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This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.

INVOKANA® (canagliflozin)

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Comparison of INVOKANA to Other SGLT2 Inhibitors

Last Updated: 10/07/2024

Summary

There are no phase 3 clinical studies that directly compare the safety and efficacy of INVOKANA to other sodium-glucose cotransporter-2 (SGLT2) inhibitors, including dapagliflozin, empagliflozin, and ertugliflozin. An indirect comparison between INVOKANA and other SGLT2 inhibitors cannot be made due to differences in patient populations, study designs, and procedures.
Summary information on each product is provided (see Table: Summary of INVOKANA, Dapagliflozin, Empagliflozin, and Ertugliflozin). The summary table does not imply head-to-head comparison. Please refer to each product's Full Prescribing Information for complete information.
A phase 1, randomized, double-blind, crossover study in healthy subjects (N=54) compared the pharmacodynamic effects of canagliflozin 300 mg and dapagliflozin 10 mg on urinary glucose excretion (UGE), renal threshold for glucose (RT_G), and postprandial glucose (PPG). Canagliflozin 300 mg was associated with a greater increase in UGE, a greater reduction in RT_G, and smaller excursions in PPG compared with dapagliflozin 10 mg.¹

Summary of INVOKANA², Dapagliflozin³, Empagliflozin⁴, and Ertugliflozin⁵

	INVOKANA²	Dapagliflozin³	Empagliflozin⁴	Ertugliflozin⁵
Boxed Warning	-	-	-	-
Indications and Usage	Adjunct to diet and exercise to improve glycemic control in adults with T2DM To reduce the risk of MACE in adults with T2DM and established CVD To reduce the risk of ESKD, doubling of serum creatinine, CV death, and hospitalization for heart failure in adults with T2DM and diabetic nephropathy with albuminuria greater than 300 mg/day	Adjunct to diet and exercise to improve glycemic control in adults with T2DM To reduce the risk of HHF in adults with T2DM and established CVD or multiple CV risk factors To reduce the risk of CV death and HHF in adults with heart failure with reduced ejection fraction (NYHA class II-IV) To reduce the risk of sustained eGFR decline, ESKD, CV death and HHF in adults with chronic kidney disease at risk of progression	Adjunct to diet and exercise to improve glycemic control in adults with T2DM To reduce the risk of CV death in adult patients with T2DM and established CVD To reduce the risk of CV death plus hospitalization for heart failure in adults with heart failure and reduced ejection fraction	Adjunct to diet and exercise to improve glycemic control in adults with T2DM
Limitation of Use	INVOKANA is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus INVOKANA is not recommended for use to improve glycemic control in adults with T2DM with an eGFR <30 mL/min/1.73 m²	Dapagliflozin is not recommended in patients with T1DM. Dapagliflozin is not recommended for use to improve glycemic control in adults with T2DM with eGFR <45 mL/min/1.73 m² Dapagliflozin is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for the treatment of kidney disease	Empagliflozin is not recommended in patients with T1DM. It may increase the risk of DKA in these patients. Empagliflozin is not recommended for use to improve glycemic control in adults with T2DM with an eGFR <30 mL/min/1.73 m²	Ertugliflozin is not recommended in patients with T1DM. It may increase the risk of DKA in these patients.
