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28 Cardio Diabetes Medicine 2017

ity. Importantly recent data suggest that other renal suggests that these cardo-renal protective effects
pathologies often coexist or drive CKD in patients could be related to a SGLT2 inhibitors’ class effect.
with T2DM.
The precise mechanism/s by which SGLT2 inhibitors
Further we should be aware that any treatment could exert their cardio-renal protective effects are current-
have a different efficacy when utilized in different ly unknown.
stages of chronic kidney disease; many of the tri- Different theories/possibilities have been postulat-
als conducted today have been considering patients ed and research is ongoing to better define the car-
solely in the advanced stages of kidney disease often dio-renal protective effects of SGLT2 inhibitors.
with macro-proteinuria. This approach could result in
us missing potential drug-related beneficial effects in In line with the rapid (6-12 months) observed car-
earlier stages of CKD (e.g. microalbuminuria); these dio-renal vascular protective effects of SGLT2 inhibi-
studies are clearly longer, more expensive, and pos- tors, two major theories have been postulated:
sibly not affordable today.
1. Intrarenal theory: this theory postulates that the
Future better phenotypic patients’ characterization SGLT2-mediated renoprotective effect is second-
with novel biomarker, possibly derived from proteom- ary to activation of tubuloglomerular feedback with
ics and metabolomics analysis, might help our un- secondary reduction in glomerular capillary pres-
derstanding of novel treatments studied at different sure, and a parallel inhibition of enhanced tubuli
stages of kidney disease. sodium-coupled glucose transport that would re-
sult in reduction of tubulointerstitial injury. Further
Recent novel advances in the mechanisms involved the use of SGLT2 inhibitors in combination with
in diabetic kidney disease have recently opened inhibitors of the renin-angiotensin-aldosterone
some hopes in the fight for the treatment of diabetic system could also result in upregulation of angio-
kidney disease. Indeed, within the class of oral hy- tensin 1-7/1-9 known to retain a vasodilatory, an-
poglycaemic agents, recent studies have suggested ti-inflammatory and anti-oxidative stress protective
a potential renoprotective effects for SGLT2 antag- effects.
onists(3) and incretin-mimetic drugs such as gluca-
gon-like peptide (GLP)-1 analogues. 2. Systemic theory: the systemic theory suggests that
plasma volume contraction (driven by SGLT2 medi-
Of the multiple factors contributing to the develop- ated glycosuria and possibly natriuresis) and blood
ment of T2DM (e.g. insulin resistance at the tissue pressure reduction observed with SGLT2 therapy
level, beta cell failure, increased glucagon secretion, could be at the basis of the cardio-renal protective
and decrease incretin effect), the increased renal mechanisms of this new class of drugs.
proximal tubular glucose reabsorption, secondary to
an upregulation of the SGLT2 transporters, has been Studies are ongoing to understand the role of these
implicated in the pathophysiology of diabetes. The compounds in reducing the burden of diabetic chron-
glucose proximal tubule reabsorption is mediated ic cardiovascular-renal complications.
by an energy-dependent sodium-coupled glucose Recent clinical trials on GLP-1 analogues have demon-
transporter called SGLT2 which has recently been strated a cardiovascular protective role for this new
proposed as a target for treatment of hyperglycae- class of drugs with suggestion of parallel renoprotec-
mia in diabetes.
tive effects(6, 7). Like for SGLT2 inhibitors the cardio-
By blocking the action of SGLT2 in patients with vascular protective role of these drugs occurs within
T2DM studies have shown an improvement in gly- 6-12 months from their initiation and it appears to be
caemic control paralleled by weight loss and by a beyond the improvement in glucose control.
modest, but clinically significant, fall in systolic and Studies have suggested direct effects of GLP-1 recep-
diastolic blood pressure. The SGLT2 inhibitors mode tor agonists on endothelial function, renal sodium ex-
of action is insulin independent and rarely results in cretion and improvement in systolic blood pressure
hypoglycaemia unless the SGLT2 inhibitor is utilized but more work is needed to dissect the mechanisms
in conjunction with insulin or beta cell secretagogues for cardio-renal protection of these agents. Experi-
(e.g. sulphonylurea).
mental research has suggested GLP-1-mediated re-
Recent clinical trials have demonstrated an important duction in glomerular filtration rate (GFR) in models
cardiovascular(4) and possibly a renoprotective effect characterized by glomerular hyperfiltration, and an
(5)of the SGLT2 inhibitor empaglifozin; importantly increase in GFR in models with normal glomerular
more recent clinical trials and observational studies filtration.

GCDC 2017