14 CLINICAL STUDIES

14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus

INVOKANA (canagliflozin) has been studied as monotherapy, in combination with metformin HCl, sulfonylurea, metformin HCl and sulfonylurea, metformin HCl and sitagliptin, metformin HCl and a thiazolidinedione (i.e., pioglitazone), and in combination with insulin (with or without other anti-hyperglycemic agents). The efficacy of INVOKANA was compared to a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin), both as add-on combination therapy with metformin HCl and sulfonylurea, and a sulfonylurea (glimepiride), both as add-on combination therapy with metformin HCl. INVOKANA was also evaluated in adults 55 to 80 years of age and patients with moderate renal impairment.

Monotherapy

A total of 584 adult patients with type 2 diabetes inadequately controlled on diet and exercise participated in a 26-week double-blind, placebo-controlled trial to evaluate the efficacy and safety of INVOKANA. The mean age was 55 years, 44% of patients were male, and the mean baseline eGFR was 87 mL/min/1.73 m 2. Patients taking other antihyperglycemic agents (N=281) discontinued the agent and underwent an 8-week washout followed by a 2-week, single-blind, placebo run-in period. Patients not taking oral antihyperglycemic agents (N=303) entered the 2-week, single-blind, placebo run-in period directly. After the placebo run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily for 26 weeks.

At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA 1C(p<0.001 for both doses) compared to placebo. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA 1Cless than 7%, in significant reduction in fasting plasma glucose (FPG), in improved postprandial glucose (PPG), and in percent body weight reduction compared to placebo (see Table 10). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -3.7 mmHg and -5.4 mmHg with INVOKANA 100 mg and 300 mg, respectively.

Table 10: Results from 26-Week Placebo-Controlled Clinical Trial with INVOKANA as Monotherapy in Adults with Type 2 Diabetes Mellitus *
Efficacy Parameter	Placebo (N=192)	INVOKANA 100 mg (N=195)	INVOKANA 300 mg (N=197)
* Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ p<0.001
HbA 1C(%)
Baseline (mean)	7.97	8.06	8.01
Change from baseline (adjusted mean)	0.14	-0.77	-1.03
Difference from placebo (adjusted mean) (95% CI) †		-0.91 ‡ (-1.09; -0.73)	-1.16 ‡ (-1.34; -0.99)
Percent of Patients Achieving HbA 1C< 7%	21	45 ‡	62 ‡
Fasting Plasma Glucose (mg/dL)
Baseline (mean)	166	172	173
Change from baseline (adjusted mean)	8	-27	-35
Difference from placebo (adjusted mean) (95% CI) †		-36 ‡ (-42; -29)	-43 ‡ (-50; -37)
2-hour Postprandial Glucose (mg/dL)
Baseline (mean)	229	250	254
Change from baseline (adjusted mean)	5	-43	-59
Difference from placebo (adjusted mean) (95% CI) †		-48 ‡ (-59.1; -37.0)	-64 ‡ (-75.0; -52.9)
Body Weight
Baseline (mean) in kg	87.5	85.9	86.9
% change from baseline (adjusted mean)	-0.6	-2.8	-3.9
Difference from placebo (adjusted mean) (95% CI) †		-2.2 ‡ (-2.9; -1.6)	-3.3 ‡ (-4.0; -2.6)

Add-on Combination Therapy with Metformin HCl

A total of 1,284 adult patients with type 2 diabetes inadequately controlled on metformin HCl monotherapy (greater than or equal to 2,000 mg/day, or at least 1,500 mg/day if higher dose not tolerated) participated in a 26-week, double-blind, placebo- and active-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with metformin HCl. The mean age was 55 years, 47% of patients were male, and the mean baseline eGFR was 89 mL/min/1.73 m 2. Patients already on the required metformin HCl dose (N=1,009) were randomized after completing a 2-week, single-blind, placebo run-in period. Patients taking less than the required metformin HCl dose or patients on metformin HCl in combination with another antihyperglycemic agent (N=275) were switched to metformin HCl monotherapy (at doses described above) for at least 8 weeks before entering the 2-week, single-blind, placebo run-in. After the placebo run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, sitagliptin 100 mg, or placebo, administered once daily as add-on therapy to metformin HCl.

At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA 1C(p<0.001 for both doses) compared to placebo when added to metformin HCl. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA 1Cless than 7%, in significant reduction in fasting plasma glucose (FPG), in improved postprandial glucose (PPG), and in percent body weight reduction compared to placebo when added to metformin HCl (see Table 11). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -5.4 mmHg and -6.6 mmHg with INVOKANA 100 mg and 300 mg, respectively.

