TABLE 4.

Clinical recommendations on the use of SGLT‐2 inhibitors for the management of Asian patients with diabetic kidney disease (DKD)

	The burden of DKD in Asia
1	Early‐onset diabetes and high prevalence of metabolic risk factors predispose Asian patients with T2D to a higher risk of DKD.
2	Patients with DKD are at a high risk of cardiovascular disease and progression to ESKD.
	Management of DKD
3	Patients with diabetes may have silent progression of kidney disease before the onset of clinical disease. Therefore, monitoring of renal function (at least annually) and albuminuria is critical for early detection and control of DKD.
4	In patients with DKD, a multifactorial management including optimal control of hyperglycaemia, blood pressure and dyslipidaemia is essential to delay the progression of renal disease and to reduce adverse cardiorenal outcomes.
	SGLT‐2 inhibitors for the management of Asian patients with DKD
5	Effect on renal outcomes In patients with DKD, SGLT‐2 inhibitors significantly reduce the risk of renal disease progression defined as onset of ESKD or doubling of creatinine level from baseline or death from renal or CV disease. The risk of doubling of creatinine level is reduced by 40% and the risk of ESRD is reduced by 32%. These renoprotective effects are achieved on the background ACEi or ARBs, and are consistent across varying levels of kidney function (eGFR >30 to <90 mL/min/1.73 m2).
6	Treatment with SGLT‐2 inhibitors is associated with an initial decline in glomerular filtration rate, which is followed by progressive recovery and slowing in the decline of renal function with follow‐up.
7	In patients with moderate‐to‐severe DKD, treatment with SGLT‐2 inhibitors is associated with a sustained reduction in albuminuria.
8	Effect on CV outcomes In patients with DKD, SGLT‐2 inhibitors significantly reduce the risk of major adverse CV events (defined as CV death or myocardial infarction or stroke) and HF hospitalizations.
9	Effect on metabolic variables The blood glucose‐lowering effects of SGLT‐2 inhibitors are attenuated in patients with moderate or severe DKD. Based on individual glycaemic targets, additional glucose‐lowering therapy may be required in patients with DKD.
10	Treatment with SGLT‐2 inhibitors is associated with reduction in body weight and SBP, and improvements in uric acid and haematocrit in patients with DKD.
11	Safety Before initiating SGLT‐2 inhibitor therapy, consider factors that may predispose patients to AKI, including hypovolaemia, dehydration, chronic renal insufficiency, congestive heart failure, peripheral vascular disease and concomitant medications such as diuretics, ACEi, ARBs and non‐steroidal anti‐inflammatory drugs.
	Renal effects of SGLT‐2 inhibitors in patients with T2D (including those with CKD)
12	In T2D patients with established or high risk of CV disease, including those with CKD, SGLT‐2 inhibitor therapy: Reduces the risk of the renal outcomes defined by worsening or renal function or ESKD or renal death. Produces sustained reduction in albuminuria and reduces the risk of progression to macroalbuminuria. Slows the decline in renal function and increases the odds for regression of albuminuria.
	Potential mechanism of renal effects
13	The beneficial renal effects of SGLT‐2 inhibitors can be attributed to their renal and systemic effects. The renal effects include: (a) decrease in glomerular hyperfiltration; (b) inhibition of proinflammatory and profibrotic pathways; (c) reduction in oxygen consumption and demand in the renal cortex, resulting in preservation of tubular cell structure integrity and function; (d) reduction of glucose flux through proximal tubular cells limiting glucotoxicity and increases in the flux through the polyol pathway; and (e) reduction of increased proximal tubular sodium and limitation of the stimulus for tubular cell growth. The favourable haemodynamic and metabolic effects such as improved cardiac function with the maintenance of renal perfusion, BP‐lowering, glycaemic control, shift towards more efficient ketone bodies as energy substrate, reduction in body weight and adiposity, and an increase in haematocrit, may contribute to renoprotection.
	Role of SGLT‐2 inhibitors in the management of patients with DKD or those at high risk of DKD
14	Considering their beneficial CV and renal effects, SGLT‐2 inhibitors represent a preferred therapy for: Delaying disease progression in patients with DKD (in combination with ACEi or ARBs). Preserving renal function and reducing albuminuria in patients at high risk of DKD and in those with hyperfiltration.

Abbreviations: ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin II receptor blocker; AKI, acute kidney injury; CKD, chronic kidney disease; CV, cardiovascular; DKD, diabetic kidney disease; DPP‐4, dipeptidyl peptidase‐4; eGFR, estimated glomerular filtration rate; ESRD, end‐stage renal disease; HHF, heart failure hospitalizations; MACE, major adverse cardiac events; SBP, systolic blood pressure; SGLT‐2, sodium‐glucose co‐transporter‐2; T2D, type 2 diabetes; UACR, urine albumin‐to‐creatinine ratio.