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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 Dapagliflozin

Last Updated: 03/07/2024

Summary

There are no phase 3 clinical studies that directly compare safety and efficacy of INVOKANA and dapagliflozin (DAPA).
An indirect comparison between INVOKANA and DAPA cannot be made due to differences in patient populations, study designs, and procedures. A summary of information on each product is provided and does not imply a 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 adults (N=54) compared the pharmacodynamic (PD) effects of canagliflozin (CANA) 300 mg and DAPA 10 mg on urinary glucose excretion (UGE), renal threshold for glucose (RT_G), and postprandial glucose (PPG). CANA 300 mg was associated with a greater increase in UGE, reduction in RT_G, and smaller excursions in PPG compared with DAPA 10 mg.¹
In a cost-effectiveness analysis of INVOKANA 100 mg or DAPA 10 mg added to standard of care (SoC) vs SoC alone in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM), INVOKANA + SoC and DAPA + SoC, respectively, yielded cost savings of Canadian dollars (C$) 33,460 and C$26,764 and generated 1.38 and 1.44 additional quality-adjusted life-years (QALYs) compared with SoC alone over the lifetime horizon.²
In a 30-year cost-effectiveness analysis of INVOKANA vs DAPA added to metformin in T2DM patients, INVOKANA 300 mg was associated with lower costs and larger improvements in QALYs vs DAPA 10 mg.³
In a retrospective analysis of the prevalence of genitourinary infections in patients with T2DM receiving sodium-glucose cotransporter-2 (SGLT2) inhibitors, 2 of 14 patients (14.2%) receiving INVOKANA 100 mg and 6 of 34 patients (17.6%) receiving DAPA 5 mg or 10 mg had 1 or more episodes of genital mycotic infection.⁴
In a real-world analysis of glycemic control among patients with T2DM treated with INVOKANA vs DAPA, those treated with INVOKANA 300 mg had better A1C goal attainment and larger A1C reduction than those treated with DAPA 10 mg.⁵

CLINICAL STUDIES

There are no phase 3 clinical studies that directly compare safety and efficacy of INVOKANA and DAPA to improve glycemic control in T2DM patients.
An indirect comparison between INVOKANA and DAPA 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 and Dapagliflozin). The table below does not imply head-to-head comparison. Please refer to each product's Full Prescribing Information for complete information.

