Type 2 diabetes is an increasing trend worldwide ༎Although the long-term prognosis of patients with type 2 diabetes is improving, the mortality rate, especially mortality from cardiovascular disease, remains unsolved . Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are recently developed oral hypoglycemic drugs whose mechanism is mainly to inhibit glucose reabsorption from renal tubules via SGLT-2. It lowers blood glucose levels through urinary disposing. Unlike insulin or other oral hypoglycemic drugs that have insulin secretion effect, SGLT-2 inhibitors have been reported to have other beneficial effects, such as body weight loss and reduction of blood pressure, while maintaining a low risk of hypoglycemia . In addition, SGLT-2 inhibitors are reported to have cardio-protective effects in patients with type 2 diabetes, not only in Western countries [4, 5], but in Asian countries as well . Renal function and urinary albumin excretion rate are associated with cardiovascular death , and renal complications need to be considered when considering the risk of cardiovascular disease (CVD) for type 2 diabetes. Recently, a SGLT-2 inhibitor, canagliflozin, was reported to reduce the relative risk of primary endpoints by 30%, such as progression to end-stage renal failure, doubling of serum creatinine (Cre) levels, and death due to renal disease in patients with type 2 diabetes with chronic kidney disease (CKD) . This is the first large-scale clinical trial with renal outcomes due to SGLT-2 inhibitors as the primary endpoint. This study addresses the growing need to focus on the renal protective effects of SGLT-2 inhibitors in diabetic patients.
Diabetic nephropathy is a diabetic microvascular complication. Nephropathy progresses to microalbuminuria, overt albuminuria, and decreased renal function, and is associated with increased mortality . The prevalence of diabetic nephropathy in type 2 diabetes is reported as the proportion with microalbuminuria or overt albuminuria, which is 30–40% in Europe and the United States  and 7–20% in Asian countries . In Japan, the prevalence of diabetic nephropathy in type 2 diabetic patients is reported as high as 42% . Since renal replacement therapy such as hemodialysis or peritoneal dialysis impairs patient quality of life, the development of a therapy to prevent the development of chronic renal failure in type 2 diabetic patients is desired. At present, treatment of diabetic nephropathy mainly consists of treatment for glomerular hypertension by diet, glycemic control, treatment of hypertension, especially suppression of the renin-angiotensin system (RAS), and treatment for dyslipidemia . Clinical studies examining the effectiveness of strict glycemic control, such as ACCORD , ADVANCE , and the Kumamoto study , showed that strict glycemic control could significantly suppress a new onset of microalbuminuria and progression to overt albuminuria༎These results suggest that strict glycemic control may be effective for the early stage of nephropathy. At the same time, however, the effectiveness of strict glycemic control was not observed in kidney-related hard endpoints such as serum creatinine doubling, progression to end-stage renal failure, and kidney-related death . In 2015, the SGLT-2 inhibitor empagliflozin reduced the deaths of diabetic patients at high risk of cardiovascular events by 40% , and also reduced the incidence and worsening rate of nephropathy by 38%, the doubling of serum creatinine by 44%, and the introduction of dialysis by 55% . Of note, more than 80% of the study participants had already taken RAS inhibitors. RAS inhibitors had already been reported as improving renal-related hard endpoints, such as promoting resolution of urinary albumin in early nephropathy and suppressing renal function decline in cases of overt nephropathy [19–22]. Similar results indicate that the CANVAS program, which administered canagliflozin to patients with type 2 diabetes at high risk for cardiovascular events, also reduced the development of albuminuria by 27%, and showed that the renal complex endpoint (decreased estimated glomerular filtration rate (GFR), initiation of renal replacement therapy, and death from renal disease) were significantly reduced by 40% . These results suggest that SGLT-2 inhibitors may be an oral hypoglycemic drug with a different mechanism from that of RAS inhibitors in inhibiting the progression of diabetic nephropathy. Accordingly, it is important for clinicians to examine the background of patients in whom the renal protective effect of SGLT-2 inhibitors is likely to be exerted.
Previous large-scale clinical studies suggest that SGLT-2 inhibitors could be used as a drug with not only a hypoglycemic effect but also a renal protective effect in patients with type 2 diabetes. However, it is not fully understood in what background a SGLT-2 inhibitor is more likely to exert its effects. Therefore, we investigated changes in renal function and urinary albumin in the short-term use of SGLT-2 inhibitors, focusing on patient background before administration, especially changes in body weight, blood pressure, and blood glucose. The purpose of this study was to clarify in which patients the renal protective effect of SGLT-2 inhibitors at a usual dose in Japan is likely to be demonstrated in actual clinical settings.