Recommended Starting Dose	INVOKANA 100 mg once daily, taken before the first meal of the day (see also Food Effects & PK/PD) For additional glycemic control, the dosage of INVOKANA may be increased to the maximum recommended dosage of 300 mg once daily.	Dapagliflozin 5 mg once daily, taken in the morning, with or without food (see also Food Effects & PK/PD)	Empagliflozin 10 mg once daily in the morning, taken with or without food (see also Food Effects & PK/PD)	Ertugliflozin 5 mg once daily, taken in the morning with or without food (see also Food Effects & PK/PD)
Dose Adjustments	Increase to 300 mg once daily if tolerating 100 mg once daily, have an eGFR of ≥60 mL/min/1.73 m2 Increase to 200 mg once daily if tolerating 100 mg once daily, have an eGFR of <60 mL/min/1.73 m2 Withhold INVOKANA at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. Resume INVOKANA when the patient is clinically stable and has resumed oral intake	Increase to 10 mg once daily if tolerating 5 mg once daily and require additional glycemic control To reduce the risk of HHF, the recommended dose of dapagliflozin is 10 mg once daily	In patients tolerating, the dose may be increased to 25 mg	Increase to 15 mg once daily if tolerating 5 mg once daily and needing additional glycemic control
Moderate Renal Impairment	INVOKANA is limited to 100 mg once daily at eGFR 30 to <60 mL/min/1.73 m²	Not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR <45 mL/min/1.73 m²	Empagliflozin should not be initiated for glycemic control in patients with an eGFR <30 mL/min/1.73 m²	Ertugliflozin should not be initiated in patients with an eGFR <45 mL/min/1.73 m²
eGFR limits	INVOKANA is limited to 100 mg once daily at eGFR 30 to <60 mL/min/1.73 m² INVOKANA should not be initiated at eGFR <30 mL/min/1.73 m²; however, patients with albuminuria >300 mg/day may continue 100 mg once daily to reduce the risk of ESKD, doubling of serum creatinine, CV death, and hospitalization for heart failure INVOKANA is contraindicated in patients on dialysis	Not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR <45 mL/mind/1.73 m² Initiation of dapagliflozin is not recommended in patients with an eGFR <25 mL/min/1.73 m², however patients may continue 10 mg once daily to reduce the risk of eGFR decline, ESKD, CV death, and HHF	Insufficient data to provide dosing recommendations in patients: Who have T2DM and established CVD with an eGFR <30 mL/min/1.73 m² Who have heart failure with reduced ejection fraction with an eGFR <20 mL/min/1.73 m²	Do not use ertugliflozin in patients with an eGFR <45 mL/min/1.73 m²
Dosage Forms and Strengths	100 mg, 300 mg tablets	5 mg, 10 mg tablets	10 mg, 25 mg tablets	5 mg, 15 mg tablets
Contraindications	History of a serious hypersensitivity reaction to INVOKANA such as anaphylaxis or angioedema [see Warnings and Precautions (5.8) and adverse reactions (6.1, 6.2) of the Prescribing Information].	History of a serious hypersensitivity reaction to dapagliflozin Patients on dialysis	History of serious hypersensitivity reaction to empagliflozin Patients on dialysis	History of serious hypersensitivity reaction to ertugliflozin Patients on dialysis