Table 11: Results from 26-Week Placebo-Controlled Clinical Trial of INVOKANA in Combination with Metformin HCl in Adults with Type 2 Diabetes Mellitus *
Efficacy Parameter	Placebo + Metformin HCl (N=183)	INVOKANA 100 mg + Metformin HCl (N=368)	INVOKANA 300 mg + Metformin HCl (N=367)
* Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ p<0.001
HbA 1C(%)
Baseline (mean)	7.96	7.94	7.95
Change from baseline (adjusted mean)	-0.17	-0.79	-0.94
Difference from placebo (adjusted mean) (95% CI) †		-0.62 ‡ (-0.76; -0.48)	-0.77 ‡ (-0.91; -0.64)
Percent of patients achieving HbA 1C< 7%	30	46 ‡	58 ‡
Fasting Plasma Glucose (mg/dL)
Baseline (mean)	164	169	173
Change from baseline (adjusted mean)	2	-27	-38
Difference from placebo (adjusted mean) (95% CI) †		-30 ‡ (-36; -24)	-40 ‡ (-46; -34)
2-hour Postprandial Glucose (mg/dL)
Baseline (mean)	249	258	262
Change from baseline (adjusted mean)	-10	-48	-57
Difference from placebo (adjusted mean) (95% CI) †		-38 ‡ (-49; -27)	-47 ‡ (-58; -36)
Body Weight
Baseline (mean) in kg	86.7	88.7	85.4
% change from baseline (adjusted mean)	-1.2	-3.7	-4.2
Difference from placebo (adjusted mean) (95% CI) †		-2.5 ‡ (-3.1; -1.9)	-2.9 ‡ (-3.5; -2.3)

Initial Combination Therapy with Metformin HCl Extended-Release

A total of 1,186 adult patients with type 2 diabetes inadequately controlled with diet and exercise participated in a 26-week double-blind, active-controlled, parallel-group, 5-arm, multicenter trial to evaluate the efficacy and safety of initial therapy with INVOKANA in combination with metformin HCl extended-release. The median age was 56 years, 48% of patients were male, and the mean baseline eGFR was 87.6 mL/min/1.73 m 2. The median duration of diabetes was 1.6 years, and 72% of patients were treatment naïve. After completing a 2-week single-blind placebo run-in period, patients were randomly assigned for a double-blind treatment period of 26 weeks to 1 of 5 treatment groups (Table 12). The metformin HCl extended-release dose was initiated at 500 mg/day for the first week of treatment and then increased to 1,000 mg/day. Metformin HCl extended-release or matching placebo was up-titrated every 2–3 weeks during the next 8 weeks of treatment to a maximum daily dose of 1,500 to 2,000 mg/day, as tolerated; about 90% of patients reached 2,000 mg/day.

At the end of treatment, INVOKANA 100 mg and INVOKANA 300 mg in combination with metformin HCl extended-release resulted in a statistically significant greater improvement in HbA 1Ccompared to their respective INVOKANA doses (100 mg and 300 mg) alone or metformin HCl extended-release alone.

Table 12: Results from 26-Week Active-Controlled Clinical Trial of INVOKANA Alone or INVOKANA as Initial Combination Therapy with Metformin HCl Extended-Release in Adults with Type 2 Diabetes Mellitus *
Efficacy Parameter	Metformin HCl extended-release (N=237)	INVOKANA 100 mg (N=237)	INVOKANA 300 mg (N=238)	INVOKANA 100 mg + Metformin HCl extended-release (N=237)	INVOKANA 300 mg + Metformin HCl extended-release (N=237)
* Intent-to-treat population † There were 121 patients without week 26 efficacy data. Analyses addressing missing data gave consistent results with the results provided in this table. ‡ Least squares mean adjusted for covariates including baseline value and stratification factor § Adjusted p=0.001 for superiority ¶ Adjusted p=0.001 for non-inferiority # Adjusted p<0.05
HbA 1C(%)
Baseline (mean)	8.81	8.78	8.77	8.83	8.90
Change from baseline (adjusted mean) †	-1.30	-1.37	-1.42	-1.77	-1.78
Difference from canagliflozin 100 mg (adjusted mean) (95% CI) ‡				-0.40 § (-0.59, -0.21)
Difference from canagliflozin 300 mg (adjusted mean) (95% CI) ‡					-0.36 § (-0.56, -0.17)
Difference from metformin HCl extended-release (adjusted mean) (95% CI) ‡		-0.06 ¶ (-0.26, 0.13)	-0.11 ¶ (-0.31, 0.08)	-0.46 § (-0.66, -0.27)	-0.48 § (-0.67, -0.28)
Percent of patients achieving HbA 1C< 7%	38	34	39	47 #	51 #

INVOKANA Compared to Glimepiride, Both as Add-on Combination With Metformin HCl

A total of 1,450 adult patients with type 2 diabetes inadequately controlled on metformin HCl monotherapy (greater than or equal to 2,000 mg/day, or at least 1,500 mg/day if higher dose not tolerated) participated in a 52-week, double-blind, active-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with metformin HCl.

The mean age was 56 years, 52% of patients were male, and the mean baseline eGFR was 90 mL/min/1.73 m 2. Patients tolerating maximally required metformin HCl dose (N=928) were randomized after completing a 2-week, single-blind, placebo run-in period. Other patients (N=522) were switched to metformin HCl monotherapy (at doses described above) for at least 10 weeks, then completed a 2-week single-blind run-in period. After the 2-week run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or glimepiride (titration allowed throughout the 52-week trial to 6 or 8 mg), administered once daily as add-on therapy to metformin HCl.

As shown in Table 13 and Figure 1, at the end of treatment, INVOKANA 100 mg provided similar reductions in HbA 1Cfrom baseline compared to glimepiride when added to metformin HCl therapy. INVOKANA 300 mg provided a greater reduction from baseline in HbA 1Ccompared to glimepiride, and the relative treatment difference was -0.12% (95% CI: –0.22; –0.02). As shown in Table 13, treatment with INVOKANA 100 mg and 300 mg daily provided greater improvements in percent body weight change, relative to glimepiride.

