Impact of Sodium-Glucose Cotransporter-2 Inhibitors in the Management of Chronic Kidney Disease: A Middle East and Africa Perspective

Figures & data

Table 1 Summary of Recommendations from International Guidelines for Screening, Diagnosis and Referral of Patients with CKD

Guidelines	Screening Population	Screening/Diagnosis	Referral to Nephrologist
KDIGO^Citation28,Citation29	Patients with hypertension, diabetes, and CVD Screening program for early detection in high-risk population based on demographics, comorbidities, environmental exposures, or genetic risk factors	Estimate eGFR and ACR Once per year G1 (if CKD present*) with A1 or A2 G2 (if CKD present*) with A1 or A2 G3a with A1 Twice per year G1 or G2 with A3 G3a with A2 G3b with A1 Thrice per year G3a with A3 G3b with A2 or A3 G4 with A1 or A2 ≥4 times per year G4 with A3 G5 with A1, A2, or A3	AKI or abrupt sustained fall in eGFR eGFR <30 mL/min/1.73 m^2 (eGFR categories G4 to G5)** Consistent finding of significant albuminuria (UACR of ≥300 mg/g or UAER of ≥300 mg/24 hours) Progression of CKD Urinary red cell casts, RBC >20 per high power field sustained and not readily explained CKD and hypertension refractory to treatment with 4 or more antihypertensive agents Persistent abnormalities of serum potassium Recurrent or extensive nephrolithiasis Hereditary kidney disease
ADA^Citation26	Patients with T1DM or T2DM with existing CVD hypertension	Estimate eGFR and spot UACR at least yearly once patients with T1DM with disease duration of ≥5 years all patients with T2DM regardless of treatment	eGFR <30 mL/min/1.73 m^2 Active urinary sediment (containing red or white blood cells or cellular casts) Rapidly increasing albuminuria or nephrotic syndrome Rapidly decreasing eGFR Absence of retinopathy (in T1DM) Uncertainty about the etiology of kidney disease For difficult management issues (anemia, secondary hyperparathyroidism, significant increases in albuminuria in spite of good blood pressure control, metabolic bone disease, resistant hypertension, or electrolyte disturbances)
Kidney Health Australia^Citation27	Patients with diabetes hypertension existing CVD family history of kidney failure obesity (BMI ≥30kg/m^2) smoking age over 60 in the absence of other risk factors aboriginal or Torres Strait Islander origin aged ≥30 years history of acute kidney injury	Estimate eGFR and spot UACR every 1 to 2 years in individuals at high-risk of CKD	Reduction in GFR is more than 25% below the baseline value A sustained decrease in eGFR of 25% or more within 12 months A sustained decrease in eGFR of 15 mL/min/1.73m^2 per year Stage 4 or 5 CKD of any cause UACR ≥ 300 mg/g CKD with uncontrolled hypertension despite at least three antihypertensive agents
KDOQI^Citation30	Patients with diabetes hypertension autoimmune diseases systemic infections urinary tract infections urinary stones lower urinary tract obstruction neoplasia family history of CKD recovery from acute kidney failure reduction in kidney mass exposure to certain drugs low birth weight older age exposure to certain chemical and environmental conditions low income/education US ethnic minority status: African American, American Indian, Hispanic, Asian, or Pacific Islander	Estimate eGFR and ACR Once per year G1 (if CKD present*) with A1 or A2 G2 (if CKD present*) with A1 or A2 G3a with A1 Twice per year G1 or G2 with A3 G3a with A2 G3b with A1 Thrice per year G3a with A3 G3b with A2 or A3 G4 with A1 or A2 > 4 times per year G4 with A3 G5 with A1, A2, or A3	Acute kidney injury eGFR of <30 mL/min/1.73 m^2 Rapid decline in eGFR Albuminuria level of ≥300 mg/g CKD progression, or CKD Hypertension refractory to treatment with ≥4 antihypertensive agents Urinary red cell casts RBC >20 per high power field sustained and not readily explained Persistent abnormalities of serum potassium Recurrent or extensive nephrolithiasis Hereditary kidney disease

Notes: GFR categories: G1, eGFR of ≥90 mL/min/1.73 m²; G2, eGFR of 60 to 89 mL/min/1.73 m^2; G3a, eGFR of 45 to 59 mL/min/1.73 m²; G3b, eGFR of 30 to 44 mL/min/1.73 m²; G4, eGFR of 15 to 29 mL/min/1.73 m²; G5, <15 mL/min/1.73 m². Albuminuria categories: A1, UACR of <30 mg/g; A2, UACR of 30 to 300 mg/g; A3, UACR of >300 mg/g. *In case kidney structural abnormalities. **If this is a stable isolated finding, formal referral might not be required.