Summary of INVOKANA and Dapagliflozin

	INVOKANA⁶	Dapagliflozin⁷
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 HHF in adults with T2DM and diabetic nephropathy with albuminuria	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 HF with reduced ejection fraction (NYHA class II-IV)
Limitation of Use	INVOKANA is not recommended in patients with T1DM. It may increase the risk of DKA in these patients INVOKANA is not recommended for use to improve glycemic control in adults with T2DM with an eGFR <30 mL/min/1.73 m²	Not for treatment of T1DM or DKA
Recommended Starting Dose	INVOKANA 100 mg once daily, taken before the first meal of the day (see also Food Effects & PD/PK)	To improve glycemic control, recommended starting dose is dapagliflozin 5 mg once daily, taken in the morning, with or without food (see also Food Effects & PD/PK)
Dose Adjustments	Increase to 300 mg once daily if tolerating 100 mg daily, have an eGFR of ≥60 mL/min/1.73 m², and require additional glycemic control Dose adjustment for patients with renal impairment may be required Adjust INVOKANA dose when taken concomitantly with UGT inducer	Increase to 10 mg daily if tolerating 5 mg daily and require additional glycemic control To reduce the risk of HHF in adults with T2DM and established CVD or multiple CV risk factors, the recommended dose of dapagliflozin is 10 mg once daily To reduce the risk of CV death and HHF in HF with reduced ejection fraction, the recommended dose of dapagliflozin is 10 mg once daily No dose adjustment is needed in patients with eGFR ≥45 mL/min/1.73 m²
Moderate Renal Impairment	INVOKANA is limited to 100 mg once daily at eGFR 30 to <60 mL/min/1.73 m²	Dapagliflozin is not recommended at 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 HHF INVOKANA is contraindicated in patients on dialysis	Dapagliflozin is not recommended at eGFR <45 mL/min/1.73 m² Dapagliflozin should be discontinued in patients with eGFR <30 mL/min/1.73 m²
Dosage Forms and Strengths	100 mg, 300 mg tablets	5 mg, 10 mg tablets
Contraindications	History of a serious hypersensitivity reaction to INVOKANA Patients on dialysis	History of a serious hypersensitivity reaction to dapagliflozin Severe renal impairment (eGFR <30 mL/min/1.73 m²) or dialysis
Warnings and Precautions	Lower LimbAmputation Volume Depletion Ketoacidosis Urosepsis and Pyelonephritis Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) GMIs Hypersensitivity Reactions Bone Fracture	Volume Depletion Ketoacidosis Acute Kidney Injury Urosepsis and Pyelonephritis Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) GMIs
Adverse Reactions and Drug-Drug Interactions
Most Common (≥5%) Adverse Reactions in Pooled PBO-Controlled Studies	Female GMIs Urinary tract infections Increased urination	Female GMIs Nasopharyngitis Urinary tract infections
Other Adverse Reactions (≥2%) in Pooled PBO-Controlled Studies	Male GMIs Vulvovaginal pruritus Thirst Constipation Nausea	Back pain Increased urination Male GMIs Nausea Influenza Dyslipidemia Constipation Discomfort with urination Pain in extremity
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
Drug-Drug Interactions	UGT enzyme inducers (eg, rifampin): canagliflozin 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 Monitor serum lithium concentrations Positive Urine Glucose Test; alternative method to monitor glycemic control recommended Interference with 1,5-anhydroglucitol (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
Pharmacovigilance Assessment
Association between euDKA/DKA and SGLT2 inhibitors	Primary analysis (since some hypoglycemic agents can be used in nondiabetic population as well, such as SGLT-2 inhibitors for heart failure and GLP-1 receptor agonists for obesity, the primary analysis was divided into 2 groups, namely diabetes and no indication, to investigate the robustness of results):⁸ euDKA (No indication filter): N=46; ROR (95% CI), 1.95 (1.45-2.61); IC (95% CI), 0.92 (0.68-1.23) euDKA (DM): N=39; ROR (95% CI), 1.89 (1.37-2.61); IC (95% CI), 0.87 (0.63-1.21) DKA (No indication filter): N=1459; ROR (95% CI), 11.39 (10.74-12.08); IC (95% CI), 3.13 (2.95-3.32) DKA (DM): N=943; ROR (95% CI), 9.00 (8.37-9.69); IC (95% CI), 2.81 (2.61-3.02)	Primary analysis:⁸ euDKA (No indication filter): N=153; ROR (95% CI), 14.43 (12.16-17.12); IC (95% CI), 3.59 (3.03-4.26) euDKA (DM): N=73; ROR (95% CI), 9.99 (7.85-12.71); IC (95% CI), 3.11 (2.45-3.96) DKA (No indication filter): N=733; ROR (95% CI), 10.96 (10.14-11.85); IC (95% CI), 3.19 (2.95–3.44) DKA (DM): N=391; ROR (95% CI), 9.16 (8.21-10.22); IC (95% CI), 2.93 (2.63–3.27)
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 years not established
Use in Geriatrics	Higher incidence of ARs related to reduced intravascular volume, particularly with the 300 mg daily dose	Higher incidence of ARs related to volume depletion and renal impairment or failure