Table 13: Results from 52–Week Clinical Trial Comparing INVOKANA to Glimepiride in Combination with Metformin HCl in Adults with Type 2 Diabetes Mellitus *
Efficacy Parameter	INVOKANA 100 mg + Metformin HCl (N=483)	INVOKANA 300 mg + Metformin HCl (N=485)	Glimepiride (titrated) + Metformin HCl (N=482)
* Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ INVOKANA + metformin HCl is considered non-inferior to glimepiride + metformin HCl because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%. § p<0.001
HbA 1C(%)
Baseline (mean)	7.78	7.79	7.83
Change from baseline (adjusted mean)	-0.82	-0.93	-0.81
Difference from glimepiride (adjusted mean) (95% CI) †	-0.01 ‡ (-0.11; 0.09)	-0.12 ‡ (-0.22; -0.02)
Percent of patients achieving HbA 1C< 7%	54	60	56
Fasting Plasma Glucose (mg/dL)
Baseline (mean)	165	164	166
Change from baseline (adjusted mean)	-24	-28	-18
Difference from glimepiride (adjusted mean) (95% CI) †	-6 (-10; -2)	-9 (-13; -5)
Body Weight
Baseline (mean) in kg	86.8	86.6	86.6
% change from baseline (adjusted mean)	-4.2	-4.7	1.0
Difference from glimepiride (adjusted mean) (95% CI) †	-5.2 § (-5.7; -4.7)	-5.7 § (-6.2; -5.1)

Figure 1: Mean HbA 1CChange in Adults with Type 2 Diabetes Mellitus Treated with INVOKANA or Glimepiride in Combination with Metformin HCl at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population)

Add-on Combination Therapy with Sulfonylurea

A total of 127 adult patients with type 2 diabetes inadequately controlled on sulfonylurea monotherapy participated in an 18-week, double-blind, placebo-controlled sub-trial to evaluate the efficacy and safety of INVOKANA in combination with sulfonylurea. The mean age was 65 years, 57% of patients were male, and the mean baseline eGFR was 69 mL/min/1.73 m 2. Patients treated with sulfonylurea monotherapy on a stable protocol-specified dose (greater than or equal to 50% maximal dose) for at least 10 weeks completed a 2-week, single-blind, placebo run-in period. After the run-in period, patients with inadequate glycemic control were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to sulfonylurea.

As shown in Table 14, at the end of treatment, INVOKANA 100 mg and 300 mg daily provided statistically significant (p<0.001 for both doses) improvements in HbA 1Crelative to placebo when added to sulfonylurea. INVOKANA 300 mg once daily compared to placebo resulted in a greater proportion of patients achieving an HbA 1Cless than 7%, (33% vs 5%), greater reductions in fasting plasma glucose (-36 mg/dL vs +12 mg/dL), and greater percent body weight reduction (-2.0% vs -0.2%).

Table 14: Results from 18-Week Placebo–Controlled Clinical Trial of INVOKANA in Combination with Sulfonylurea in Adults with Type 2 Diabetes Mellitus *
Efficacy Parameter	Placebo + Sulfonylurea (N=45)	INVOKANA 100 mg + Sulfonylurea (N=42)	INVOKANA 300 mg + Sulfonylurea (N=40)
* Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value ‡ p<0.001
HbA 1C(%)
Baseline (mean)	8.49	8.29	8.28
Change from baseline (adjusted mean)	0.04	-0.70	-0.79
Difference from placebo (adjusted mean) (95% CI) †		-0.74 ‡ (-1.15; -0.33)	-0.83 ‡ (-1.24; -0.41)

Add-on Combination Therapy with Metformin HCl and Sulfonylurea

A total of 469 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (maximal or near-maximal effective dose) participated in a 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with metformin HCl and sulfonylurea. The mean age was 57 years, 51% of patients were male, and the mean baseline eGFR was 89 mL/min/1.73 m 2. Patients already on the protocol-specified doses of metformin HCl and sulfonylurea (N=372) entered a 2-week, single-blind, placebo run-in period. Other patients (N=97) were required to be on a stable protocol-specified dose of metformin HCl and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to metformin HCl and sulfonylurea.

At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA 1C(p<0.001 for both doses) compared to placebo when added to metformin HCl and sulfonylurea. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA 1Cless than 7%, in a significant reduction in fasting plasma glucose (FPG), and in percent body weight reduction compared to placebo when added to metformin HCl and sulfonylurea (see Table 15).

