Preventing and treating kidney disease in patients with type 2 diabetes

Abstract

Introduction: Chronic kidney disease (CKD) represents a huge burden in patients with type 2 diabetes (T2DM). This review therefore has the aim of assessing the add-on value of new glucose-lowering agents compared or combined with inhibitors of the renin angiotensin aldosterone system (RAAS) on renal outcomes in T2DM patients. Areas covered: This article first summarizes the results reported with RAAS inhibitors, mainstay of nephroprotection in T2DM with albuminuria. Second, it describes the positive results with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and, even more impressive, sodium-glucose cotransporter type 2 inhibitors (SGLT2is). Third, besides the potential of combined therapies, it briefly considers some new approaches currently in development. Expert opinion: RAAS inhibitors exert renoprotective effects beyond their blood pressure lowering effects while SGLT2is, and possibly GLP-1RAs, exert nephroprotection independently of their glucoselowering activity. These effects were demonstrated not only on surrogate endpoints such as albuminuria and estimated glomerular filtration rate decline, but also on hard endpoints, including progression to end-stage renal disease requiring replacement therapy. The underlying mechanisms are different and potentially complementary on glomerular hemodynamics, arguing for combined therapies. Nevertheless, there is still room for new emerging drugs to tackle CKD in T2DM.

Sodium–glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus

“…Although the glucose-lowering efficacy of SGT2is was dependent on renal function and attenuated in patients with eGFR <45 ml/min/1.73 m 2 (refs 71,98 ), the blood pressure-lowering effect was maintained in people with CKD 105 . This property potentially offers synergistic effects with antihypertensive therapies 101 , in particular blockers of the RAAS 106 . Small reductions in eGFR were seen shortly after initiating therapy with SGLT2is but this reduction was transient and eGFR returned to baseline levels after discontinuation 107 .…”

Effects of glucose-lowering agents on surrogate endpoints and hard clinical renal outcomes in patients with type 2 diabetes

“…In T2DM patients at high CV risk recruited for four large prospective trials showing significant reductions in renal outcomes (LEADER, SUSTAIN-6, EMPA-REG OUTCOME, CANVAS), almost three-quarters of all patients were treated with RAAS blockers. The potential complementary mechanism between RAAS inhibitors and SGLT2is has been emphasized, as discussed in a recent review [157].…”

Series: Implications of the recent CVOTs in type 2 diabetes

“…Endocrinologists were increasingly interested in detecting this complication since the discovery of microalbuminuria as a simple marker of early CKD and a validated indicator of prognosis of more severe renal disease. The interest was even increased following the demonstration of the remarkable renoprotective effect of blockers of the reninangiotensin system [35]. Both SGT2is and GLP-1RAs, added to RAS blockers, have been shown to reduce microalbuminuria and proteinuria in patients with T2DM, although SGLT2is appear to exert a stronger protective effect on hard clinical outcomes [36].…”

“…One additional difficulty is that eGFR may fluctuate from time to time, being influenced not only by the chemical assay of serum creatinine, but also by a variety of physiological (level of hydration, for instance) or pharmacological (use of nonsteroidal anti-inflammatory agents or blockers of the renin-angiotensin system, for instance) confounding factors. Furthermore, SGLT2is may transiently reduce eGFR within the first few weeks of administration [35]. Because the use of SGLT2i is currently restricted in patients with low eGFR (no initiation if eGFR < 60 ml/min/1.73 m 2 and treatment interruption recommended if eGFR falls < 45 ml/min/1.73 m 2 ), difficulties in evaluating renal function may render the task of the clinician (including endocrinologists) somewhat hazardous.…”

“…As emphasized in a report from the European Society of Cardiology Cardiovascular Roundtable, addressing cardiovascular risk in T2DM requires a better collaboration between diabetologists and cardiologists [21]. Considering the increasing importance of CKD in T2DM [4,5,35] and the specific action of SGLT2is to slow down the progression of renal disease [36], a closer collaboration between endocrinologists and nephrologists may also become mandatory [43].…”