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: Did not have improvement in glycemic control Higher incidence of ARs related to renal function and more bone fractures Dapagliflozin should not be initiated at eGFR <45 mL/min/1.73 m² Safety and efficacy in severe renal impairment, ESRD, or dialysis not established
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
Clinical Pharmacology
Mechanism of Action	SGLT2 inhibitor; reduces reabsorption of filtered glucose and lowers renal threshold for glucose, thereby increasing UGE
UGE	~100 g/dayⁱ	~70 g/day
Caloric Loss^a (1 g = ~4 kcal)	~400 kcal/day	~280 kcal/day
Food Effects & PD/PK	INVOKANA may be taken with or without food. Co-administration of a high-fat meal with canagliflozin had no effect on the PK of canagliflozin. In single-dose studies in healthy and T2DM subjects, treatment with canagliflozin 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.⁹^,¹⁰ Based on potential to reduce PPG 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 C_max by up to 50% and prolongs T_max by ~1 hour but does not alter AUC as compared with fasted state. These changes are not considered to be clinically meaningful; dapagliflozin can be administered with or without food.
PK	Half-life (t_1/2): 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 canagliflozin, which is mainly glucuronidated by UGT1A9 and UGT2B4. CYP3A4-mediated (oxidative) metabolism is minimal (~7%) in humans Excretion: ~33% excreted in urine	Half-life (t_1/2): ~12.9 hours for 10-mg dose Metabolism: Primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans Excretion: Dapagliflozin and related metabolites are primarily eliminated via renal pathway
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 (ie, pioglitazone), or insulin (± other AHAs) Vs sitagliptin + metformin and Vs sitagliptin with each added onto metformin and sulfonylurea Vs glimepiride, each added to metformin In adults 55 to 80 years In patients with moderate renal impairment	Monotherapy Initial therapy in combo with metformin XR In combo with metformin, pioglitazone, glimepiride, sitagliptin (± metformin), metformin + sulfonylurea, or insulin (± other oral AHAs) Vs glipizide added onto metformin In combo with a GLP-1 agonist (exenatide extended-release) added to metformin In patients with moderate renal impairment
Clinical Study: Renal Outcomes in Patients with DM	Primary outcome:¹¹ The annual eGFR slope of INVOKANA (N=2100) was -1.24 (95% CI, -1.44 to -1.04) mL/min/1.73 m²	Primary outcome:¹¹ The annual eGFR slope of dapagliflozin (N=2214) was 1.14 (95% CI, -1.32 to -0.96) mL/min/1.73 m²
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 T2DM and atherosclerotic CVD in patients with established CVD or ≥2 risk factors for CVD INVOKANA (100 mg and 300 mg), N=5795 PBO, N=4347	DECLARE-TIMI 58¹² 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
Clinical Studies: Renal and CV Outcomes in Patients with Diabetic Nephropathy and Albuminuria	CREDENCE¹³ compared INVOKANA 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 standard of care, including a maximum-tolerated, labeled daily dose of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker Primary objective was to assess the efficacy of INVOKANA vs PBO in reducing the composite endpoint of ESKD, doubling of serum creatinine, and renal or CV death INVOKANA 100 mg, N=2202 PBO, N=2199	DAPA-CKD¹⁴ compared dapagliflozin with PBO in patients with CKD, with or without T2DM, an eGFR ≥25 to ≤75 mL/min/1.73 m², and albuminuria (urine albumin/creatinine ≥200 to ≤5000 mg/g) who were receiving standard of care, including a maximum-tolerated, labeled daily dose of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker Primary objective was to assess the efficacy of dapagliflozin vs PBO in reducing the composite endpoint of ≥50% decline in eGFR, ESKD, or renal or CV death Dapagliflozin 10 mg, N=2152 PBO, N=2152
Study Durations	18-26 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 (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 CREDENCE¹³ was 136 weeks	24 weeks for PBO-controlled studies 52 weeks for active-controlled study vs glipizide Median exposure of 4.2 years in DECLARE-TIMI 58¹² The median follow-up duration for the 4094 randomized subjects within DAPA-CKD¹⁴ was 125 weeks
Efficacy
A1C - 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
Initial Therapy with Combo Metformin XR, LSM change from BL (%)	Initial therapy combo metformin XR (inclusion A1C 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 Metformin XR (BL 8.8): -1.30	5 mg initial therapy combo metformin XR (inclusion A1C 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 A1C 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
Studies/Analyses with High BL A1C, LSM change from BL (%)	Monotherapy subgroup analysis (A1C ≥9.0%)¹⁵: 100 mg: -1.29 300 mg: -1.83 PBO: -0.18 Monotherapy substudy (inclusion A1C >10 to ≤12%)¹⁵: 100 mg (BL 10.6): -2.1 300 mg (BL 10.6): -2.6 INVOKANA vs sitagliptin, combo metformin + sulfonylurea (BL A1C ≥9% subgroup analysis)¹⁶: INVOKANA 300 mg: -1.99 Sitagliptin 100 mg: -1.44 Initial therapy combo metformin XR (inclusion A1C 7.5 to 12%)¹⁷: See Initial Therapy with Combo Metformin XR	5 mg initial therapy combo metformin XR (inclusion A1C 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 A1C 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