Table 15: Results from 26-Week Placebo-Controlled Clinical Trial of INVOKANA in Combination with Metformin HCl and Sulfonylurea in Adults with Type 2 Diabetes Mellitus *
Efficacy Parameter	Placebo + Metformin HCl and Sulfonylurea (N=156)	INVOKANA 100 mg + Metformin HCl and Sulfonylurea (N=157)	INVOKANA 300 mg + Metformin HCl and Sulfonylurea (N=156)
* Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ p<0.001
HbA 1C(%)
Baseline (mean)	8.12	8.13	8.13
Change from baseline (adjusted mean)	-0.13	-0.85	-1.06
Difference from placebo (adjusted mean) (95% CI) †		-0.71 ‡ (-0.90; -0.52)	-0.92 ‡ (-1.11; -0.73)
Percent of patients achieving A 1C< 7%	18	43 ‡	57 ‡
Fasting Plasma Glucose (mg/dL)
Baseline (mean)	170	173	168
Change from baseline (adjusted mean)	4	-18	-31
Difference from placebo (adjusted mean) (95% CI) †		-22 ‡ (-31; -13)	-35 ‡ (-44; -25)
Body Weight
Baseline (mean) in kg	90.8	93.5	93.5
% change from baseline (adjusted mean)	-0.7	-2.1	-2.6
Difference from placebo (adjusted mean) (95% CI) †		-1.4 ‡ (-2.1; -0.7)	-2.0 ‡ (-2.7; -1.3)

Add-on Combination Therapy with Metformin HCl and Sitagliptin

A total of 217 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 1,500 mg/day) and sitagliptin 100 mg/day (or equivalent fixed-dose combination) participated in a 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with metformin HCl and sitagliptin. The mean age was 57 years, 58% of patients were male, 73% of patients were White, 15% were Asian, and 12% were Black or African American. The mean baseline eGFR was 90 mL/min/1.73 m 2and the mean baseline BMI was 32 kg/m 2. The mean duration of diabetes was 10 years. Eligible patients entered a 2-week, single-blind, placebo run-in period and were subsequently randomized to INVOKANA 100 mg or placebo, administered once daily as add-on to metformin HCl and sitagliptin. Patients with a baseline eGFR of 70 mL/min/1.73 m 2or greater who were tolerating INVOKANA 100 mg and who required additional glycemic control (fasting finger stick 100 mg/dL or greater at least twice within 2 weeks) were up-titrated to INVOKANA 300 mg. While up-titration occurred as early as Week 4, most (90%) patients randomized to INVOKANA were up-titrated to INVOKANA 300 mg by 6 to 8 weeks.

At the end of 26 weeks, INVOKANA resulted in a statistically significant improvement in HbA 1C(p<0.001) compared to placebo when added to metformin HCl and sitagliptin.

Table 16: Results from 26–Week Placebo-Controlled Clinical Trial of INVOKANA in Combination with Metformin HCl and Sitagliptin in Adults with Type 2 Diabetes Mellitus
Efficacy Parameter	Placebo + Metformin HCl and Sitagliptin (N=108 *)	INVOKANA + Metformin HCl and Sitagliptin (N=109 *)
* To preserve the integrity of randomization, all randomized patients were included in the analysis. The patient who was randomized once to each arm was analyzed on INVOKANA. † Early treatment discontinuation before week 26, occurred in 11.0% and 24.1% of INVOKANA and placebo patients, respectively. ‡ Estimated using a multiple imputation method modeling a "wash-out" of the treatment effect for patients having missing data who discontinued treatment. Missing data was imputed only at week 26 and analyzed using ANCOVA. § p<0.001 ¶ Patients without week 26 efficacy data were considered as non-responders when estimating the proportion achieving HbA 1C < 7%. # Estimated using a multiple imputation method modeling a "wash-out" of the treatment effect for patients having missing data who discontinued treatment. A mixed model for repeated measures was used to analyze the imputed data.
HbA 1C(%)
Baseline (mean)	8.40	8.50
Change from baseline (adjusted mean)	-0.03	-0.83
Difference from placebo (adjusted mean) (95% CI) †‡		-0.81 § (-1.11; -0.51)
Percent of patients achieving HbA 1C< 7% ¶	9	28
Fasting Plasma Glucose (mg/dL)#
Baseline (mean)	180	185
Change from baseline (adjusted mean)	-3	-28
Difference from placebo (adjusted mean) (95% CI)		-25 § (-39; -11)

INVOKANA Compared to Sitagliptin, Both as Add-on Combination Therapy with Metformin HCl and Sulfonylurea

A total of 755 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (near-maximal or maximal effective dose) participated in a 52-week, double-blind, active-controlled trial to compare the efficacy and safety of INVOKANA 300 mg versus sitagliptin 100 mg in combination with metformin HCl and sulfonylurea. The mean age was 57 years, 56% of patients were male, and the mean baseline eGFR was 88 mL/min/1.73 m 2. Patients already on protocol-specified doses of metformin HCl and sulfonylurea (N=716) entered a 2-week single-blind, placebo run-in period. Other patients (N=39) were required to be on a stable protocol-specified dose of metformin HCl and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 300 mg or sitagliptin 100 mg as add-on to metformin HCl and sulfonylurea.

As shown in Table 17 and Figure 2, at the end of treatment, INVOKANA 300 mg provided greater HbA 1Creduction compared to sitagliptin 100 mg when added to metformin HCl and sulfonylurea (p<0.05). INVOKANA 300 mg resulted in a mean percent change in body weight from baseline of -2.5% compared to +0.3% with sitagliptin 100 mg. A mean change in systolic blood pressure from baseline of -5.06 mmHg was observed with INVOKANA 300 mg compared to +0.85 mmHg with sitagliptin 100 mg.