Warnings and Precautions	Diabetic ketoacidosis in patients with type 1 diabetes mellitus and other ketoacidosis Lower limb amputation Volume depletion Urosepsis and pyelonephritis Hypoglycemia with concomitant use with insulin and insulin secretagogues Necrotizing fasciitis of the perineum (Fournier’s gangrene) Genital mycotic infections Hypersensitivity reactions Bone fracture	Ketoacidosis in patients with T2DM. Volume depletion Urosepsis and pyelonephritis Hypoglycemia with concomitant use with insulin and insulin secretagogues Necrotizing fasciitis of the perineum (Fournier’s gangrene) Genital mycotic infections	Ketoacidosis Volume depletion Urosepsis and pyelonephritis Hypoglycemia with concomitant use with insulin and insulin secretagogues Necrotizing fasciitis of the perineum (Fournier’s gangrene) Genital mycotic infections Hypersensitivity reactions	Ketoacidosis Lower limb amputation Volume depletion Urosepsis and pyelonephritis Hypoglycemia with concomitant use with insulin or insulin secretagogues Necrotizing fasciitis of the perineum (Fournier’s gangrene) Genital mycotic infections
Adverse Reactions and Drug-Drug Interactions
Most Common (≥5%) Adverse Reactions in Pooled PBO-Controlled Studies	Female genital mycotic infections Urinary tract infections Increased urination	Female genital mycotic infections Nasopharyngitis Urinary tract infections	Urinary tract infection Female genital mycotic infections	Female genital mycotic infections
Other Adverse Reactions (≥2%) in Pooled PBO-Controlled Studies	Male genital mycotic infections Vulvovaginal pruritus Thirst Constipation Nausea	Back pain Increased urination Male genital mycotic infections Nausea Influenza Dyslipidemia Constipation Discomfort with urination Pain in extremity	Upper respiratory tract infection Increased urination Dyslipidemia Arthralgia Male genital mycotic infections Nausea	Male genital mycotic infections Urinary tract infections Headache Vaginal pruritus Increased urination Nasopharyngitis Back pain Weight decreased Thirst
Additional Adverse Reactions from Clinical Studies Experience	Please refer to the full prescribing information for more information	Please refer to the full prescribing information for more information	Please refer to the full prescribing information for more information	Please refer to the full prescribing information for more information
Drug-Drug Interactions	UGT enzyme inducers (eg, rifampin): CANA exposure reduced UGT enzyme inducer and patients with eGFR ≥60 mL/min/1.73 m²: consider increasing dose from 100 mg once daily to 200 mg (taken as two 100 mg tablets) once daily in patients currently tolerating 100 mg. The dose may be increased to 300 mg once daily in patients currently tolerating 200 mg and who require additional glycemic control UGT enzyme inducer and patients with eGFR <60 mL/min/1.73 m²: consider increasing dose from 100 mg once daily to 200 mg (taken as two 100 mg tablets) once daily in patients currently tolerating 100 mg. Consider adding another AHA in patients who require additional glycemic control Monitor digoxin levels Positive Urine Glucose Test; alternative method to monitor glycemic control recommended Interference with 1,5-AG Assay; alternative method to monitor glycemic control recommended	Positive Urine Glucose Test; alternative method to monitor glycemic control recommended Interference with 1,5-AG Assay; alternative method to monitor glycemic control recommended	Diuretics Insulin or insulin secretagogues Positive urine glucose test; alternative method to monitor glycemic control recommended Interference with 1,5-AG assay; alternative method to monitor glycemic control recommended	Insulin or insulin secretagogues Positive urine glucose test; alternative method to monitor glycemic control recommended Interference with 1,5-AG assay; alternative method to monitor glycemic control recommended
Use in Specific Populations
Use in Pregnancy	Not recommended during the second and third trimesters of pregnancy
Use in Nursing Mothers	Discontinue drug or nursing
Use in Pediatrics	Safety and effectiveness in age <18 not established
