Dual inhibition of sodium–glucose linked cotransporters 1 and 2 exacerbates cardiac dysfunction following experimental myocardial infarction

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.

Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity

“…This aligns with our previous findings showing that cardiac SGLT1 is involved in an important protective mechanism against IRI by replenishing ATP stores in ischemic cardiac tissues via enhanced glucose utilization [7]. Consistent with a series of our studies, Connelly et al showed that oral administration of a dual SGLT1/2-inhibitor led to an impaired cardiac function after myocardial infarction in a rat model with left anterior descending coronary artery ligation, while a selective SGLT2-inhibitor had no significant effect on this condition [38]. These data indicate that cardiac SGLT1 exerts protective effects against myocardial ischemia even in vivo, although they used a non-diabetic model rather than HFD-induced diabetic Fig.…”

Load-independent effects of empagliflozin contribute to improved cardiac function in experimental heart failure with reduced ejection fraction

“…Accordingly, we focused on the latter to assess cardiac function in rats with heart failure. Whilst cardiac function was impaired post MI, empagliflozin failed to improve load dependent measures such as fractional shortening consistent with previous reports from our group using dapagliflozin in the post MI setting [12]. In contrast, load independent measures of cardiac contractility were improved in empagliflozin treated animals post MI.…”

“…Diameter measurements were taken membrane to membrane across the narrowest point that crosses the nucleus. The average diameter of 30-50 myocytes per animal was measured, as previously described [12].…”

Sodium–glucose cotransporters: Functional properties and pharmaceutical potential

“…A recent study reported that chronic cardiac overexpression of SGLT1 in mice led to pathological cardiac hypertrophy and left ventricular failure, and cardiac knockdown of SGLT1 attenuated the disease phenotype 107 . In contrast, a recent study also reported that dual SGLT1/SGLT2 inhibitor exacerbated cardiac dysfunction after experimental myocardial infarction in rats 108 . Considering that SGLT2 is not expressed in the heart, this effect might be linked to SGLT1 inhibition.…”