Table 17: Results from 52-Week Clinical Trial Comparing INVOKANA to Sitagliptin in Combination with Metformin HCl and Sulfonylurea in Adults with Type 2 Diabetes Mellitus *
Efficacy Parameter	INVOKANA 300 mg + Metformin HCl and Sulfonylurea (N=377)	Sitagliptin 100 mg + Metformin HCl and Sulfonylurea (N=378)
* Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ INVOKANA + metformin HCl+ sulfonylurea is considered non-inferior to sitagliptin + metformin HCl + sulfonylurea because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%. § p<0.001
HbA 1C(%)
Baseline (mean)	8.12	8.13
Change from baseline (adjusted mean)	-1.03	-0.66
Difference from sitagliptin (adjusted mean) (95% CI) †	-0.37 ‡ (-0.50; -0.25)
Percent of patients achieving HbA 1C< 7%	48	35
Fasting Plasma Glucose (mg/dL)
Baseline (mean)	170	164
Change from baseline (adjusted mean)	-30	-6
Difference from sitagliptin (adjusted mean) (95% CI) †	-24 (-30; -18)
Body Weight
Baseline (mean) in kg	87.6	89.6
% change from baseline (adjusted mean)	-2.5	0.3
Difference from sitagliptin (adjusted mean) (95% CI) †	-2.8 § (-3.3; -2.2)

Figure 2: Mean HbA 1CChange in Adults with Type 2 Diabetes Mellitus Treated with INVOKANA or Sitagliptin in Combination with Metformin HCl and Sulfonylurea at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population)

Add-on Combination Therapy with Metformin HCl and Pioglitazone

A total of 342 adult patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and pioglitazone (30 or 45 mg/day) participated in a 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with metformin HCl and pioglitazone. The mean age was 57 years, 63% of patients were male, and the mean baseline eGFR was 86 mL/min/1.73 m 2. Patients already on protocol-specified doses of metformin HCl and pioglitazone (N=163) entered a 2-week, single-blind, placebo run-in period.

Other patients (N=181) were required to be on stable protocol-specified doses of metformin HCl and pioglitazone for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to metformin HCl and pioglitazone.

At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA 1C(p<0.001 for both doses) compared to placebo when added to metformin HCl and pioglitazone. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA 1Cless than 7%, in significant reduction in fasting plasma glucose (FPG) and in percent body weight reduction compared to placebo when added to metformin HCl and pioglitazone (see Table 18). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -4.1 mmHg and -3.5 mmHg with INVOKANA 100 mg and 300 mg, respectively.

Table 18: Results from 26-Week Placebo-Controlled Clinical Trial of INVOKANA in Combination with Metformin HCl and Pioglitazone in Adults with Type 2 Diabetes Mellitus *
Efficacy Parameter	Placebo + Metformin HCl and Pioglitazone (N=115)	INVOKANA 100 mg + Metformin HCl and Pioglitazone (N=113)	INVOKANA 300 mg + Metformin HCl and Pioglitazone (N=114)
* Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ p<0.001
HbA 1C(%)
Baseline (mean)	8.00	7.99	7.84
Change from baseline (adjusted mean)	-0.26	-0.89	-1.03
Difference from placebo (adjusted mean) (95% CI) †		-0.62 ‡ (-0.81; -0.44)	-0.76 ‡ (-0.95; -0.58)
Percent of patients achieving HbA 1C< 7%	33	47 ‡	64 ‡
Fasting Plasma Glucose (mg/dL)
Baseline (mean)	164	169	164
Change from baseline (adjusted mean)	3	-27	-33
Difference from placebo (adjusted mean) (95% CI) †		-29 ‡ (-37; -22)	-36 ‡ (-43; -28)
Body Weight
Baseline (mean) in kg	94.0	94.2	94.4
% change from baseline (adjusted mean)	-0.1	-2.8	-3.8
Difference from placebo (adjusted mean) (95% CI) †		-2.7 ‡ (-3.6; -1.8)	-3.7 ‡ (-4.6; -2.8)

Add-On Combination Therapy with Insulin (With or Without Other Antihyperglycemic Agents)

A total of 1,718 adult patients with type 2 diabetes inadequately controlled on insulin greater than or equal to 30 units/day or insulin in combination with other antihyperglycemic agents participated in an 18-week, double-blind, placebo-controlled subtrial of a cardiovascular trial to evaluate the efficacy and safety of INVOKANA in combination with insulin. The mean age was 63 years, 66% of patients were male, and the mean baseline eGFR was 75 mL/min/1.73 m 2. Patients on basal, bolus, or basal/bolus insulin for at least 10 weeks entered a 2-week, single-blind, placebo run-in period. Approximately 70% of patients were on a background basal/bolus insulin regimen. After the run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to insulin. The mean daily insulin dose at baseline was 83 units, which was similar across treatment groups.

At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA 1C(p<0.001 for both doses) compared to placebo when added to insulin. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA 1Cless than 7%, in significant reductions in fasting plasma glucose (FPG), and in percent body weight reductions compared to placebo (see Table 19). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -2.6 mmHg and -4.4 mmHg with INVOKANA 100 mg and 300 mg, respectively.