Use in Geriatrics	Higher incidence of adverse reactions related to reduced intravascular volume, particularly at the 300 mg daily dose	No dosage adjustment is recommended based on age Higher incidence of adverse reaction of hypotension	Higher incidence of adverse reactions related to volume-depletion and UTI Diminished glycemic efficacy in elderly patients with renal impairment	No dosage adjustment is recommended based on age Higher incidence of adverse reactions related to volume depletion
Use in Renal Impairment	Moderate renal impairment: Less overall glycemic efficacy and transient increases in serum potassium Patients with renal impairment may also be more likely to experience hypotension and may be at higher risk for acute kidney injury INVOKANA is limited to 100 mg once daily at eGFR 30 to <60 mL/min/1.73 m2 Efficacy and safety studies with INVOKANA did not enroll patients with ESKD on dialysis or patients with an eGFR <30 mL/min/1.73 m² INVOKANA is contraindicated in patients with ESKD on dialysis	Moderate renal impairment: Patients with diabetes and renal impairment may be more likely to experience hypotension and may be at a higher risk for acute kidney injury secondary to volume depletion Higher incidence of bone fractures compared to placebo among patients with eGFR 30 to <60 mL/min/1.73 m² Dapagliflozin should not be initiated in patients without established CV disease or CV risk factors when eGFR is <45 mL/min/1.73 m² Safety and efficacy in severe renal impairment are not established (<25 mL/min/m²) Dapagliflozin is contraindicated in patients on dialysis	Moderate renal impairment: Decreased glucose lowering benefit Increased risks of renal impairment, volume depletion adverse reactions and urinary tract infection-related adverse reactions with worsening renal function Empagliflozin should not be initiated in patients without established CV disease or CV risk factors when eGFR is <30 mL/min/1.73 m² Consistent CV death findings in a subgroup of patients with eGFR <60 mg/min/1.73 m² in a CV outcomes study Safety and efficacy in severe renal impairment (<20 mL/min/m²) are not established Empagliflozin is contraindicated in patients on dialysis	Those with moderate renal impairment did not have improvement in glycemic control Ertugliflozin is contraindicated in patients on dialysis
Use in Hepatic Impairment	Not studied in patients with severe hepatic impairment and is therefore not recommended	No dose adjustments. Assess risk vs benefit in severe hepatic impairment since safety and efficacy not evaluated	May be used in patients with hepatic impairment	No dosage adjustment for mild or moderate hepatic impairment. Not recommended in patients with severe hepatic impairment
Clinical Pharmacology
Mechanism of Action	SGLT2 inhibitor; reduces reabsorption of filtered glucose and lowers the RT_G, and thereby increases UGE
UGE	~100 g/day^k	~70 g/day	Empagliflozin 10 mg: ~64 g/day Empagliflozin 25 mg: ~78 g/day	See note
Caloric Loss^a (1 g =~4 kcal)	~400 kcal/day	~280 kcal/day	~256 - 312 kcal/day	See note
Food Effects & PK/PD	INVOKANA may be taken with or without food. Co-administration of a high-fat meal with CANA had no effect on the PK of CANA. In single-dose studies in healthy and type 2 diabetic subjects, treatment with CANA 300 mg before a mixed-meal delayed intestinal glucose absorption and reduced PPG (potentially due to transient intestinal SGLT1 inhibition). Glucose malabsorption was not reported.