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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 Ertugliflozin

Last Updated: 10/07/2024

SUMMARY

There are no phase 3 clinical studies that directly compare the safety and efficacy of INVOKANA and ertugliflozin.
An indirect comparison between INVOKANA and ertugliflozin cannot be made due to differences in patient populations, study designs, and procedures. Summary 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.

CLINICAL Studies

There are no phase 3 clinical studies that directly compare the safety and efficacy of INVOKANA and ertugliflozin to improve glycemic control in patients with type 2 diabetes mellitus.
An indirect comparison between INVOKANA and ertugliflozin 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 Ertugliflozin).

Summary of INVOKANA¹ and Ertugliflozin²

	INVOKANA¹	Ertugliflozin²
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	Adjunct to diet and exercise to improve glycemic control in adults with T2DM
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	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)	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, and require additional glycemic control Dose adjustment for patients with renal impairment may be required Adjust CANA dose when taken concomitantly with UGT inducer	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	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	Do not use ertugliflozin in patients with an eGFR <45 mL/min/1.73 m² Ertugliflozin is contraindicated in patients on dialysis
Dosage Forms and Strengths	100 mg, 300 mg tablets	5 mg, 15 mg tablets
Contraindications	History of a serious hypersensitivity reaction to INVOKANA Patients on dialysis	History of serious hypersensitivity reaction to ertugliflozin Patients on dialysis
Warnings and Precautions	Lower Limb Amputation Volume Depletion Ketoacidosis 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 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
Other Adverse Reactions (≥2%) in pooled PBO-controlled studies	Male genital mycotic infections Vulvovaginal pruritus Thirst Constipation 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
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	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 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	Those with moderate renal impairment did not have improvement in glycemic control Ertugliflozin is contraindicated in patients receiving dialysis
Use in Hepatic Impairment	Not studied in patients with severe hepatic impairment and is therefore not recommended	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 renal threshold for glucose, and thereby increases urinary glucose excretion
UGE	~100 g/day^b	See note
Caloric Loss^a (1 g = ~ 4 kcal)	~400 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 postprandial glucose (potentially due to transient intestinal SGLT1 inhibition). Glucose malabsorption was not reported.³^,⁴ 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 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 (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 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 (t_1/2): 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 or sulfonylurea or metformin + sulfonylurea or 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 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 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 standard of care 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	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 standard-of-care, 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
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	26 weeks for placebo-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 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/MET XR (BL 8.8): -1.77 300 mg/MET XR (BL 8.9): -1.78 MET XR (BL 8.8): -1.30	None specified
Studies/Analyses with High BL HbA1C, LSM change from BL (%)	Monotherapy Subgroup Analysis (HbA1C ≥9.0%):⁵ 100 mg: -1.29 300 mg: -1.83 PBO: -0.18 Monotherapy substudy (Inclusion HbA1C >10 to ≤12%):⁵ 100 mg (BL 10.6): -2.1 300 mg (BL 10.6): -2.6 INVOKANA vs sitagliptin, combo metformin + sulfonylurea (BL HbA1C ≥9% Subgroup Analysis):⁶ 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	None specified
HbA1C Across Multiple Add-on Combo AHA Studies^c, 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 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 myocardial infarction, nonfatal stroke	CANA: 585 (9.2%) PBO: 426 (10.4%) HR: 0.86 (0.75, 0.97)	None specified
Nonfatal myocardial infarction	CANA: 215 (3.4%) PBO: 159 (3.9%) HR: 0.85 (0.69, 1.05)	None specified
Nonfatal stroke	CANA: 158 (2.5%) PBO: 116 (2.8%) HR: 0.90 (0.71, 1.15)	None specified
CV death	CANA: 268 (4.1%) PBO: 185 (4.6%) HR: 0.87 (0.72, 1.06)	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
ESKD	CANA: 116 (5.3%) PBO: 165 (7.5%) HR: 0.68 (0.54, 0.86)	None specified
Doubling of serum creatinine	CANA: 118 (5.4%) PBO: 188 (8.5%) HR: 0.60 (0.48, 0.76)	None specified
Renal death	CANA: 2 (0.1%) PBO: 5 (0.2%) HR: --	None specified
CV death	CANA: 110 (5.0%) PBO: 140 (6.4%) HR: 0.78 (0.61, 1.00)	None specified
Selected Prespecified Secondary Endpoints
Systolic Blood Pressure, mean change from BL, range	-2.6 to -6.6 mmHg^d	-3.8 to -5.7 mmHg^h
Body Weight, mean change from BL, range	-1.8 to -4.7%^f,g	-2.6 to -3.2 kg^i,j
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; CANA, INVOKANA; C_max, maximum plasma concentration; combo, combination; CV, cardiovascular; CVD, cardiovascular disease; DKA, diabetic ketoacidosis; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; ESKD, end-stage kidney disease; HbA1C, hemoglobin A1C; HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; LSM, least-squares mean; MACE, major adverse cardiovascular events; PBO, placebo; PD, pharmacodynamics; PK, pharmacokinetics; SGLT1, sodium-glucose cotransporter-1; SGLT2, sodium-glucose cotransporter-2; 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; XR, extended-release. Note: Difference in LSM UGE_0-24h Placebo-corrected change from baseline to week 4: Ertugliflozin 5 mg: ~64 g/day.⁷ 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/day.⁸ Estimated caloric loss: ~156-276 kcal/day.^aCalculated based on 1 g of glucose excreted in the urine (UGE) equates to approximately 4 kcal of energy.⁹ See UGE section for grams excreted. ^bIncreases in mean UGE with either 100 mg or 300 mg of canagliflozin. ^cIncludes add-on combination placebo- and active-controlled studies from Prescribing Information, excluding monotherapy studies (canagliflozin, dapagliflozin, and empagliflozin) and initial therapy in combination with metformin XR studies (dapagliflozin).^dStudies 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). ^eStudies 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. ^fReported in the full Prescribing Information as percent change in body weight from baseline. ^gStudies 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). ^hStudies included: add-on combination with metformin and add-on combination with metformin and sitagliptin. ⁱStudies included: monotherapy, add-on combination with metformin, active-controlled study vs glimepiride (each as add-on to metformin), add-on combination with metformin and sitagliptin. ^jReported in full Prescribing Information as change in kilograms from baseline. 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 12 September 2024.

