Effects of SGLT2 Inhibitors beyond Glycemic Control—Focus on Myocardial SGLT1

Sayour, Alex Ali; Ruppert, Mihály; Oláh, Attila; Benke, Kálmán; Barta, Bálint András; Zsáry, Eszter; Merkely, Béla; Radovits, Tamás

doi:10.3390/ijms22189852

Cited by 15 publications

(14 citation statements)

References 84 publications

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“…Further investigation is required to understand possible mechanisms behind the association of genetic variation in SGLT1 with favourable LV GLS. As SGLT1 is highly expressed on cardiomyocytes 16 and higher LV myocardial SGLT1 expression is associated with more advanced cardiac remodelling and reduced systolic function, 17 further investigation is required to understand if genetic variation in SGLT1 leads to improved LV systolic function through direct cardiac effects (as opposed to mediation through improved glucose tolerance). The incremental benefit of SGLT1 inhibition in the setting of SGLT2 inhibition requires further understanding, as genetic variation in SGLT2 is also associated with reduced HF risk.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation in sodium glucose co‐transporter 1 and cardiac structure and function at middle age

et al. 2022

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AimsThe effects of inhibition of sodium glucose cotransporter (SGLT)-1, as opposed to SGLT2, on cardiovascular structure and function are not well known. We assessed the associations of a missense genetic variant of SGLT1 with cardiac structure and function. Methods and resultsWe evaluated associations of a functionally modifying variant of SLC5A1 (rs17683011 [p.Asn51Ser]), the gene that encodes SGLT1, with cardiac structure and function on echocardiography among middle-aged adults in the Coronary Artery Risk Development in Young Adults Study. Of 1904 participants (55.3 ± 3.5 years, 57% female, 34% Black), 166 (13%) White participants and 18 (3%) Black participants had at least one copy of rs17683011. There were no significant differences in age, sex, body mass index, glucose, or diabetes status by the presence of the rs17683011 variant. In Black participants, the presence of at least one copy of the rs17683011 variant was significantly associated with better GLS compared with those without a copy of the variant after covariate adjustment (À15.8 ± 0.7% vs. À14.0 ± 0.1%, P = 0.02). Although the direction of effect was consistent, the association between the presence of at least one copy of rs17683011 and GLS was not statistically significant in White participants (À15.1 ± 0.2% vs. À14.8 ± 0.1%, P = 0.16). There were no significant associations between rs17683011 and other measures of LV structure, systolic function, or diastolic function. Conclusions The rs17683011 variant, a functionally modifying variant of the SGLT1 gene, was associated with higher GLS among middle-age adults. These exploratory findings require further validation and suggest that SGLT1 inhibition may have beneficial effects upon LV systolic function.

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Section: Discussionmentioning

confidence: 99%

Genetic variation in sodium glucose co‐transporter 1 and cardiac structure and function at middle age

et al. 2022

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“…The role of SGLT1 which has a broader distribution in the intestine and heart might add extra benefit [16]. Experiments in mice suggest that canagliflozin reprograms metabolism , modulates nutrient-sensitive pathways with activation of AMPK, and inhibition of mTOR , independent of insulin or glucagon sensitivity or signaling [21].…”

Section: Introductionmentioning

confidence: 99%

“…Although several mechanisms have been proposed [16, 17], it is generally believed that by shunting substantial amounts of carbohydrates into the urine, SGLT2 inhibitors-mediated glycosuria results in a progressive shift in fuel utilization toward fatty substrates and ketogenesis, partly through an increase in glucagon, and decrease in insulin levels [18-20]. The role of SGLT1 which has a broader distribution in the intestine and heart might add extra benefit[16]. Experiments in mice suggest that canagliflozin reprograms metabolism, modulates nutrient-sensitive pathways with activation of AMPK, and inhibition of mTOR, independent of insulin or glucagon sensitivity or signaling [21].…”

Section: Introductionmentioning

confidence: 99%

“…Several large cardiovascular or renal outcome trials of SGLT2 inhibitors have been carried out and showed benefit in patients with diabetes[11-13] or without diabetes[14, 15]. Although several mechanisms have been proposed [16, 17], it is generally believed that by shunting substantial amounts of carbohydrates into the urine, SGLT2 inhibitors-mediated glycosuria results in a progressive shift in fuel utilization toward fatty substrates and ketogenesis, partly through an increase in glucagon, and decrease in insulin levels [18-20]. The role of SGLT1 which has a broader distribution in the intestine and heart might add extra benefit[16].…”

Section: Introductionmentioning

confidence: 99%

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Canagliflozin extends life span and leads to less weight gain in C57BL6 male mice

Habeos

Filippopoulou

Kanakis

et al. 2022

Preprint

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SGLT2 inhibitors are widely prescribed drugs for type 2 diabetes and heart failure. It seems that their beneficial health effects are multifaceted and not only limited to the amelioration of glycemic profile. It is suggested that SGLT2 inhibitors-induced glycosuria causes a metabolic shift that mimics the fasting response. It is also known that calorie restriction leads to enhanced longevity in mice. Thus, we hypothesized that long-term treatment of mice with SGLT2 inhibitors might extend their life span. To this end male C57BL6 mice at the age of 4 months were put on a normal chow diet or on a diet supplemented with 200 mg/kg canagliflozin. The canagliflozin-treated mice showed lower body weight gain over time and increased life span. The median survival of control mice was 107.5 weeks, while that of the canagliflozin-treated group was 112.5 weeks (p=0.011). No difference was seen in the presence or severity of cataracts. This study showed for the first time an enhanced median survival of canagliflozin-treated male mice with a homogeneous genetic background (C57BL6). Further analyses are in progress to elucidate the metabolic adaptations and mechanisms underlying this effect.

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“…The authors provided an overview of physiological cardiomyocyte Na + handling and its deterioration in heart failure, and then proceeded to describe the salutary effects of the gliflozins on Na + homeostasis by influencing sodium/proton exchanger (NHE)-1 activity, late sodium currents, and calcium/calmodulin-dependent kinase II (CaMKII) activity [ 4 ]. Given the aforementioned controversy surrounding the absence of myocardial SGLT2, Sayour et al reviewed the effects of dual SGLT1/2 inhibitors, such as sotagliflozin, and explored the additional benefits afforded by SGLT1 inhibition [ 6 ]. In addition, the authors elegantly demonstrated the clinical significance of myocardial SGLT1 inhibition and how this blockade might factor into the clinical benefits of SGLT2 inhibitors [ 6 ].…”

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confidence: 99%