⁶^,⁷ Based on the potential to reduce postprandial plasma glucose excursions due to delayed intestinal glucose absorption, it is recommended that INVOKANA be taken before the first meal of the day	Administration of dapagliflozin with a high-fat meal decreases its C_max by up to 50% and prolongs T_max by approximately 1 hour but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and dapagliflozin can be administered with or without food	Administration of empagliflozin 25 mg after intake of a high-fat and high-calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and C_max decreased by approximately 37%, compared to fasted condition. The observed effect of food on empagliflozin PK was not considered clinically relevant and empagliflozin may be administered with or without food	Administration of ertugliflozin with a high-fat meal and high-calorie meal decreases ertugliflozin C_max by 29% and prolongs T_max by 1 hour but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and ertugliflozin may be administered with or without food
PK	Half-life (t1/2): 10.6 hours and 13.1 hours for the 100 mg and 300 mg doses, respectively Metabolism: Oglucuronidation is the major metabolic elimination pathway for CANA, which is mainly glucuronidated by UGT1A9 and UGT2B4. CYP3A4-mediated (oxidative) metabolism is minimal (approximately 7%) in humans Excretion: ~33% excreted in urine	Half-life (t1/2): approximately 12.9 hours for 10-mg dose Metabolism: The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans Excretion: Dapagliflozin and related metabolites are primarily eliminated via the renal pathway	Half-life (t1/2): 12.4 hours Metabolism: Primary route suggested to be glucuronidation by UGT2B7, UGT1A3, UGT1A8, and UGT1A9. No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide) Excretion: ~95.6% eliminated in feces (41.2%; majority as unchanged drug) or urine (54.4%; approximately half as unchanged drug)	Half-life (t1/2): Approximately 16.6 hours Metabolism: The primary route of metabolism is via UGT1A9 and UGT2B7-mediated O-glucuronidation. CYP-mediated metabolism is minimal Excretion: ~40.9% in feces (33.8% unchanged); ~50.2% excreted in urine (1.5% unchanged)
Clinical Studies Overview
Clinical Studies: Glycemic Control Trials in Adults with T2DM	Monotherapy Initial therapy in combo with metformin XR In combo with metformin, sulfonylurea, metformin + sulfonylurea, metformin + a thiazolidinedione (i.e. pioglitazone), or insulin (± other AHAs) Vs sitagliptin + metformin and Vs sitagliptin with each added onto metformin and sulfonylurea Vs glimepiride, each added onto metformin In adults 55 to 80 years of age In patients with moderate renal impairment	Monotherapy Initial therapy in combo with metformin XR Vs glipizide added onto metformin Add-on combination with metformin or glimepiride or metformin + sulfonylurea or pioglitazone or DPP4 inhibitor (± metformin) or insulin (± other oral AHAs) In combo with a GLP-1 agonist (exenatide extended-release) added-on to metformin Monotherapy in patients with moderate renal impairment	Monotherapy Add-on combination with metformin or metformin + sulfonylurea or linagliptin + metformin or pioglitazone (± metformin) or insulin (± metformin and/or sulfonylureas) or MDI insulin (± metformin) Vs glimepiride, each added onto metformin Monotherapy in patients with mild, moderate, and severe renal impairment	Monotherapy Add-on combination with metformin or metformin and sitagliptin or sitagliptin or insulin (± metformin) or metformin and sulfonylurea VS glimepiride added onto metformin In combo with sitagliptin and vs sitagliptin, as add-on to metformin Monotherapy in patients with moderate renal impairment