A1C 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
MACE – Primary Endpoint
Composite of CV death, nonfatal MI, nonfatal stroke	INVOKANA: 585 (9.2%) PBO: 426 (10.4%) HR: 0.86; 95% CI: 0.75-0.97	Dapagliflozin: 756 (8.8%)¹² PBO: 803 (9.4%) HR: 0.93; 95% CI: 0.84-1.03
Nonfatal MI	INVOKANA: 215 (3.4%) PBO: 159 (3.9%) HR: 0.85; 95% CI: 0.69-1.05	Dapagliflozin: 393 (4.6%) PBO: 441 (5.1%) HR: 0.89; 95% CI: 0.77-1.01
Nonfatal stroke	INVOKANA: 158 (2.5%) PBO: 116 (2.8%) HR: 0.90; 95% CI: 0.71-1.15 Nonfatal stroke	Dapagliflozin: 235 (2.7%) PBO: 231 (2.7%) HR: 1.01; 95% CI: 0.84-1.21 Ischemic stroke
CV death	INVOKANA: 268 (4.1%) PBO: 185 (4.6%) HR: 0.87; 95% CI: 0.72-1.06	Dapagliflozin: 245 (2.9%) PBO: 249 (2.9%) HR: 0.98; 95% CI: 0.82-1.17
Primary Composite Renal Endpoint
Composite of ESKD, doubling of serum creatinine, renal death, or CV death (CREDENCE¹³)	INVOKANA: 245 (11.1%) PBO: 340 (15.5%) HR: 0.70; 95% CI: 0.59-0.82^j	Composite of ≥50% decline in eGFR, ESKD, renal death, or CV death (DAPA-CKD¹⁴)	Dapagliflozin: 197 (9.2%) PBO: 312 (14.5%) HR: 0.61; 95% CI: 0.51-0.72^k
ESKD	INVOKANA: 116 (5.3%) PBO: 165 (7.5%) HR: 0.68; 95% CI: 0.54-0.86	ESKD	Dapagliflozin: 109 (5.1%) PBO: 161 (7.5%) HR: 0.64; 95% CI: 0.50-0.82^l
Doubling of serum creatinine	INVOKANA: 118 (5.4%) PBO: 188 (8.5%) HR: 0.60; 95% CI: 0.48-0.76	Decline in eGFR of ≥50%	Dapagliflozin: 112 (5.2%) PBO: 201 (9.3%) HR: 0.53; 95% CI: 0.42-0.67^l
Renal death	INVOKANA: 2 (0.1%) PBO: 5 (0.2%) HR: --	Renal death	Dapagliflozin: 2 (<0.1%) PBO: 6 (0.3%) HR: NA; 95% CI: NA^l
CV death	INVOKANA: 110 (5.0%) PBO: 140 (6.4%) HR: 0.78; 95% CI: 0.61-1.00	CV death	Dapagliflozin: 65 (3.0%) PBO: 80 (3.7%) HR: 0.81; 95% CI: 0.58-1.12^l
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
Body Weight, mean change from BL, range	-1.8 to -4.7%^e,f	+0.1 to -3.3 kg^g,h
Abbreviations: 1,5-AG, 1,5-anhydroglucitol; A1C, hemoglobin A1C; AHAs, antihyperglycemic agents; ARs, adverse reactions; AUC, area under the curve; BL, baseline; C_max, maximum plasma concentration; combo, combination; CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; CYP, cytochrome P450; DKA, diabetic ketoacidosis; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; ESRD, end-stage renal disease; euDKA, euglycemic diabetic ketoacidosis; GLP-1, glucagon-like peptide-1; GMIs, genital mycotic infections; HF, heart failure; HHF, hospitalization for heart failure; HR, hazard ratio; IC (95% CI), information components with 95% credible interval; LDL-C, low-density lipoprotein cholesterol; LSM, least-squares mean; MACE, major adverse cardiovascular events; MI, myocardial infarction; NA, not applicable; NYHA, New York Heart Association; PBO, placebo; PD, pharmacodynamics; PK, pharmacokinetics; PPG, postprandial glucose; ROR, reporting odd ratio; SCr, serum creatinine; 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 taken to reach maximum plasma concentration; UGE, urinary glucose excretion; UGT, UDP-glucuronosyl transferase; XR, extended-release. ^aCalculated based on 1 g of UGE; equates to ~4 kcal of energy.¹⁸ See UGE section for grams excreted. ^bIncludes add-on combo PBO- and active-controlled studies from Prescribing Information, excluding monotherapy studies (INVOKANA and dapagliflozin) and initial therapy in combo with metformin XR studies (dapagliflozin). ^cStudies included: monotherapy, add-on combo with metformin, active-controlled study vs sitagliptin (each as add-on to metformin and sulfonylurea), add-on combo with metformin and pioglitazone, add-on combo with insulin (± other AHAs). ^dStudies included: add-on combo with metformin, active-controlled study vs glipizide (each as add on to metformin), add-on combo with a sulfonylurea, add-on combo with a thiazolidinedione, add-on combo with insulin. ^eReported in the full Prescribing Information as percent change in body weight from baseline. ^fStudies included: monotherapy, add-on combo with metformin, vs glimepiride (each as add on to metformin), add-on combo with sulfonylurea, add-on combo with metformin and sulfonylurea, active-controlled study vs sitagliptin (each as add-on to metformin and sulfonylurea), add-on combo with metformin and pioglitazone, add-on combo with insulin (± other AHAs). ^gReported in the full Prescribing Information as change in kilograms from baseline. ^hStudies included: initial combo with metformin XR, add-on combo with metformin, active-control (glipizide) (each as add-on to metformin), add-on to other AHAs (sulfonylurea, thiazolidinedione, dipeptidyl peptidase-4 inhibitor ± metformin, insulin ± up to 2 oral AHAs). ⁱIncreases in mean UGE with either 100 mg or 300 mg of INVOKANA. ^jP-value <0.0001. ^kP-value <0.001. ^lP-value NA.

