SUMMARY  

• In a pooled analysis of 6 randomized, placebo (PBO)-controlled, phase 3 studies^1-6, both INVOKANA 100 mg and 300 mg reduced systolic blood pressure (SBP) and diastolic BP (DBP) vs. PBO across a range of baseline blood pressures (BPs).⁷ The BP-lowering effects of INVOKANA were similar whether or not patients were taking antihypertensive agents (AHAs).⁸ INVOKANA was not associated with notable changes in heart rate vs PBO.^7,8
• In the CREDENCE study, BP was evaluated as an intermediate outcome. INVOKANA demonstrated greater mean change in SBP (-3.30 mm Hg) and DBP (-0.95 mm Hg) vs PBO.^9-11
• In the CANVAS program, INVOKANA demonstrated statistically significant reductions in the mean difference in SBP (-3.93 mm Hg) and DBP (-1.39 mm Hg) vs PBO.¹²
• In a 6-week, randomized, double-blind, PBO-controlled study, INVOKANA 300 mg provided greater reductions in mean 24-hour ambulatory SBP than PBO.¹³
• In 2 active-controlled studies, INVOKANA demonstrated reductions from baseline in SBP and DBP vs glimepiride¹⁴ and sitagliptin.¹⁵
• In post hoc analyses of pooled data from phase 3 studies, higher proportions of patients treated with INVOKANA achieved BP-related quality measures vs sitagliptin 100 mg.^16,17
• In 3 active-controlled, observational studies, INVOKANA showed greater BP-lowering over other AHAs.^18-20
• In a retrospective, observational study, 60.0% and 75.6% of patients treated with INVOKANAin a real-world setting (with baseline BP ≥140/90 mm Hg) attained SBP <140 mm Hg and DBP <90 mm Hg, respectively, after 3 months.²¹
• Changes in BP and heart rate were also reported with INVOKANA in other studies, systematic reviews, and post hoc analyses.^{6, 8, 22-36}

CLINICAL DATA

CREDENCE

CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), was a randomized, double-blind, PBO-controlled, parallel group multicenter, event-driven clinical trial to assess the effects of INVOKANA (100 mg) compared to PBO on clinically important renal outcomes in people with T2DM and established chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] 30 to <90 mL/min/1.73m²) and albuminuria (ratio of albumin to creatinine >300 to 5000 mg/g), who were receiving a stable, maximum tolerated or labelled dose (for >4 weeks prior to randomization) of an angiotensin converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB).^{9-11, 37-39}

• Patients who were eligible to participate were ≥30 years with T2DM (A1c ≥6.5% to ≤12.0%; participants in Germany required a A1c range of ≥6.5% to <10.5%), had CKD, and an eGFR 30 to <90 mL/min/1.73m² and albuminuria (urine albumin:creatinine ratio [UACR] >300 to 5000 mg/g).^{9, 37}
• Patients who were excluded from the study included, but were not limited to, those with a history of cardiovascular (CV) events within the previous 12 weeks or a history of New York Heart Association class IV heart failure (HF) at any time.^{9, 11, 37}
• Patients were randomly assigned in a 1:1 ratio to either INVOKANA 100 mg or matching PBO using randomly permuted blocks with stratification by baseline eGFR categories (30 to <45, 45 to <60, and 60 to <90 mL/min/1.73 m²).
• Use of other therapies for glycemic management and CV risk factor control was recommended in accordance with clinical practice guidelines.
• Intermediate outcomes included BP change from baseline.

Baseline Characteristics^9-11

• A total of 4401 participants were randomized from 690 sites across 34 countries between March 2014 and May 2017 in the intention-to-treat (ITT) analysis set. There were 4 participants that were not dosed, leading to 4397 participants in the on-treatment and on-study analysis sets.
• Baseline characteristics were similar between INVOKANA and PBO. These included mean age 63 years, 66% male participants, mean duration of T2DM 15.8 years; mean A1c 8.3%, mean eGFR 56.2 mL/min/1.73m², median UACR 927 mg/g; 50.4% had prior CV disease (CVD)
  • At baseline, 96.8% (n=4260/4401) of the total population had a history of hypertension.
  • The mean systolic and diastolic blood pressure of the total population was 140 mm Hg and 78.3 mm Hg, respectively.¹¹
• Across both treatment groups, mean exposure to study drug was 115 weeks.