Clinical Studies: CV Outcomes in Patients with T2DM and Atherosclerotic CVD	Integrated analysis of 2 trials (CANVAS and CANVAS-R) evaluated INVOKANA vs PBO, each added to and used concomitantly with SOC treatments for diabetes and atherosclerotic CVD in patients with established CVD or ≥2 risk factors for CVD CANA (100 mg and 300 mg), N=5795 PBO, N=4347	DECLARE-TIMI 58⁸ evaluated dapagliflozin vs PBO, each added to SOC for T2DM and atherosclerotic CVD in patients with established CVD or multiple risk factors for CVD Dapagliflozin 10 mg, N=8582 PBO, N=8578	EMPA-REG OUTCOME study evaluated empagliflozin vs PBO, each added to and used concomitantly with SOC treatments for diabetes and atherosclerotic CVD in patients with established, stable, atherosclerotic CVD EMPA, N=4687 PBO, N=2333	None specified
Clinical Studies: Renal and CV Outcomes in Patients with Diabetic Nephropathy and Albuminuria	CREDENCE compared CANA with PBO in patients with T2DM, an eGFR ≥30 to <90 mL/min/1.73 m², and albuminuria (urine albumin/creatinine >300 to ≤5000 mg/g) who were receiving SOC, including a maximum-tolerated, labeled daily dose of an ACEi or ARB Primary objective was to assess the efficacy of CANA vs PBO in reducing the composite endpoint of ESKD, doubling of serum creatinine, and renal or CV death CANA 100 mg, N=2202 PBO, N=2199	None specified	None specified	None specified
Study Durations	Ranged from 18 to 26 weeks for PBO-controlled studies (not including extension periods) 52 weeks for active-controlled studies vs sitagliptin and vs glimepiride (not including extension periods) Mean exposure duration of 149 weeks in the integrated analysis of CV outcomes trials (mean exposure 4.3 years in CANVAS and 1.8 years in CANVAS-R). Patients were followed up to 338 weeks as shown in Kaplan-Meier curve depicting time to first occurrence of MACE in the integrated analysis (see Figure 3 in full prescribing information) The median follow-up duration for the 4401 randomized subjects within CREDENCE was 137 weeks	24 weeks for PBO-controlled studies 52 weeks for active-controlled study vs glipizide Median exposure of 4.2 years in DECLARE-TIMI 58⁸	24 weeks for PBO-controlled studies 52 weeks for active-controlled vs glimepiride 78 weeks for PBO-controlled combo insulin study Median 3.1 years for CV outcomes trial	26 weeks for PBO-controlled studies 52 weeks for active-controlled vs glimepiride 26 weeks for active-controlled vs and add-on to sitagliptin study
Efficacy
HbA1C - Primary Endpoint
Monotherapy, LSM change from BL (%)	100 mg (BL 8.06): 0.77 300 mg (BL 8.01): -1.03 PBO (BL 7.97): +0.14	5 mg (BL 7.8): -0.8 10 mg (BL 8.0): -0.9 PBO (BL 7.8): -0.2	10 mg (BL 7.9): -0.7 25 mg (BL 7.9): -0.8 PBO (BL 7.9): 0.1	5 mg (BL 8.2): -0.7 15 mg (BL 8.4): -0.8 PBO (BL 8.1): -0.2
Initial Therapy with Combination Metformin (XR), LSM change from BL (%)	Initial therapy combo metformin XR (inclusion HbA1C 7.5 to 12%): 100 mg (BL 8.8): -1.37 300 mg (BL 8.8): -1.42 100 mg/metformin XR (BL 8.8): -1.77 300 mg/metformin XR (BL 8.9): -1.78 MET XR (BL 8.8): -1.30	5 mg initial therapy combo metformin XR (inclusion HbA1C 7.5 to 12%): 5 mg + metformin XR (BL 9.2): -2.1 5 mg + PBO (BL 9.1): -1.2 Metformin XR + PBO (BL 9.1): -1.4 10 mg initial therapy combo metformin XR (inclusion HbA1C 7.5 to 12%): 10 mg + metformin XR (BL 9.1): -2.0 10 mg + PBO (BL 9.0): -1.5 Metformin XR + PBO (BL 9.0): -1.4	None specified	None specified
Studies/Analyses with High BL HbA1C, LSM change from BL (%)	Monotherapy Subgroup Analysis (HbA1C ≥9.0%):⁹ 100 mg: -1.29 300 mg: -1.83 PBO: -0.18 Monotherapy substudy (Inclusion HbA1C >10 to ≤12%):⁹ 100 mg (BL 10.6): -2.1 300 mg (BL 10.6): -2.6 INVOKANA vs sitagliptin, combo metformin + sulfonylurea (BL HbA1C ≥9% Subgroup Analysis):¹⁰ INVOKANA 300 mg: -1.99 Sitagliptin 100 mg: -1.44 Initial therapy combo metformin XR (Inclusion HbA1C 7.5 -12%): See Initial Therapy with Combination Metformin XR	5 mg initial therapy combo metformin XR (inclusion HbA1C 7.5 to 12%): 5 mg + metformin XR (BL 9.2): -2.1 5 mg + PBO (BL 9.1): -1.2 Metformin XR + PBO (BL 9.1): -1.4 10 mg initial therapy combo metformin XR (inclusion HbA1C 7.5 to 12%): 10 mg + metformin XR (BL 9.1): -2.0 10 mg + PBO (BL 9.0): -1.5 Metformin XR + PBO (BL 9.0): -1.4	None specified	None specified