Additional Information

Phase 1 Pharmacokinetic (PK)/PD Study

Sha et al (2014)¹ conducted a randomized, double-blind, 2-period crossover study comparing PD effects of CANA 300 mg and DAPA 10 mg on UGE, RT_G, and PPG excursion in healthy patients (N=54).

Patients were randomized to a treatment sequence with either CANA for 4 days followed by a washout period, then DAPA for 4 days, or vice versa.
Demographic and baseline characteristics were generally similar between groups.
CANA 300 mg was associated with a greater reduction in RT_G and a greater increase in UGE compared with DAPA 10 mg.
- For the first 4 hours after dosing, CANA 300 mg and DAPA 10 mg had similar effects on UGE and RT_G; however, for the rest of the 24-hour interval, CANA was associated with a larger increase in UGE and greater reduction in RT_G than DAPA.
- On day 4, mean 24-hour UGE was ~25% higher with CANA vs DAPA (51.4 g and 40.8 g, respectively).
- Total plasma CANA concentrations were higher than corresponding DAPA concentrations, but IC₅₀-normalized unbound plasma concentrations were generally similar, with lower normalized DAPA concentrations overnight vs CANA. Using normalized concentrations, the PK/PD relationship appeared virtually identical for both drugs, and greater effect of CANA on RT_G may be explained by higher normalized concentrations maintained by CANA overnight.
Treatment with CANA 300 mg delayed and reduced PPG excursion during a mixed-meal tolerance test compared with DAPA 10 mg.
- Compared to DAPA, CANA lowered PPGΔAUC_0-2h by ~10%; mean PPGΔAUC_0-2h was 65.9 h•mg/dL with CANA 300 mg and 73.5 h•mg/dL with DAPA 10 mg (least-squares mean difference: -7.58 h•mg/dL; P<0.0122).
Treatment with CANA 300 mg and DAPA 10 mg was generally well-tolerated in healthy patients, and incidence of adverse events observed was similar between groups.