Abbreviations: ADA, American Diabetes Association; ACR, albumin-creatinine ratio; AKI, acute kidney injury; BMI, body mass index; CKD, chronic kidney disease; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease: Improving Global Outcomes; KDOQI, Kidney Disease Outcomes Quality Initiative; RBC, red blood cell; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; UACR, urine albumin-creatinine ratio; UAER, urine albumin excretion rate; US, United States.

Figure 1 Recommended algorithm for screening and diagnosis of CKD.

Note: *Prefer first morning void.

Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; UACR, urine albumin-creatinine ratio.

Figure 2 Recommended nephrology referral pathway.

Note: *In the absence of other referral indicators.

Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; UACR, urine albumin-creatinine ratio.

Table 2 Clinical Trials Describing the Kidney-Protective Outcome of SGLT-2i

Name of Study	Design	Objective	Population Characteristics	Number of Patients	Treatment Modality	Outcome
CANVAS and CANVAS-R^Citation9	Randomized, placebo-controlled study	Effect of canagliflozin on CV, kidney, and safety outcomes	Patients with T2DM established ASCVD-65.6%	10,142 (CANVAS:4330, CANVAS-R:5812)	CANVAS (1:1:1) – canagliflozin (300 mg), canagliflozin (100 mg), or matching placebo CANVAS-R (1:1) – canagliflozin: 100 mg with an optional increase to 300 mg or matched placebo	Canagliflozin group (versus placebo) had less frequent progression of albuminuria (89.4 versus 128.7 participants with an event per 1000 patient-years) with HR of 0.73 (95% CI, 0.67 to 0.79) more frequent regression of albuminuria (293.4 versus 187.5 participants with regression per 1000 patient-years; HR, 1.70; 95% CI, 1.51 to 1.91) a composite outcome of sustained 40% reduction in eGFR, the need for kidney replacement therapy, or death from kidney causes (HR, 0.60; 95% CI, 0.47 to 0.77) A greater effect was observed in in CANVAS-R (HR, 0.64; 95% CI, 0.57 to 0.73) compared to CANVAS (HR, 0.80; 95% CI, 0.72 to 0.90; p=0.02 for homogeneity)
CREDENCE^Citation37	Randomized, double-blind, event-driven, placebo-controlled, multicenter study	Effects of canagliflozin on kidney and CV outcomes in participants with diabetic nephropathy	Patients with T2DM diabetic nephropathy	4401	Canagliflozin 100 mg versus placebo	Canagliflozin group (versus placebo) had 30% lower relative risk of composite of ESKD (dialysis, transplantation, or a sustained eGFR of <15 mL/minute/1.73 m^2), a doubling of the serum creatinine level, or death from kidney or CV causes with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (HR, 0.70; 95% CI, 0.59 to 0.82; p=0.00001) Canagliflozin group (versus placebo) had lower relative risk of the kidney-specific composite of ESKD, a doubling of the creatinine level, or death from kidney causes by 34% (HR, 0.66; 95% CI, 0.53 to 0.81; p<0.001) relative risk of ESKD by 32% (HR, 0.68; 95% CI, 0.54 to 0.86; p=0.02) Risk of CV death, MI, or stroke (HR, 0.80; 95% CI, 0.67 to 0.95; p=0.01 and HHF (HR, 0.61; 95% CI, 0.47 to 0.80; p<0.001)
DAPA-CKD^Citation11	International, multicenter, randomized, double-blind, parallel group, placebo-controlled study	Effect of dapagliflozin on kidney outcomes and CV mortality in patients with CKD	Patients with CKD with or without T2DM	4304	Dapagliflozin 10 mg versus placebo	Dapagliflozin group (versus placebo) had lower occurrence of composite of a sustained decline in the eGFR of at least 50%, ESKD, or death from kidney-related or CV (9.2% versus 14.5%; HR, 0.61; 95% CI, 0.51 to 0.72; p<0.001; number needed to treat to prevent one primary outcome event, 19; 95% CI, 15 to 27) occurrence of death (4.7% versus 6.8%; HR, 0.69; 95% CI, 0.53 to 0.88; p=0.004) risk of composite of a sustained decline in the eGFR of at least 50%, ESKD, or death from kidney-related causes (HR, 0.56; 95% CI, 0.45 to 0.68, p<0.001) risk for the composite of death from CV causes or HHF (HR, 0.71; 95% CI, 0.55 to 0.92; p=0.009)
DECLARE-TIMI 58^Citation34,Citation35	Randomized, double-blind, multinational, placebo-controlled study	Effect of dapagliflozin on CV outcomes	Patients with established ASCVD-40.6%	17,160	Dapagliflozin 10 mg versus matched placebo (1:1)	DECLARE-TIMI 58, 2019 Dapagliflozin group (versus placebo) had reduced risk of kidney-specific outcome (HR, 0.53; 95% CI, 0.43 to 0.66; p<0.0001) reduced risk of cardiorenal secondary composite outcome (HR, 0.76: 95% CI, 0.67 to 0.87; p<0.0001) reduced risk of ESKD or kidney death (HR, 0.41; 95% CI, 0.20–0.82; p=0·012) 46% reduction in sustained decline in eGFR by at least 40% to less than 60 mL/min/ 1·73 m^2 (HR, 0.54; 95% CI, 0.43 to 0.67; p<0.0001) DECLARE-TIMI 58, 2021 Dapagliflozin group (versus placebo) had reduced risk of kidney-specific outcome (HR, 0.51; 95% CI, 0.37 to 0.69) and CV death or HHF (HR, 0.84; 95% CI, 0.67 to 1.04) higher eGFR (p<0.001) lowered HbA1C, SBP, and urinary albumin-to-creatinine ratio (p<0.001)
EMPA-REG^Citation38	Randomized, double-blind, placebo-controlled study	Long-term kidney effects of empagliflozin	Patients with T2DM eGFR of at least 30 mL/minute per 1.73 m^2	4124	Empagliflozin 10 mg or 25 mg versus placebo	Empagliflozin group (versus placebo) had significant relative risk reduction of 44% of doubling of the serum creatinine level 55% lower relative risk of kidney replacement therapy
EMPEROR-Reduced^Citation14	Randomized, event-driven double-blind, parallel-group, placebo-controlled study	Efficacy and safety of once daily empagliflozin	Patients with chronic HFrEF	3730	Empagliflozin 10 mg versus placebo	Empagliflozin group (versus placebo) had slower annual rate of decline in the estimated glomerular filtration rate (−0.55 versus −2.28 mL per minute per 1.73 m^2 of body-surface area per year, p<0.001)
VERTIS^Citation36	Randomized, double-blind, placebo-controlled multicentric study	CV outcomes with ertugliflozin in subjects with T2DM and established atherosclerotic cardiovascular disease	Patients with T2DM established ASCVD	8246	Ertugliflozin 5 mg versus ertugliflozin 15 mg versus matched placebo once daily (1:1:1)	Ertugliflozin group (versus placebo) had lower risk of death from kidney causes, kidney replacement therapy, or doubling of the serum creatinine level (HR, 0.81; 95.8% CI, 0.63 to 1.04) death from CV causes (HR, 0.92; 95.8% CI, 0.77 to 1.11)