HbA1C Across Multiple Add-on Combo AHA Studies^b, LSM change from BL (%), range	100 mg (BL 7.78-8.33): -0.7 to -0.89 300 mg (BL 7.79-8.28): -0.79 to -1.06 PBO (BL 7.8-8.49): -0.26 to 0.04 Active comparators (BL 7.83 -8.13): -0.66 to -0.81	5 mg (BL 8.1-8.6): -0.6 to -0.8 10 mg (BL 7.7-8.6): -0.45 to -1.0 PBO (BL 7.8-8.5): -0.4 to +0.04 Active comparator (BL 7.7): -0.5	10 mg (BL 7.9-8.3): -0.4 to -0.8 25 mg (BL 7.9-8.3): -0.6 to -0.8 PBO (BL 7.9-8.2): 0.1 to -0.2 Active comparator (BL 7.9): -0.7	5 mg (BL 7.8-8.1): -0.5 to -0.7 15 mg (BL 7.8-8.0): -0.5 to -0.8 PBO (BL 8.0): -0.2 Active comparator (BL 7.8): -0.6
MACE – Primary Endpoint
Composite of CV death, nonfatal MI, nonfatal stroke	CANA: 585 (9.2%) PBO: 426 (10.4%) HR: 0.86 (0.75, 0.97)	Dapagliflozin: 756 (8.8%)⁸ PBO: 803 (9.4%) HR: 0.93; 95% CI: 0.84-1.03	EMPA: 490 (10.5%) PBO: 282 (12.1%) HR: 0.86 (0.74, 0.99)	None specified
Nonfatal MI	CANA: 215 (3.4%) PBO: 159 (3.9%) HR: 0.85 (0.69, 1.05)	Dapagliflozin: 393 (4.6%) PBO: 441 (5.1%) HR: 0.89; 95% CI: 0.77-1.01	EMPA: 213 (4.5%) PBO: 121 (5.2%) HR: 0.87 (0.70, 1.09)	None specified
Nonfatal stroke	CANA: 158 (2.5%) PBO: 116 (2.8%) HR: 0.90 (0.71, 1.15)	Dapagliflozin: 235 (2.7%) PBO: 231 (2.7%) HR: 1.01; 95% CI: 0.84-1.21 ischemic stroke	EMPA: 150 (3.2%) PBO: 60 (2.6%) HR: 1.24 (0.92, 1.67)	None specified
CV death	CANA: 268 (4.1%) PBO: 185 (4.6%) HR: 0.87 (0.72, 1.06)	Dapagliflozin: 245 (2.9%) PBO: 249 (2.9%) HR: 0.98; 95% CI: 0.82-1.17	EMPA: 172 (3.7%) PBO: 137 (5.9%) HR: 0.62 (0.49, 0.77)	None specified
Time to first occurrence of ESKD (eGFR <15 mL/min/1.73 m², initiation of chronic dialysis, or renal transplant), doubling of serum creatinine, and renal or CV death - Primary Endpoint
Composite of ESKD, doubling of serum creatinine, renal death, or CV death	CANA: 245 (11.1%) PBO: 340 (15.5%) HR: 0.70 (0.59, 0.82)ⁿ	None specified	None specified	None specified
ESKD	CANA: 116 (5.3%) PBO: 165 (7.5%) HR: 0.68 (0.54, 0.86)	None specified	None specified	None specified
Doubling of serum creatinine	CANA: 118 (5.4%) PBO: 188 (8.5%) HR: 0.60 (0.48, 0.76)	None specified	None specified	None specified
Renal death	CANA: 2 (0.1%) PBO: 5 (0.2%) HR: --	None specified	None specified	None specified
CV death	CANA: 110 (5.0%) PBO: 140 (6.4%) HR: 0.78 (0.61, 1.00)	None specified	None specified	None specified
Selected Prespecified Secondary Endpoints
Systolic Blood Pressure, mean change from BL, range	-2.6 to -6.6 mmHg^c	-2.8 to -5.3 mmHg^d	-3.6 mmHg (vs glimepiride study) PBO-adjusted mean range: -2.6 to -4.8 mmHgⁱ	-3.8 to -5.7 mmHg^l
Body Weight, mean change from BL, range	-1.8 to -4.7%^e,f	+0.1 to -3.3 kg^g,h	-1.8 to -3.9%^e,j	-2.6 to -3.2 kg^g,m
Abbreviations: 1,5-AG, 1,5-anhydroglucitol; ACEi, angiotensin-converting enzyme inhibitor; AHA, antihyperglycemic agent; ARB, angiotensin receptor blocker; AUC, area under the curve; BL, baseline; CYP, Cytochrome P450; CANA, canagliflozin; C_max, maximum plasma concentration; combo, combination; CV, cardiovascular; CVD, cardiovascular disease; DPP4, Dipeptidyl peptidase 4; DKA, diabetic ketoacidosis; eGFR, estimated glomerular filtration rate; EMPA, empagliflozin; ESKD, end-stage kidney disease; ESRD, end-stage renal disease; GLP-1, glucagon-like peptide 1; HbA1C, hemoglobin A1C; HHF, hospitalization for heart failure; HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; LSM, least-squares mean; MACE, major adverse cardiovascular events; MI, myocardial infarction; NYHA, New York Heart