Abstract
BackgroundInhibiting both type 1 and 2 sodium–glucose linked cotransporter (SGLT1/2) offers the potential to not only increase glucosuria beyond that seen with selective SGLT2 inhibition alone but to reduce glucose absorption from the gut and to thereby also stimulate glucagon-like peptide 1 secretion. However, beyond the kidney and gut, SGLT1 is expressed in a range of other organs particularly the heart where it potentially assists GLUT-mediated glucose transport. Since cardiac myocytes become more reliant on glucose as a fuel source in the setting of stress, the present study sought to compare the effects of dual SGLT1/2 inhibition with selective SGLT2 inhibition in the normal and diseased heart.MethodsFischer F344 rats underwent ligation of the left anterior descending coronary artery or sham ligation before being randomized to receive the dual SGLT1/2 inhibitor, T-1095, the selective SGLT2 inhibitor, dapagliflozin or vehicle. In addition to measuring laboratory parameters, animals also underwent echocardiography and cardiac catheterization to assess systolic and diastolic function in detail.ResultsWhen compared with rats that had received either vehicle or dapagliflozin, T-1095 exacerbated cardiac dysfunction in the post myocardial infarction setting. In addition to higher lung weights, T-1095 treated rats had evidence of worsened systolic function with lower ejection fractions and reduction in the rate of left ventricle pressure rise in early systole (dP/dtmax). Diastolic function was also worse in animals that had received T-1095 with prolongation of the time constant for isovolumic-pressure decline (Tau) and an increase in the end-diastolic pressure volume relationship, indices of the active, energy-dependent and passive phases of cardiac relaxation.ConclusionsThe exacerbation of post myocardial infarction cardiac dysfunction with T-1095 in the experimental setting suggests the need for caution with the use of dual SGLT1/2 inhibitors in humans.
Highlights
Inhibiting both type 1 and 2 sodium–glucose linked cotransporter (SGLT1/2) offers the potential to increase glucosuria beyond that seen with selective SGLT2 inhibition alone but to reduce glucose absorption from the gut and to thereby stimulate glucagon-like peptide 1 secretion
When compared with rats that had been treated with dapagliflozin, those randomized to receive T-1095 had lower body weights in the post-myo‐ cardial infarction (MI) setting (Table 1)
Left ventricular weight, indexed to tibial length, increased following myocardial infarction with lower values noted in rats that had received dapagliflozin but lower still in those randomized to T-1095
Summary
Inhibiting both type 1 and 2 sodium–glucose linked cotransporter (SGLT1/2) offers the potential to increase glucosuria beyond that seen with selective SGLT2 inhibition alone but to reduce glucose absorption from the gut and to thereby stimulate glucagon-like peptide 1 secretion. Beyond the kidney and gut, SGLT1 is expressed in a range of other organs the heart where it potentially assists GLUT-mediated glucose transport. Combined SGLT1/2 inhibition offers the potential to increase glucosuria beyond that seen with SGLT2 inhibition alone but to reduce glucose absorption allowing the monosaccharide to stimulate release of glucagonlike peptide-1 (GLP-1) in the ileum. The facilitated glucose transporters GLUT1 and GLUT4 were previously thought to account entirely for glucose transport in the heart, more recent studies attest to the additional contribution of SGLT1 [9,10,11,12]
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