REAL-World Evidence

Nguyen et al (2023)²evaluated the cost-effectiveness of adding INVOKANA 100 mg or DAPA 10 mg to SoC vs SoC alone in patients with CKD and T2DM.

This analysis used a Markov microsimulation model to simulate a hypothetical cohort of 1000 patients with CKD and T2DM. Baseline clinical and demographic characteristics were based on those observed in the CREDENCE trial for INVOKANA.¹³Costs were estimated from a healthcare system perspective and measured in 2021 C$, and effectiveness was measured in QALYs.
Over a patient's lifetime, INVOKANA + SoC and DAPA + SoC, respectively, yielded cost savings of C$33,460 and C$26,764 and generated 1.38 and 1.44 additional QALYs compared with SoC alone. The cost savings and QALY gains may be attributed to the delay for need of dialysis compared with SoC alone.
- Although QALY gains with DAPA + SoC were higher than those with INVOKANA + SoC, this strategy was more costly, with the incremental cost-effectiveness ratio exceeding the willingness-to-pay threshold of C$50,000 per QALY.
Over shorter time horizons of 5 or 10 years, DAPA + SoC generated cost savings and QALY gains compared with INVOKANA + SoC.

Neslusan et al (2018)³ evaluated cost-effectiveness of INVOKANA 300 mg vs DAPA 10 mg in T2DM patients inadequately controlled on metformin monotherapy.

This 30-year, cost-effectiveness analysis utilized the validated Economic and Health Outcomes Model of T2DM (ECHO-T2DM) from the perspective of the third-party health care system in the United States (US).
Patient demographics, biomarker values, and treatment effects for the ECHO-T2DM model were derived from a network meta-analysis including studies of INVOKANA and DAPA in T2DM patients on background metformin. Costs were derived from US sources.
Over the 30-year period, INVOKANA 300 mg dominated DAPA 10 mg as add-on to metformin, with an estimated cost offset of $13,991, a life-year gain of 0.02, and a QALY gain of 0.08 compared with DAPA 10 mg.
- INVOKANA 300 mg was associated with greater A1C lowering, larger systolic blood pressure (SBP) reductions, and greater weight loss vs DAPA 10 mg, all of which contributed to cost offsets and QALY gains.

Shrikrishna et al (2023)⁴ conducted a retrospective analysis to determine the prevalence of genitourinary infections in patients with T2DM receiving SGLT2 inhibitors for at least 12 months. Of the 120 patients included in the study (mean [SD] duration of T2DM, 10.5 [6.4] years), 20 (16.7%) had 1 or more episodes of genital mycotic infection. This included 2 of 14 (14.3%) patients receiving INVOKANA 100 mg and 6 of 34 (17.6%) receiving DAPA 5 mg or 10 mg.

Blonde et al (2018)⁵ conducted a retrospective, matched cohort study comparing real-world effectiveness of INVOKANA 300 mg vs DAPA 10 mg on A1C reduction in T2DM patients.

