Sodium glucose co-transporter 2 inhibition: a new avenue to protect the kidney.

Increasing knowledge on the role of the kidneys in maintaining optimal glucose homoeostasis has led to the development of pharmacologic agents that block the sodium glucose co-transporter 2 (SGLT2) in the proximal tubule of the kidney. The SGLT2 transporter is responsible for the reabsorption of virtually all filtered glucose. Blockade of the transporter with SGTL2 inhibitors induces glycosuria of approximately 70–80 g/day and decreases HbA1c by 0.5–0.8% [1]. As a result of the glycosuric effects, and accompanied net calorie loss, SGLT2 inhibition leads to sustained reductions in body weight of 2–3 kg [2].

SGLT2 transporters reabsorb not only glucose but also sodium in a 1:1 stoichiometry. This leads to enhanced sodium excretion of ∼25 mmol/day. As a result of the increased natriuresis, and concurrent osmotic diuresis, owing to glycosuric effects, SGLT2 inhibitors decrease blood pressure, plasma volume and increase haematocrit. In addition, SGLT2 inhibition decreases albuminuria by 30–40% [3, 4]. These combined effects render SGLT2 inhibitors promising agents for the management of diabetic kidney disease (DKD).

The long-term benefits of SGLT2 inhibitors are demonstrated in three large cardiovascular outcome trials [5-7]. These trials reported reductions in cardiovascular risk as well as strong and consistent reductions in risk for heart failure. The trials also suggested improvements in kidney outcomes, but these effects were mainly based on creatinine-based outcomes. The number of dialysis or kidney transplantation endpoints was very small. This is not surprising since the cardiovascular outcome trials were not designed to test the effects of SGLT2 inhibitors on slowing progressive kidney function loss. However, they provide a strong rationale to test the efficacy and safety of SGLT2 inhibitors in patients with kidney disease.

According to the label of the registered SGLT2 inhibitors in the USA and Europe—dapagliflozin, canagliflozin, empagliflozin and ertugliflozin—they should not be used in patients with severe kidney impairment due to reduced efficacy. Indeed, various studies have shown that the glycaemic efficacy of these drugs attenuates at lower glomerular filtration rate (GFR) levels [8, 9]. However, effects on other cardiovascular risk markers, such as body weight, blood pressure and albuminuria, persist even in patients with moderate-to-severe kidney impairment, suggesting that long-term benefits on clinical endpoints remain present in this population. This notion is supported by subgroup analyses from cardiovascular outcome trials demonstrating that SGLT2 inhibitors slow progression of kidney disease and reduce the risk of clinical endpoints in the subgroup of patients with an estimated GFR (eGFR) between 30 and 60 mL/min/1.73 m2 [10, 11]. Against this background, the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial was designed and initiated in 2014. The objective of the trial was to examine the efficacy and safety of the SGLT2 inhibitor canagliflozin 100 mg/day in patients with type 2 diabetes, macroalbuminuria and eGFR between 30 and 90 mL/min/1.73 m2. The trial was stopped early due to overwhelming efficacy. Although the results are not yet available, it is expected that the trial represents a new landmark in the management of DKD and will improve the outlook of many patients with DKD for whom no new treatment strategy has become available in the last 18 years.

What could be the mechanism of action giving rise to the benefits of SGLT2 inhibitors in slowing progression of DKD? It is unlikely that the long-term beneficial effects on kidney function are explained by improvements in glycaemic control as the HbA1c reductions observed in most trials were modest. Furthermore, active controlled studies have shown that at equal glycaemic control, eGFR decline was significantly less in SGLT2 inhibitor-treated compared with control-treated patients [12]. Other mechanisms have been described, as reviewed in detail elsewhere [13]. These include improving renal proximal tubule oxygenation, suppressing anti-inflammatory and anti-fibrotic pathways, and restoration of tubuloglomerular feedback. With respect to the latter, it is assumed that decreased sodium delivery to the macula densa, as may occur in type 2 diabetes due to increased SGLT2 expression, results in suppression of tubuloglomerular feedback resulting in afferent vasodilation, increased renal blood flow and hyperfiltration, which is the first clinical manifestation of DKD. A clinical trial in patients with type 1 diabetes demonstrated reductions in intra-glomerular pressure and acute reductions in the GFR, reflecting diminished single-nephron hyperfiltration (Figure 1) [14]. Whether these effects are also applicable in patients with type 2 diabetes is unknown and subject of investigation in the RED study (NCT02682563). Nevertheless, at least in type 1 diabetes, they offer a logical explanation for the profound benefits of SGLT2 inhibitors in preventing progression of kidney disease.

FIGURE 1

Proposed mechanism of renoprotective effect of sodium glucose co-transporter 2 inhibitors: restoration of tubulo-glomerular feedback. SGLT2 inhibitors increase the delivery of sodium to the macula densa. Sodium reabsorption in the macula densa results in adenosine release which can bind to the adenosine 1 receptor in the afferent arteriole thereby causing afferent vasoconstriction and a decrease in hyperfiltration.

The restoration of tubuloglomerular feedback is thus thought to be an important mechanism to account for the kidney benefits of SGLT2 inhibitors. Based on this non-glycaemic mechanism, it is tempting to speculate whether the use of these agents can be extended to patients without diabetes. Various non-DKD aetiologies, such as obesity-induced chronic kidney disease, hypertensive nephrosclerosis or focal segmental glomerulosclerosis, are characterized by single-nephron hyperfiltration and significant albuminuria. Reversing the hyperfiltering state in these conditions may slow or prevent progressive kidney function loss. Studies in obese non-diabetic individuals has shown reductions in blood pressure, eGFR and uric acid, suggesting that the pharmacodynamic effects of SGLT2 inhibition remain present in patients without diabetes [15]. Simulation studies have also suggested that SGLT2 inhibitors slow progression of kidney function decline in non-DKD, albeit the magnitude of the effect may be somewhat smaller compared with in DKD [16]. Whether SGLT2 inhibitors are truly effective in non-DKD will be answered in the future by two different trials. The ongoing DAPA-CKD trial is designed to assess the kidney protective effects of dapagliflozin in a mixed population of patients with and without diabetes and chronic kidney disease. Another trial with a similar objective, the EMPA-KIDNEY trial, has been announced to start in 2019.

Will all patients benefit from SGLT2 inhibition? A study that investigated the albuminuria-lowering effects of the SGLT2 inhibitor dapagliflozin reported a strong statistically significant reduction in albuminuria of 36% in the overall population compared with placebo treatment [17, 18]. However, the study also demonstrated a large variation in albuminuria response between individual patients, indicating that some patients showed a marked reduction in albuminuria, whereas others did not and remained at high risk of end-stage kidney disease. Thus, although SGLT2 inhibitors have brought us to the entrance of a new era for renal protective medicine, the search for new agents to further improve our pharmacological armamentarium should continue in order to protect every patient from progressive kidney function loss in the future.

CONFLICT OF INTEREST STATEMENT

Dr H.J.L.H is member of the steering committees of the CREDENCE and DAPA-CKD trials. He is consultant to Abbvie, AstraZeneca, Boehringer Ingelheim, Janssen, Gilead, Fresenius, Merck, Mundipharma and Mitshubishi Tanabe.