Association; PBO, placebo; PD, pharmacodynamics; PK, pharmacokinetics; PPG, postprandial glucose; RT_G, renal threshold for glucose; SGLT1, sodium-glucose cotransporter-1; SGLT2, sodium-glucose cotransporter-2; SOC, standard of care; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; T_max, time to maximum plasma concentration; UGE, urinary glucose excretion; UGT, UDP-glucuronosyl transferase; UTI, urinary tract infection; XR, extended-release. Note: Difference in LSM UGE_0-24h placebo-corrected change from baseline to week 4: Ertugliflozin 5 mg: ~64 g/day¹¹;Based on the log-linear regression of change from baseline in 24-hour UGE versus BSA-unnormalized eGFR, the predicted mean change from baseline in 24-hour UGE values on day 1 for T2DM subjects.Ertugliflozin 15 mg, eGFR 105 mL/min: ~69 g/day; ertugliflozin 15 mg, eGFR 75 mL/min: ~39 g/day¹²; estimated caloric loss: ~156-276 kcal/day^aaCalculated based on 1 g of glucose excreted in the urine (UGE) equates to approximately 4 kcal of energy.⁹See UGE section for grams excreted. ^bIncludes add-on combination placebo- and active-controlled studies from Prescribing Information, excluding monotherapy studies (INVOKANA, dapagliflozin, empagliflozin, and ertugliflozin) and initial therapy in combination with metformin XR studies (dapagliflozin). ^cStudies included: monotherapy, add-on combination therapy with metformin, active-controlled study vs sitagliptin (each as add-on to metformin and sulfonylurea), add-on combination therapy with metformin and pioglitazone, add-on combination therapy with Insulin (± other AHAs). ^dStudies included: add-on combination with metformin, active-controlled study vs glipizide (each as add on to metformin), add-on combination therapy with a sulfonylurea, add-on combination therapy with a thiazolidinedione, add-on combination therapy with insulin. ^eReported in the full Prescribing Information as percent change in body weight from baseline. ^fStudies included: monotherapy, add-on combination therapy with metformin, vs Glimepiride (each as add on to metformin), add-on combination therapy with sulfonylurea, add-on combination therapy with metformin and sulfonylurea, active-controlled study vs sitagliptin (each as add-on to metformin and sulfonylurea), add-on combination therapy with metformin and pioglitazone, add-on combination therapy with insulin (± other AHAs). ^gReported in the full Prescribing Information as change in kilograms from baseline. ^hStudies included: initial combination therapy with metformin XR, add-on combination with metformin, active-controlled study vs glipizide (each as add-on to metformin), add-on combination therapy with other AHAs (sulfonylurea, thiazolidinedione, DPP4 Inhibitor ± metformin, insulin ± up to 2 Oral AHAs). ⁱStudies included: monotherapy and add-on combination therapy with metformin. ^jStudies included: monotherapy, add-on combination therapy with metformin, add-on combination therapy with metformin and sulfonylurea, active-controlled study vs glimepiride in combination with metformin, add-on combination therapy with pioglitazone with or without metformin, and add-on combination with insulin with or without metformin and/or sulfonylureas. ^kIncreases in mean UGE with either 100 mg or 300 mg of canagliflozin. ^lStudies included: add-on combination with metformin and add-on combination with metformin and sitagliptin. ^mStudies included: monotherapy, add-on combination therapy with metformin, active-controlled study vs glimepiride (each as add-on to metformin), add-on combination with metformin and sitagliptin. ⁿP-value<0.0001.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 10 September 2024.

References

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