References

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1	INVOKANA (canagliflozin) [Prescribing Information]. Titusville, NJ: Janssen Pharmaceuticals, Inc;https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/INVOKANA-pi.pdf.
2	Steglatro (ertugliflozin) [Prescribing Information]. Whitehouse Station, NJ: Merck & Co. Inc;https://www.merck.com/product/usa/pi_circulars/s/steglatro/steglatro_pi.pdf.
3	Stein P, Berg JK, Morrow L, et al. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces post-meal glucose excursion in patients with type 2 diabetes by a non-renal mechanism: results of a randomized trial. Metabolism. 2014;63(10):1296-1303.
4	Polidori D, Sha S, Mudaliar S, et al. Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: results of a randomized, placebo-controlled study. Diabetes Care. 2013;36(8):2154-2161.
5	Stenlöf K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15(4):372-382.
6	Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care. 2013;36(9):2508-2515.
7	Amin NB, Wang X, Mitchell JR, et al. Blood pressure‐lowering effect of the sodium glucose co‐transporter‐2 inhibitor ertugliflozin, assessed via ambulatory blood pressure monitoring in patients with type 2 diabetes and hypertension. Diabetes Obes Metabolism. 2015;17(8):805-808.
8	Sahasrabudhe V, Terra SG, Hickman A, et al. The effect of renal impairment on the pharmacokinetics and pharmacodynamics of Ertugliflozin in subjects with type 2 diabetes mellitus. J Clin Pharmacol. 2017;57(11):1432-1443.
9	Rosenstock J, Aggarwal N, Polidori D, et al. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care. 2012;35(6):1232-1238.