Sodium-glucose linked transporter 2 (SGLT2) inhibitors have emerged as a promising class of antidiabetic drugs, offering benefits to diabetes patients beyond glycemic control. A recent study of canagliflozin, an SGLT2 inhibitor, has suggested that this class of drug may offer renoprotective effects independent of its glucose-lowering effects.1 In the 2017 American Society of Nephrology (ASN) Kidney Week, an exploratory analysis from the EMPA-REG OUTCOME trial was presented, suggesting apparent renal benefits in patients who received the SGLT2 inhibitor, empagliflozin.2
Potential renoprotective effects of SGLT2 inhibitors
Although senescence or healthy aging of the kidney is characterized by progressive decline in renal function, current evidence suggests that age-related loss of kidney function is mainly due to comorbidities, such as diabetes and hypertension.3,4 In this aspect, the potential renoprotective effects of SGLT2 inhibitors, which inhibit renal glucose reabsorption and promote glucosuria,5 represent a promising treatment approach for patients with type 2 diabetes (T2DM).
Earlier this year, a 2-year follow up data from a randomized control trial has demonstrated that canagliflozin slowed the progression of kidney function decline, independent of its glycemic effects.1 The authors of the study suggested that, “the beneficial effects of canagliflozin on kidney function and albuminuria are unlikely to be explained by the modest differential effect on glucose levels.”1 Such findings are remarkable, considering that SGLT2 inhibitors are already associated with benefits beyond glycemic control, including reductions in body weight, blood pressure, and most importantly – cardiovascular risk.6
Less rapid eGFR decline with empagliflozin
In the exploratory analysis of EMPA-REG OUTCOME, the landmark trial of empagliflozin, Prof. Christoph Wanner and colleagues analysed the data from 7,020 patients with T2DM and established cardiovascular disease (CVD).2 The effect of empagliflozin on the incidence of patients experiencing a more rapid decline in estimated glomerular filtration rate (eGFR) was evaluated.2 The mean baseline of eGFR was 74 ± 21.4ml/min/1.73m2, and differences between the empagliflozin and placebo groups were assessed using a logistic regression analysis.2
With a median observation time of 3.1 years,7 the post-hoc analysis found that patients treated with empagliflozin were significantly less likely to experience a rapid eGFR decline.2 Although the rapid eGFR decline was defined as an annual decline of ≥5ml/min/1.73m2, similar risk reductions were also observed with a lower threshold of ≥3.3ml/min/1.73m2 (Figure 1).2
“Our findings suggest that empagliflozin may have the potential to protect against declining renal function and reduce the incidence of renal impairment in patients with type 2 diabetes in the long term,” said Professor Merlin C. Thomas of the Monash University, Melbourne, Australia.8
Consistent renal benefits irrespective of background medications
Meanwhile, a separate post-hoc analysis of the EMPA-REG OUTCOME, which assessed the renal effects of empagliflozin in patients who already received other agents to prevent the development or progression of CVD and chronic kidney disease (CKD), was also presented in the 2017 ASN Kidney Week.9
The findings, presented by Dr. Gert J. Mayer and colleagues, have shown that the addition of empagliflozin produced consistent risk reductions in the incident or worsening nephropathy across background medication subgroups (Figure 2).9 Among these subgroups, at least 19% risk reduction was produced with the addition of empagliflozin.9 The overall risk reduction was 39% for all patients.9 “Addition of empagliflozin resulted in a consistent reduction in CKD progression in T2D patients at high CV risk, irrespective of commonly used background medications that also alter renal hemodynamics,” the study authors concluded.9
SGLT2 inhibitors: a new renoprotective approach?
“If these drugs [SGLT2-inhibitors] can influence the course of kidney disease progression,” commented Dr. Raymond R. Townsend, the panel moderator of the session, “maybe that’s a standalone indication and maybe they do other things besides just cause a better HbA1c, a little weight loss, etc.” he said.8
Indeed, if the SGLT2 inhibitors can potentially reduce the incidence of chronic renal failure for T2DM patients in the long run, then a critical question would be: are SGLT2 inhibitors ready for prime time in chronic kidney disease (CKD)?10
Major clinical trials of SGLT2 inhibitors that included a kidney endpoint are still ongoing (Table 1),10 and the results are highly awaited. If these studies can confirm the renoprotective effects of SGLT2 inhibitors, then they might shift the therapeutic paradigm in diabetic kidney disease and perhaps other progressive kidney diseases as well.10
“More than 10 percent of people worldwide are affected by chronic kidney disease. Its prevalence and severity markedly influence the prognosis and quality of life of patients,” said Prof. Christoph Wanner of the University Hospital of Wuerzburg, Germany. “New treatments that may have the potential to help address this crucial medical need are desperately needed.”11