Key result
In non-diabetic mice with cardiac pressure overload, sotagliflozin attenuated cardiac hypertrophy and fibrosis, but it did not attenuate cardiac injury in high fat diet-induced diabetic mice.
Why the study?
While selective SGLT2 inhibition reduces heart failure worsening and cardiovascular death irrespective of diabetes, the effects of dual SGLT1/2 inhibition on cardiac outcomes in non-diabetic and diabetic models remained to be investigated.
Does sotagliflozin improve cardiac outcomes in a mouse model of early heart failure with and without diabetes?
Does sotagliflozin improve cardiac outcomes in a mouse model of early heart failure with and without diabetes?
Dual SGLT1/2 inhibition with sotagliflozin attenuates cardiac hypertrophy and fibrosis in non-diabetic mice with pressure overload, but lacks efficacy in a high-fat diet-induced diabetic model with proximal tubular damage.
Dual SGLT1/2 inhibition effects in pressure-overload mice remain hypothesis-generating; human trials needed before clinical consideration.
Aims Selective SGLT2 inhibition reduces the risk of worsening heart failure and cardiovascular death in patients with existing heart failure, irrespective of diabetic status. We aimed to investigate the effects of dual SGLT1/2 inhibition, using sotagliflozin, on cardiac outcomes in non-diabetic and diabetic mice with cardiac pressure overload. Methods and Results Five-week old male C57BL/6J mice were randomized to receive a high fat diet (HFD; 60% of calories from fat) to induce diabetes or remain on normal diet (ND) for 12 weeks. Transverse aortic constriction (TAC) was then employed to induce cardiac pressure-overload (50% increase in right:left carotid pressure versus sham surgery), resulting in features representative of heart failure with preserved ejection fraction. At five weeks into the dietary protocol, mice were treated for seven weeks by oral gavage once daily with sotagliflozin (10mg/kg body weight) or vehicle (0.1% tween 80). In ND non-diabetic mice, treatment with sotagliflozin attenuated cardiac hypertrophy and histological markers of cardiac fibrosis induced by TAC. These benefits were associated with profound diuresis and glucosuria, without shifts toward whole-body fatty acid utilisation nor increased cardiac ketolysis. In HFD diabetic mice, sotagliflozin did not attenuate cardiac injury induced by TAC. HFD mice had vacuolation of proximal tubular cells, associated with less profound diuresis and glucosuria, which may have compromised drug action and subsequent cardio-protection. Conclusion We demonstrate the utility of dual SGLT1/2 inhibition in treating heart failure risk factors in the non-diabetic state. Its efficacy in high fat-induced diabetes with proximal tubular damage requires further study.
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Young et al. (2020) studied Cardiac pressure overload (heart failure model). Sotagliflozin vs. Vehicle (0.1% tween 80) was evaluated on Cardiac hypertrophy and histological markers of cardiac fibrosis. In non-diabetic mice with cardiac pressure overload, sotagliflozin attenuated cardiac hypertrophy and fibrosis, but it did not attenuate cardiac injury in high fat diet-induced diabetic mice.
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