Could you please send me links to these discussions? I don’t think I’ve read them.
I agree that these are different notions. Still, I think that “decreasing all-cause mortality” helps to reach the goal of “increasing maximum life span”. Preventing incurable diseases helps as well. And it turns out that in all longitudinal studies I found on people with T1D, T2D, CKD, or HF, after several years, we see lower all-cause mortality and lower comorbidities (cancer, Alzheimer’s, other dementia, Parkinson’s, depression, atrial fibrillation, arrhythmia, T2D, CKD, HF, etc.). [And often, empa or dapa perform a bit better than cana.] Given that diabetes + pre-diabetes + CKD + pre-CKD + HF + pre-HF = the vast majority of the US population above 65yo, one can assume SGLT2 will increase maximum lifespan in this group, and that it might translate to the general population.
Mendelian randomization studies I found, most of them don’t look at deaths/all-cause mortality unfortunately:
- “Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90).” (Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk 2018)
- “Genetically proxied SGLT1i was associated with 75% reduction in gout risk (OR 0.25; 95%CI 0.06, 0.99; p = 0.048) and 32.0 μmol/L reduction in serum urate (95%CI −56.7, −7.3; p = 0.01), per 6.7 mmol/mol reduction in HbA1c. SGLT1i was associated with increased levels of low-density lipoprotein cholesterol (0.37 mmol/L; 95%CI 0.17, 0.56; p = 0.0002) but not risk of coronary heart disease, stroke, or chronic kidney disease.” (Sodium-glucose cotransporter 1 inhibition and gout: Mendelian randomisation study 2022) (SGLTi indeed increase cholesterol a bit: “Canagliflozin showed the largest effect in increasing LDL-C (0.13 mmol/L), while Empagliflozin had the highest increase in total cholesterol (0.11 mmol/L).”)
- “Overall, genetically proxied SGLT-1i is associated with improved liver health, this may be underpinned by SGLT-1-specific mechanisms.” (Mendelian randomisation reveals Sodium-glucose Cotransporter-1 inhibition’s potential in reducing Non-Alcoholic Fatty Liver Disease risk 2023)
- “SGLT2 inhibition (per 1 SD, 6.75 mmol/mol [1.09%] lowering of HbA1c) was associated with lower risk of T2D and CAD (odds ratio [OR] 0.25 [95% CI 0.12, 0.54], and 0.51 [0.28, 0.94], respectively)” (SGLT2 Inhibition, Choline Metabolites, and Cardiometabolic Diseases: A Mediation Mendelian Randomization Study 2022)
- “Genetically predicted SGLT2 inhibition (per 1 SD decrement in HbA1c) was associated with reduced risk of T2DM (odds ratio [OR] = 0.63 [95% CI 0.45, 0.88], P = 0.006) and AF (0.51 [0.27, 0.97], P = 0.039)” (SGLT2 inhibition, circulating metabolites, and atrial fibrillation: a Mendelian randomization study 2023)
Anyway, @Neo, if you really believe in SGLT1 inhibition, I’d love to submit an application for sotagliflozin (“the first dual SGLT inhibitor”) with you for the ITP: About the ITP | National Institute on Aging Anyone else, feel free to join this effort!
The only comparison of dual SGLTi vs SGLT2i-only is this one and they conclude: Metabolic, Intestinal, and Cardiovascular Effects of Sotagliflozin Compared With Empagliflozin in Patients With Type 2 Diabetes: A Randomized, Double-Blind Study 2022
In summary, sotagliflozin and empagliflozin did not show any major differences in overall glycemic and BP control or in selected metabolic, urinary, and intestinal parameters. In contrast, mechanistic differences were confirmed. Inhibition of SGLT1 by sotagliflozin was accompanied by prolonged lowering of plasma GIP levels as well as a postprandial increase in aGLP-1. For the most part, the current study was unable to identify obvious features that would convincingly relate to a different clinical impact of dual versus single SGLT inhibition in patients with T2D, but the potential benefit of lower GIP levels on cardiovascular outcomes suggests the need for additional studies to determine if prolonged sotagliflozin-mediated lowering of plasma GIP levels contributes to improved cardiovascular outcomes observed with this drug.
The authors also make an interesting remark on GIP:
However, they highlight the effect of the two SGLT inhibitors, particularly sotagliflozin, on GIP levels, noting that recent research suggests that GIP inhibition may be cardioprotective, contrary to the development of GLP-1/GIP co-agonists to treat type 2 diabetes.
Walther and team suggest this paradox may be explained if GIP agonists work by “desensitizing” the GIP receptor, leading to a decrease rather than an increase in GIP receptor signaling.
(from a news article commenting on the paper Sotagliflozin effects differ from empagliflozin only at breakfast)
Also: Managing heart failure in diabetics with dual acting sotagliflozin—A review 2023
Sotaglifozin is equally effective at inhibiting SGLT-2 as the specific SGLT-2 inhibitors dapaglifozin and canaglifozin, although it is ten times more potent at inhibiting SGLT-1 than these drugs. Less is known about its impact on SGLT-1 in various tissues. According to the information available, sotaglifozin doesn’t appear to affect renal SGLT-1, indicating that its low affinity only has clinical effects in the gut and other tissues where SGLT-1 is highly expressed. Because sotaglifozin concentrations in the intestinal lumen is higher than that in the bloodstream as a whole, another explanation is that sotaglifozin functions as a powerful intestinal SGLT1 inhibitor [30].
