Sodium-glucose cotransporter 2 (SGLT2) inhibitors have received extensive evaluation in phase 2 and 3 clinical trials and now represent a well-defined class of antihyperglycaemic agents. In addition to the demonstrated benefits on cardiovascular outcomes for some SGLT2 inhibitors, there is increasing evidence that this class of agents may also result in nephroprotection and fewer adverse renal outcomes in individuals with type 2 diabetes.¹

Renal SGLTs are responsible for the reabsorption for most filtered glucose. Tubular glucose that escapes SGLT2 subsequently is reabsorbed by SGLT1 in more distal tubular segments; 97% of filtered glucose is reabsorbed by SGLT2, while the remaining 3% is reabsorbed by SGLT1 under physiological conditions. Thus, inhibitors of SGLT2 decrease the capacity of the renal tubules to reabsorb glucose with the result that urinary glucose excretion is increased with a subsequent decrease in plasma glucose levels. SGLT2 inhibitors lead to a variety of metabolic effects, including improvements in insulin sensitivity and reduced glucose toxicity, as well as weight loss.

However, in addition, SGLT2 inhibitors have important effects that are not directly related to glycaemia. These include lowering of blood pressure (with subsequent decrease in arterial stiffness), renal hemodynamic modulation and reduced albuminuria, and decreases in uric acid. In addition, an increase in tubuloglomerular feedback results in decreased intragloumerular hypertension and decreased hyperfiltration, while the decrease in plasma volume observed with SGLT2 inhibitors likely improves myocardial stretch. Adenosine appears to be implicated in the afferent vasoconstriction seen with SGLT2 inhibitors. The combined result of these diverse mechanisms has led to the hypothesis that SGLT2 inhibitors may exert both cardiovascular and renal protection.

SGLT2 inhibitors have also been associated with reduction in inflammatory markers both in vitro and in human subjects, as well as improvements in hypoxia-related pathways that may potentially reduce ischaemia. These effects may be related to the cardiorenal benefits observed with SGLT2 inhibitors. In the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes who were at high risk for cardiovascular events. The trial also reported that in the same patient population, empagliflozin was associated with significantly less worsening of nephropathy and lower rates of clinically relevant renal events than placebo when added to standard care.² Moreover, both short-term and long-term benefits of empagliflozin on urinary albumin excretion have been seen that are independent of albuminuria status at baseline.³

In the CANVAS trial, also carried out in individuals with elevated risk of cardiovascular disease, treatment with canagliflozin was associated with a lower risk of cardiovascular events than placebo.⁴ The study also reported a possible benefit of canagliflozin with respect to progression of albuminuria and a composite outcome of sustained 40% reduction in eGFR, need for renal-replacement therapy, or death from renal causes.

To further extend and better understand the potential advantages of SGLT2 inhibitors in providing renal protection, a number of trials are being carried out, such as CREDENCE (recently stopped early due to positive efficacy findings), DAPA-CKD and EMPA-KIDNEY.⁵ Other studies in progress are primarily cardiovascular/heart failure trials with renal endpoints such as DECLARE-TIMI58, VERTIS-CV and other trials with ertugliflozin.

While intensive control of glucose levels and blood pressure is currently the mainstay of treatment of diabetic nephropathy, this strategy cannot fully prevent the development and progression of diabetic kidney disease, and thus an unmet need remains for additional therapies. In this regard, incretin-based agents, namely agonists of the glucagon-like peptide 1 receptor (GLP-1R) and inhibitors of dipeptidyl peptidase 4 (DPP-4), improve pancreatic islet function and induce extrapancreatic effects that ameliorate various defects of type 2 diabetes that go beyond glucose control.

Both GLP-1R agonists and DPP-4 inhibitors reduce blood pressure, dyslipidaemia and inflammation, while GLP-1R agonists also decrease body weight. Of interest in renal protection, both types of incretin-based agents have been shown to inhibit renal tubular sodium reabsorption and decrease glomerular pressure as well as albuminuria in both rodents and humans⁶. The renal effects of incretin-based agents have been reported in several clinical studies, although the effects across trials are not entirely consistent.

Trials with DPP-4 inhibitors were mostly cardiovascular safety studies and have shown mostly neutral results; considering renal function, these agents have had no effects or only slightly reduced albuminuria, with no effect on eGFR. However, in these studies, the cohorts examined were not those with diabetic kidney disease. In animal studies with diabetic mice, DPP-4 inhibition, independent of GLP-1R signaling, has been shown to contribute to protection of the diabetic kidney through antioxidative and antifibrotic effects and amelioration of adverse renal haemodynamics.⁷ DPP-4 inhibition further increases distal natriuresis.

While intensive control of glucose levels and blood pressure is currently the mainstay of treatment of diabetic nephropathy, this strategy cannot fully prevent the development and progression of diabetic kidney disease, and thus an unmet need remains for additional therapies. In this regard, incretin-based agents, namely agonists of the glucagon-like peptide 1 receptor (GLP-1R) and inhibitors of dipeptidyl peptidase 4 (DPP-4), improve pancreatic islet function and induce extrapancreatic effects that ameliorate various defects of type 2 diabetes that go beyond glucose control.

Both GLP-1R agonists and DPP-4 inhibitors reduce blood pressure, dyslipidaemia and inflammation, while GLP-1R agonists also decrease body weight. Of interest in renal protection, both types of incretin-based agents have been shown to inhibit renal tubular sodium reabsorption and decrease glomerular pressure as well as albuminuria in both rodents and humans⁶. The renal effects of incretin-based agents have been reported in several clinical studies, although the effects across trials are not entirely consistent.

Trials with DPP-4 inhibitors were mostly cardiovascular safety studies and have shown mostly neutral results; considering renal function, these agents have had no effects or only slightly reduced albuminuria, with no effect on eGFR. However, in these studies, the cohorts examined were not those with diabetic kidney disease. In animal studies with diabetic mice, DPP-4 inhibition, independent of GLP-1R signaling, has been shown to contribute to protection of the diabetic kidney through antioxidative and antifibrotic effects and amelioration of adverse renal haemodynamics.⁷ DPP-4 inhibition further increases distal natriuresis.