Table 19: Results from 18-Week Placebo-Controlled Clinical Trial of INVOKANA in Combination with Insulin ≥ 30 Units/Day (With or Without Other Oral Antihyperglycemic Agents) in Adults with Type 2 Diabetes Mellitus *
Efficacy Parameter	Placebo + Insulin (N=565)	INVOKANA 100 mg + Insulin (N=566)	INVOKANA 300 mg + Insulin (N=587)
* Intent-to-treat population using last observation in the trial prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ p<0.001
HbA 1C(%)
Baseline (mean)	8.20	8.33	8.27
Change from baseline (adjusted mean)	0.01	-0.63	-0.72
Difference from placebo (adjusted mean) (95% CI) †		-0.65 ‡ (-0.73; -0.56)	-0.73 ‡ (-0.82; -0.65)
Percent of patients achieving HbA 1C< 7%	8	20 ‡	25 ‡
Fasting Plasma Glucose (mg/dL)
Baseline	169	170	168
Change from baseline (adjusted mean)	4	-19	-25
Difference from placebo (adjusted mean) (97.5% CI) †		-23 ‡ (-29; -16)	-29 ‡ (-35; -23)
Body Weight
Baseline (mean) in kg	97.7	96.9	96.7
% change from baseline (adjusted mean)	0.1	-1.8	-2.3
Difference from placebo (adjusted mean) (97.5% CI) †		-1.9 ‡ (-2.2; -1.6)	-2.4 ‡ (-2.7; -2.1)

Trial in Patients Ages 55 to 80

A total of 714 type 2 diabetes patients ages 55 to 80 years and inadequately controlled on current diabetes therapy (either diet and exercise alone or in combination with oral or parenteral agents) participated in a 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with current diabetes treatment. The mean age was 64 years, 55% of patients were male, and the mean baseline eGFR was 77 mL/min/1.73 m 2. Patients were randomized in a 1:1:1 ratio to the addition of INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily. At the end of treatment, INVOKANA provided statistically significant improvements from baseline relative to placebo in HbA 1C(p<0.001 for both doses) of -0.57% (95% CI: -0.71%; -0.44%) for INVOKANA 100 mg and -0.70% (95% CI: -0.84%; -0.57%) for INVOKANA 300 mg [see Use in Specific Populations (8.5)] .

Glycemic Control in Patients with Moderate Renal Impairment

A total of 269 adult patients with type 2 diabetes and a baseline eGFR of 30 mL/min/1.73 m 2to less than 50 mL/min/1.73 m 2inadequately controlled on current diabetes therapy participated in a 26-week, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of INVOKANA in combination with current diabetes treatment (diet or antihyperglycemic agent therapy, with 95% of patients on insulin and/or sulfonylurea). The mean age was 68 years, 61% of patients were male, and the mean baseline eGFR was 39 mL/min/1.73 m 2. Patients were randomized in a 1:1:1 ratio to the addition of INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily.

At the end of treatment, INVOKANA 100 mg and INVOKANA 300 mg daily provided greater reductions in HbA 1Crelative to placebo (-0.30% [95% CI: -0.53%; -0.07%] and -0.40%, [95% CI: -0.64%; -0.17%], respectively) [see Warnings and Precautions (5.3), Adverse Reactions (6.1), Use in Specific Populations (8.6), and Clinical Studies (14.4)] .

14.2 Glycemic Control Trial in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus

In a double-blind, placebo-controlled, parallel-group pediatric trial (NCT03170518), 171 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus (HbA 1C≥6.5% and ≤11.0%) were randomized to INVOKANA (84 patients) or placebo (87 patients) as add-on to diet and exercise, metformin HCl (≥1,000 mg per day or maximally tolerated dosage), insulin, or a combination of metformin HCl and insulin, for a total of 52-weeks. At Week 13, patients in the INVOKANA arm whose HbA 1Cwas ≥7.0% and eGFR ≥60 mL/min/1.73 m 2were re-randomized to either continue on INVOKANA 100 mg orally once daily (n=16) or to up-titrate to INVOKANA 300 mg orally once daily (n=17).

At baseline, background therapies included diet and exercise only (14%), insulin monotherapy (11%), metformin HCl and insulin (29%), and metformin HCl monotherapy (46%). The mean HbA 1Cat baseline was 8.0% and the mean duration of type 2 diabetes mellitus was 2 years. The mean eGFR at baseline was 157.3 mL/min/1.73 m 2, and approximately 16% (24/151) of the trial population with measurements had microalbuminuria or macroalbuminuria. Patients with an eGFR less than 60 mL/min/1.73 m 2were not enrolled in the trial; no patients in the trial reached an eGFR < 60 mL/min/1.73 m 2. The mean age was 14.3 years, 47% were under 15 years of age, and 68% were female. Approximately 42% were Asian, 42% were White, 11% were Black or African American, 5% were American Indian/Alaska Native, and 36% were of Hispanic or Latino ethnicity. The mean BMI was 30.8 kg/m 2(range 18–57 kg/m 2) and the mean BMI Z-score was 1.84.

At Week 26, treatment with canagliflozin provided statistically significant improvement in HbA 1Cfrom baseline, compared with placebo (see Table 20).