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CI, confidence interval; CKD, chronic kidney disease; CV, cardiovascular; ESKD, end-stage kidney disease; eGFR, estimated glomerular filtration rate; HbA_1C, glycated haemoglobin; HHF, hospitalization for heart failure; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; MI, myocardial infarction; SBP, systolic blood pressure; SGLT-2i, sodium-glucose cotransporter 2 inhibitor; T2DM, type 2 diabetes mellitus.

Figure 3 Mechanism of action of SGLT-2i and RAASi.

Abbreviations: RAASi, renin-angiotensin-aldosterone system inhibitor; SGLT-2i, sodium-glucose cotransporter-2 inhibitor.

Figure 4 Algorithm for management of CKD in patients with hypertension.

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; RAASi, renin-angiotensin-aldosterone system inhibitors; SGLT-2i, sodium-glucose cotransporter-2 inhibitor.

Figure 5 Algorithm for management of patients with DKD.

Notes: *Add-on GLP-1RA for uncontrolled metabolic risk. **GLP-1RA is preferred with coexisting uncontrolled metabolic risks. ***As an alternative if SGLT-2i is contraindicated and as an add-on for uncontrolled metabolic risks.

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; DKD, diabetic kidney disease; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HHF, hospitalization for heart failure; SGLT-2i, sodium-glucose cotransporter-2 inhibitor; UACR, urinary albumin-creatinine ratio.

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