De-identified claims data within the Optum Clinformatics database (January 1, 2014, to September 30, 2016) were utilized to identify patients newly initiated on INVOKANA 300 mg or DAPA 10 mg.
Key inclusion criteria included: ≥1 medical claim with T2DM diagnosis on or before index date; ≥18 years at time of initiation; ≥12 months of continuous eligibility preindex and ≥6 months postindex; ≥1 eGFR >60 mL/min/1.73 m² reading within 6 months prior to index date; and no pharmacy claims for other SGLT2 inhibitors within the preindex period. Key exclusion criteria included: switched antihyperglycemic agent (AHA) within 3 months preindex; claims for both INVOKANA and DAPA on index date; and ≥1 claim with pregnancy or gestational diabetes diagnosis during study period.
The recommended starting doses of INVOKANA and DAPA are 100 mg and 5 mg, respectively. The maximum doses of each drug (INVOKANA 300 mg and DAPA 10 mg) were chosen for evaluation based on previous clinical evidence demonstrating the largest A1C reduction.
Propensity score matching was used to create balanced cohorts.
The primary outcome was the proportion of patients with A1C <8.0% (HEDIS target) after 6 months of follow-up; secondary outcomes included proportion of patients with A1C <7.0% (American Diabetes Association target) and >9.0% (HEDIS poor control), and absolute change in A1C. Treatment patterns were also assessed during the postindex period.
A total of 2546 patients were initiated on either INVOKANA 300 mg (n=1982) or DAPA 10 mg (n=564). Of these, 558 INVOKANA patients were matched with 558 DAPA patients.
A significantly higher proportion of INVOKANA-treated patients vs DAPA-treated patients achieved the primary outcome of A1C <8.0% (70.8% vs 59.1%, respectively; odds ratio [OR], 1.60; 95% confidence interval [CI], 1.26-2.04; P=0.0001) and the secondary outcome of A1C <7.0% (36.7% vs 25.1%, respectively; OR, 1.75; 95% CI, 1.34-2.27; P<0.0001) at 6 months postindex (intent-to-treat [ITT] population).
The proportion with A1C >9.0% was similar among the INVOKANA and DAPA cohorts (12.0% vs 15.1%, respectively; OR, 0.77; 95% CI, 0.55-1.09; P=0.1386).
At 6 months postindex (ITT population), mean A1C was lower with INVOKANA than DAPA (7.57% vs 7.85%, respectively; mean difference: -0.28%; P=0.0003). Mean A1C reduction from baseline was -1.17% with INVOKANA 300 mg and -0.91% with DAPA 10 mg (difference of -0.26%; P=0.0049).
INVOKANA-treated patients were less likely to discontinue treatment (OR, 0.75; 95% CI, 0.57-0.99; P=0.0400) or switch medication (OR, 0.72; 95% CI, 0.54-0.96; P=0.0229) than DAPA-treated patients. The likelihood of adding an AHA was similar between cohorts (OR, 1.30; 95% CI, 0.96-1.74; P=0.0865).⁵

In a single-center study conducted in India, Babu (2018)¹⁹ directly compared efficacy of DAPA and INVOKANA in long-standing (>10 years) T2DM over 1 year. Patients were given DAPA 10 mg (N=100) or INVOKANA 100 mg (N=100) in addition to their current regimens (including metformin and a sulfonylurea) and had A1C >10%. For efficacy comparison, see Table: Change from Baseline to 1 Year in Efficacy Parameters. Incidence of genital mycotic infection was 2 and 3%, respectively, in the DAPA and INVOKANA groups. Incidence of urinary tract infection was 3% for each group.

Change from Baseline to 1 Year in Efficacy Parameters¹⁹

Efficacy Endpoints	DAPA 10 mg		INVOKANA 100 mg
Efficacy Endpoints	Baseline	1 year	Baseline	1 year
FPG (mg/dL)	180 (±58)	97 (±9)	158 (±45)	94 (±9)
PPG (mg/dL)	289 (±86)	163 (±22)	267 (±76)	159 (±22)
A1C (%)	9.9 (±1.9)	7.4 (±0.6)	9.5 (±1.7)	7.4 (±0.7)
BW (kg)	72 (±12)	69 (±11)	74 (±12)	70 (±10)
SBP (mm Hg)	-4 mm Hg (both groups)
Abbreviations: A1C, glycated hemoglobin; BW, body weight; DAPA, dapagliflozin; FPG, fasting plasma glucose; PPG, postprandial glucose; SBP, systolic blood pressure.

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 14 February 2024.

References

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