Results

• A total of 4361 (99.1%) of participants were followed until study completion for clinical and safety endpoints. Final vital status was collected in 99.9% of participants.9 At study conclusion, the median follow-up time was 2.62 years (range 0.02-4.53 years).⁹
• INVOKANA demonstrated a greater mean change in SBP (-3.30 mm Hg; 95% CI -2.73, -3.87 mm Hg) and DBP (-0.95 mm Hg; 95% CI -0.61, -1.28 mm Hg), compared to PBO.⁹

CANVAS Program

The CANVAS Program (N=10,142) was comprised of 2 large INVOKANA cardiovascular (CV) outcome studies: CANagliflozin cardioVascular Assessment Study (CANVAS) and CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R).⁴⁰ The CANVAS Program included a prespecified integrated analysis of these 2 studies.⁴⁰

Study Design/Methods

• Eligible patients included men and women with T2DM (A1C ≥7.0% and ≤10.5%) who were either ≥30 years with a history of symptomatic atherosclerotic disease or ≥50 years with ≥2 of the following risk factors for CVD: duration of diabetes ≥10 years, SBP >140 mm Hg while on ≥1 antihypertensive agent, current smoker, microalbuminuria or macroalbuminuria, or high-density lipoprotein cholesterol <1 mmol/L.^{12, 41, 42}
• Use of all other therapies beyond use of sodium-glucose cotransporter-2 inhibitors were according to best practice, instituted according to local guidelines and policies.^{12, 41, 42}

Results

• Baseline characteristics were well-balanced between groups. Mean SBP was 136.4 mm Hg with INVOKANA and 136.9 mm Hg with PBO. Mean DBP was 77.6 mm Hg and 77.8 mm Hg, respectively. Most patients taking INVOKANA had a history of hypertension (89.5%) and were taking an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) (80.2%), beta blocker (BB) (52.4%), and/or diuretic (43.8%).¹²
• Mean follow-up was 188.2 weeks, with greater mean follow-up in CANVAS (295.9 weeks) compared with CANVAS-R (108.0 weeks).¹²
• Mean difference in SBP was -3.93 mm Hg (95% CI: -4.30 to -3.56 mm Hg). Mean difference in DBP was -1.39 mm Hg (95% CI: -1.61 to -1.17 mm Hg) (P<0.001 vs PBO for both SBP and DBP).¹²

PBO-Controlled, Phase 3 Glycemic Control Studies

Weir et al (2013)⁷ evaluated the BP-lowering effect of INVOKANAusing pooled data from 6 randomized, double-blind, PBO-controlled, phase 3 studies^1-6  in T2DM patients (N=4,158; mean age, 59.0 years; A1C, 8.1%; body mass index, 32.7 kg/m²).

Study Design/Methods

• The BP efficacy analyses were based on 3 datasets: (1) pooled data from subjects enrolled in 6 randomized, double-blind, PBO-controlled, phase 3 studies^{1, 3, 4, 6, 23} (N=4,158), (2) pooled data from 4 PBO-controlled, 26-week studies^{1,3,6,23, 43} (N=2,313), and (3) data from the CANVAS insulin substudy⁴ (N=1,718).
• Primary efficacy endpoints included changes from baseline in SBP and DBP. Change in SBP and proportion of subjects achieving SBP <140 or <130 mm Hg were assessed in subjects with SBP ≥140 mm Hg; change in DBP and proportion of subjects achieving DBP <80 or <90 mm Hg were assessed in subjects with DBP ≥90 mm Hg. A subgroup analysis assessing changes in SBP and DBP, based on use of antihypertensives (ACE inhibitors, ARBs, or diuretics) at baseline, was also conducted.

Results

Efficacy

• In the overall population, both INVOKANA doses showed modest reductions in SBP and DBP (see Table: Change in SBP and DBP for Overall Population [6 Pooled, PBO-Controlled Studies, LOCF]).
• In subjects with baseline SBP ≥140 mm Hg (n=1,267), greater reductions in SBP were observed with both INVOKANA doses vs PBO (P<0.001). INVOKANA 100 mg and 300 mg resulted in a greater number of subjects achieving SBP <140 mm Hg vs PBO (53.8%, 58.9%, and 44.0%, respectively) or SBP <130 mm Hg (23.5%, 31.7%, and 18.7%, respectively).
• In subjects with baseline DBP ≥90 mm Hg (n=355), greater reduction in DBP was seen with INVOKANA 300 mg vs PBO (P=0.028). Among subjects with baseline DBP ≥90, INVOKANA 300 mg resulted in more subjects achieving DBP <90 mm Hg vs INVOKANA 100 mg and PBO (77.7%, 64.4%, and 64.6%, respectively) or DBP <80 mm Hg (26.2%, 21.2%, and 19.5%, respectively).
• The BP-lowering effects of INVOKANA were similar between subjects on antihypertensives and those not on antihypertensives.

Safety

• INVOKANA 100 mg and 300 mg were associated with higher rates of osmotic diuresis-related AEs and AEs related to reduced intravascular volume vs PBO in the CANVAS insulin substudy (osmotic: 9.2%, 10.4%, and 2.1%, respectively; volume: 4.1%, 5.8%, and 2.3%, respectively). Most these AEs were mild or moderate in intensity; rates of serious volume-related AEs were low across groups (0.5%, 0.2%, and 0.9%, respectively).
• INVOKANA was not associated with notable changes in heart rate vs PBO; changes were -0.6, -0.4, and 0.0 beats/min with INVOKANA 100 mg, INVOKANA 300 mg, and PBO, respectively.

