLT2) inhibitors and macular degeneration in patients with diabetes: a nationwide population-based study in Taiwan 2024

Compared to non-SGLT2i cohort, patients who received SGLT2i had a significantly lower risk of MD (adjusted hazard ratio = 0.70, 95%CI = 0.66–0.75).
We found that SGLT2is has a strong protective effect against MD in patients with diabetes. SGLT2is may have benefits beyond glycemic control in patients with DR. However, additional clinical and experimental studies are required.

Blood pressure reduction with empagliflozin in Japanese patients with type 2 diabetes and cardiovascular diseases: a post-hoc sub-analysis of the placebo-controlled randomized EMBLEM trial 2024

Empagliflozin therapy, compared to placebo, reduced systolic/diastolic BPs (mean group difference in change from baseline to week 24; −5.9 [95% confidence interval (CI), −10.4 to −1.4] mmHg/−2.9 [95% CI, −6.2 to 0.4] mmHg) and MAP ( −3.8 [95% CI, −7.0 to −0.7] mmHg).

Newer Glucose-Lowering Drugs and Risk of Gout: A Network Meta-Analysis of Randomized Outcomes Trials 2024

Compared with placebo, SGLT2 inhibitors were significantly associated with decreased risk of gout (RR, 0.51; 95% CI, 0.29–0.91) while both GLP-1RAs and DPP-4 inhibitors have no significant effects on gout risk. There were no significant differences between SGLT2 inhibitors and GLP-1RAs (RR, 0.75; 95%CI, 0.31–1.82) and between GLP-1RAs and DPP-4 inhibitors (RR, 0.39; 95%CI, 0.14–1.10).

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#873

After reading this entire thread, I am definitely considering starting empaglifozin asap.

Lots of evidence about lots of different benefits. Only fear about weight loss (I’m already very thin).

Is there any evidence of the effects on the gastro system, on the microbiota? (my Achilles’ heel)

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#874

I’m not sure that the weight loss effect are universal and that they apply to people already thin (contrary to semaglutide for instance).

Some papers (I probably posted them in this thread) suggest that the effects of SGLT2i are off target via microbiota rebalancing. But that’s just an assumption at this stage.

1 Like
#875

I wanted some clarification on this topic, so I asked Dr. Oracle and here was his answer. Quite interesting and informative, IMO, so I figured I’d pass it along:

Vascular Calcification in Chronic Kidney Disease vs. Atherosclerosis

Differences in Pathogenesis

Vascular Calcification in Chronic Kidney Disease (CKD)

Occurs primarily in the medial layer of the arterial wall (medial calcification)

Involves transformation of vascular smooth muscle cells (VSMCs) into an osteoblast-like phenotype

Driven by dysregulated mineral metabolism, including elevated calcium, phosphate, and parathyroid hormone levels

Atherosclerotic Calcification

Occurs primarily in the intimal layer of the arterial wall (intimal calcification)

Associated with inflammatory processes and lipid deposition within the atherosclerotic plaque

Driven by traditional cardiovascular risk factors, such as dyslipidemia, hypertension, and diabetes

Clinical Implications

Both forms of vascular calcification are associated with increased cardiovascular morbidity and mortality.

In CKD patients, medial calcification contributes to increased arterial stiffness and left ventricular hypertrophy, leading to cardiovascular complications.

Atherosclerotic calcification is a marker of advanced atherosclerotic disease and increased risk of myocardial infarction and stroke.

Treatment Considerations

CKD-related Vascular Calcification

Strict control of mineral metabolism (calcium, phosphate, and parathyroid hormone levels)

Use of non-calcium-based phosphate binders (e.g., sevelamer, lanthanum carbonate)

Vitamin K supplementation (potential inhibition of vascular calcification)

Atherosclerotic Calcification

Management of traditional cardiovascular risk factors (lipid-lowering, blood pressure control, glycemic control)

Antiplatelet and anticoagulant therapy for secondary prevention

Caveats and Guidelines

There are no specific guidelines for the treatment of vascular calcification in CKD or atherosclerosis.

Treatment strategies are based on managing the underlying disease processes and risk factors.

Early detection and monitoring of vascular calcification through imaging techniques (e.g., computed tomography, ultrasound) are recommended in high-risk populations.

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