Table 20: Results at Week 26 in a Placebo-Controlled Trial of INVOKANA in Combination with Metformin HCl and/or Insulin or as Monotherapy in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus *
Efficacy Parameter	Placebo (N=87)	INVOKANA (N=84)
* Modified intent-to-treat set (All randomized and treated patients with baseline HbA 1C measurement). † Multiple imputation using retrieved dropout approach with 1000 iterations for missing data (canagliflozin N=7 (8.3%), placebo N=7 (8.1%) for HbA 1C and canagliflozin N=9 (10.7%), placebo N=7 (8.1%) for FPG). ‡ Least-Square Mean from Analysis of Covariance (ANCOVA) adjusted for baseline value, baseline age stratum (< 15 years vs 15 to < 18 years) and baseline antihyperglycemic agent (AHA) background (i.e, diet and exercise only, metformin monotherapy, insulin monotherapy, or combination of insulin and metformin). § P-value=0.008 (two-sided) ¶ Not evaluated for statistical significance, not part of sequential testing procedure.
HbA 1C(%)
Baseline (mean)	8.3	7.8
Change from baseline †‡	0.34	-0.38
Difference from placebo 95% CI †‡		-0.73 (-1.26, -0.19) §
FPG (mg/dL)
Baseline (mean)	156.5	154.8
Change from baseline †‡	17.29	-8.22
Difference from placebo 95% CI †‡		-25.51 (-49.55, -1.47) ¶

14.3 Cardiovascular Outcomes in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease

The CANVAS and CANVAS-R trials were multicenter, multi-national, randomized, double-blind parallel group, with similar inclusion and exclusion criteria. Patients eligible for enrollment in both CANVAS and CANVAS-R trials were: 30 years of age or older and had established, stable, cardiovascular, cerebrovascular, peripheral artery disease (66% of the enrolled population) or were 50 years of age or older and had two or more other specified risk factors for cardiovascular disease (34% of the enrolled population).

The integrated analysis of the CANVAS and CANVAS-R trials compared the risk of Major Adverse Cardiovascular Event (MACE) between canagliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and atherosclerotic cardiovascular disease. The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.

In CANVAS, patients were randomly assigned 1:1:1 to canagliflozin 100 mg, canagliflozin 300 mg, or matching placebo. In CANVAS-R, patients were randomly assigned 1:1 to canagliflozin 100 mg or matching placebo, and titration to 300 mg was permitted at the investigator's discretion (based on tolerability and glycemic needs) after Week 13. Concomitant antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.

A total of 10,134 adult patients were treated (4,327 in CANVAS and 5,807 in CANVAS-R; total of 4,344 randomly assigned to placebo and 5,790 to canagliflozin) for a mean exposure duration of 149 weeks (223 weeks [4.3 years] in CANVAS and 94 weeks [1.8 years] in CANVAS-R) .Approximately 78% of the trial population was White, 13% was Asian, and 3% was Black or African American. The mean age was 63 years and approximately 64% were male.

The mean HbA 1Cat baseline was 8.2% and mean duration of diabetes was 13.5 years with 70% of patients having had diabetes for 10 years or more. Approximately 31%, 21% and 17% reported a past history of neuropathy, retinopathy and nephropathy, respectively, and the mean eGFR 76 mL/min/1.73 m 2. At baseline, patients were treated with one (19%) or more (80%) antidiabetic medications including metformin HCl (77%), insulin (50%), and sulfonylurea (43%).

At baseline, the mean systolic blood pressure was 137 mmHg, the mean diastolic blood pressure was 78 mmHg, the mean LDL was 89 mg/dL, the mean HDL was 46 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 115 mg/g. At baseline, approximately 80% of patients were treated with renin angiotensin system inhibitors, 53% with beta-blockers, 13% with loop diuretics, 36% with non-loop diuretics, 75% with statins, and 74% with antiplatelet agents (mostly aspirin). During the trial, investigators could modify anti-diabetic and cardiovascular therapies to achieve local standard of care treatment targets with respect to blood glucose, lipid, and blood pressure. More patients receiving canagliflozin compared to placebo initiated anti-thrombotics (5.2% vs 4.2%) and statins (5.8% vs 4.8%) during the trial.

For the primary analysis, a stratified Cox proportional hazards model was used to test for non-inferiority against a pre-specified risk margin of 1.3 for the hazard ratio of MACE.

In the integrated analysis of CANVAS and CANVAS-R trials, canagliflozin reduced the risk of first occurrence of MACE. The estimated hazard ratio (95% CI) for time to first MACE was 0.86 (0.75, 0.97). Refer to Table 21. Vital status was obtained for 99.6% of patients across the trials. The Kaplan-Meier curve depicting time to first occurrence of MACE is shown in Figure 3.

Table 21: Treatment Effect for the Primary Composite Endpoint, MACE, and its Components in the Integrated Analysis of CANVAS and CANVAS-R Trials in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease *
	Placebo N=4,347(%)	Canagliflozin N=5,795 (%)	Hazard ratio (95% C.I.) †
* Intent-To-Treat Analysis Set † Stratified Cox-proportional hazards model with treatment as a factor and stratified by the trial and by prior CV disease ‡ P-value for superiority (2-sided) = 0.0158 § Number and percentage of first events ¶ Due to pooling of unequal randomization ratios, Cochran-Mantel-Haenszel weights were applied to calculate percentages
Composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence) ‡,§,¶	426 (10.4)	585 (9.2)	0.86 (0.75, 0.97)
Non-fatal myocardial infarction §,¶	159 (3.9)	215 (3.4)	0.85 (0.69, 1.05)
Non-fatal Stroke §,¶	116 (2.8)	158 (2.5)	0.90 (0.71, 1.15)
Cardiovascular Death §,¶	185 (4.6)	268 (4.1)	0.87 (0.72, 1.06)

Figure 3: Time to First Occurrence of MACE in Adults with Type 2 Diabetes Mellitus

14.4 Renal and Cardiovascular Outcomes in Adults with Diabetic Nephropathy and Albuminuria

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation Trial (CREDENCE) was a multinational, randomized, double-blind, placebo-controlled trial comparing canagliflozin with placebo in adult patients with type 2 diabetes mellitus, an eGFR ≥ 30 to < 90 mL/min/1.73 m 2and albuminuria (urine albumin/creatinine > 300 to ≤ 5,000 mg/g) who were receiving standard of care including a maximum-tolerated, labeled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).

The primary objective of CREDENCE was to assess the efficacy of canagliflozin relative to placebo in reducing the composite endpoint of end stage kidney disease (ESKD), doubling of serum creatinine, and renal or CV death.

Patients were randomized to receive canagliflozin 100 mg (N=2,202) or placebo (N=2,199) and treatment was continued until the initiation of dialysis or renal transplantation.

The median follow-up duration for the 4,401 randomized subjects was 137 weeks. Vital status was obtained for 99.9% of subjects.

The population was 67% White, 20% Asian, and 5% Black or African American; 32% were of Hispanic or Latino ethnicity. The mean age was 63 years and 66% were male.

At randomization, the mean HbA 1Cwas 8.3%, the median urine albumin/creatinine was 927 mg/g, the mean eGFR was 56.2 mL/min/1.73 m 2, 50% had prior CV disease, and 15% reported a history of heart failure. The most frequent antihyperglycemic agents (AHA) medications used at baseline were insulin (66%), biguanides (58%), and sulfonylureas (29%). Nearly all subjects (99.9%) were on ACEi or ARB at randomization, approximately 60% were taking an anti-thrombotic agent (including aspirin), and 69% were on a statin.

The primary composite endpoint in the CREDENCE trial was the time to first occurrence of ESKD (defined as an eGFR < 15 mL/min/1.73 m 2, initiation of chronic dialysis or renal transplant), doubling of serum creatinine, and renal or CV death. Canagliflozin 100 mg significantly reduced the risk of the primary composite endpoint based on a time-to-event analysis [HR: 0.70; 95% CI: 0.59, 0.82; p<0.0001] (see Figure 4). The treatment effect reflected a reduction in progression to ESKD, doubling of serum creatinine and cardiovascular death as shown in Table 22 and Figure 4. There were few renal deaths during the trial. Canagliflozin 100 mg also significantly reduced the risk of hospitalization for heart failure [HR: 0.61; 95% CI: 0.47 to 0.80; p<0.001].

Table 22: Analysis of Primary Endpoint (including the Individual Components) and Secondary Endpoints from the CREDENCE Trial in Adults with Diabetic Nephropathy and Albuminuria
	Placebo		canagliflozin
Endpoint	N=2,199 (%)	Event Rate *	N=2,202 (%)	Event Rate *	HR † (95% CI)
Intent-To-Treat Analysis Set (time to first occurrence)
The individual components do not represent a breakdown of the composite outcomes, but rather the total number of subjects experiencing an event during the course of the trial.
* Event rate per 100 patient-years. † Hazard ratio (canagliflozin compared to placebo), 95% CI and p-value are estimated using a stratified Cox proportional hazards model including treatment as the explanatory variable and stratified by screening eGFR (≥ 30 to < 45, ≥ 45 to < 60, ≥ 60 to < 90 mL/min/1.73 m 2). HR is not presented for renal death due to the small number of events in each group. ‡ P-value <0.0001 § P-value <0.001 ¶ P-value <0.02
Primary Composite Endpoint (ESKD, doubling of serum creatinine, renal death, or CV death)	340 (15.5)	6.1	245 (11.1)	4.3	0.70 (0.59, 0.82) ‡
ESKD	165 (7.5)	2.9	116 (5.3)	2.0	0.68 (0.54, 0.86)
Doubling of serum creatinine	188 (8.5)	3.4	118 (5.4)	2.1	0.60 (0.48, 0.76)
Renal death	5 (0.2)	0.1	2 (0.1)	0.0
CV death	140 (6.4)	2.4	110 (5.0)	1.9	0.78 (0.61, 1.00)
CV death or hospitalization for heart failure	253 (11.5)	4.5	179 (8.1)	3.1	0.69 (0.57, 0.83) §
CV death, non-fatal myocardial infarction or non-fatal stroke	269 (12.2)	4.9	217 (9.9)	3.9	0.80 (0.67, 0.95) ¶
Non-fatal myocardial infarction	87 (4.0)	1.6	71 (3.2)	1.3	0.81 (0.59, 1.10)
Non-fatal stroke	66 (3.0)	1.2	53 (2.4)	0.9	0.80 (0.56, 1.15)
Hospitalization for heart failure	141 (6.4)	2.5	89 (4.0)	1.6	0.61 (0.47, 0.80) §
ESKD, doubling of serum creatinine or renal death	224 (10.2)	4.0	153 (6.9)	2.7	0.66 (0.53, 0.81) ‡

The Kaplan-Meier curve (Figure 4) shows time to first occurrence of the primary composite endpoint of ESKD, doubling of serum creatinine, renal death, or CV death. The curves begin to separate by Week 52 and continue to diverge thereafter.

Figure 4: CREDENCE: Time to First Occurrence of the Primary Composite Endpoint