Blonde et al (2016)⁴⁴ conducted a post hoc analysis to evaluate the proportion of T2DM patients achieving SBP <140 mm Hg with INVOKANA based on the pool of 4 phase 3, 26-week, PBO-controlled studies.^1,3,6,23  Safety and tolerability were assessed based on reported AEs.

• The mean SBP (mm Hg) at baseline was 128.0, 128.8, and 128.5 in the INVOKANA 100 mg, 300 mg, and PBO groups, respectively.
• At baseline, 95% of patients were taking ≥1 medication, including AHAs (75%), antihypertensive agents (i.e., ACE inhibitors, ARBs, and diuretics; 58%), and/or lipid-modifying agents (47%).
• At week 26, a higher proportion of subjects treated with INVOKANA achieved SBP <140 mm Hg compared with PBO. Additionally, clinically meaningful reductions were noted with INVOKANA compared with PBO through week 26.
  • Baseline: SBP <140 mm Hg reported in 82.2%, 79.9% and 78.8% of patients in the INVOKANA 100 mg, 300 mg, and PBO groups, respectively.
  • Week 26: SBP <140 mm Hg was observed in 89.8%, 89%, and 80.3% of patients treated with INVOKANA 100 mg, 300 mg, and PBO, respectively.
• Incidence of AEs was 60.1%, 59.2%, and 59.4% with INVOKANA 100 mg, 300 mg, and PBO, respectively. AEs leading to treatment discontinuation were reported in 4.3%, 3.6%, and 3.1% of patients receiving INVOKANA 100 mg, 300 mg, and PBO, respectively.
• GMIs and AEs related to osmotic diuresis were higher with both INVOKANA doses vs PBO.

Townsend et al (2015)¹³ evaluated early effects of INVOKANA using ambulatory BP monitoring (ABPM) in a 6-week, randomized, double-blind, PBO-controlled, parallel-group, 3-arm, multicenter study (N=169).

Study Design/Methods

• Subjects ≥18 to <75 years with SBP ≥130 and <160 mm Hg and DBP ≥70 mm Hg, on stable doses of 1-3 antihypertensives for ≥5 weeks before screening, with A1C ≥7.0% to <10% despite stable AHA doses, were included. Patients taking insulin were excluded.
• At day 1, eligible subjects were stratified by use of beta-blockers and randomly assigned in a 1:1:1 ratio to INVOKANA 100 mg, 300 mg, or PBO once daily for 6 weeks.
• Using ABPM, BP was recorded over 24 hours every 20 minutes during daytime and every 30 minutes during nighttime at 3 time-points during the study. Seated office BP, seated heart rate, standing office BP, and standing heart rate were measured during clinic visits on day 1 (randomization) and day 2, and at the start of week 3 and week 6.

Results

• A total of 80.5% of randomized patients were not taking BBs. Seated BP at baseline was 138.5/82.7 mm Hg and mean 24-hour ambulatory BP was 137.6/78.6 mm Hg.
• Least squares mean (LSM) change from baseline to week 6 in mean 24-hour ABPM SBP was -6.2 mm Hg for INVOKANA 300 mg, -4.5 mm Hg for INVOKANA 100 mg, and -1.2 mm Hg for PBO. PBO-subtracted (LSM) changes were 4.9 mm Hg (95% CI: 8.4 to 1.5; P=0.006) for INVOKANA 300 mg and 3.3 mm Hg (95% CI: 6.7 to 0.2; P=0.062) for INVOKANA 100 mg.
• Reductions in mean 24-hour SBP and DBP were observed as early as day 2 after the first treatment with INVOKANA 100 mg and 300 mg.
• Treatment-emergent AEs were higher in the INVOKANA 300 mg and 100 mg groups (26.8% and 26.3%, respectively) compared to PBO (19.6%).

Active-Controlled, Phase 3 Glycemic Control Studies

In 2 active-controlled studies, INVOKANA demonstrated reductions from baseline in SBP and DBP compared with glimepiride¹⁴ and sitaglptin¹⁵. Higher incidences of GMIs and osmotic diuresis-related AEs were observed with INVOKANA.^14,15

Observational Study

de Lucas et al (2018)¹⁸ performed a prospective, multicenter, observational study of 50 T2DM patients treated with metformin and/or gliclazide and sitagliptin in Spain. At the initial visit, the sitagliptin (and sulfonylurea, where applicable) was switched to INVOKANA for 26 weeks. BP and heart rate were measured. At baseline, A1C, SBP, DBP, and HR were 8.0%, 128.8 mm Hg, 76.4 mm Hg, HR 76.7 beats/minute (bpm), respectively. At 26 weeks, significant reductions (P<0.005) from baseline in A1C 7.1% (-0.9%), SBP 123.5 mm Hg (-5.3 mm Hg), DBP 72.0 mm Hg (-4.4 mm Hg), and HR 72.0 bpm (-4.7 bpm) were reported.

QUALITY MEASURES

In a post hoc analysis of a 52-week, randomized, double-blind, active-controlled, phase 3 study¹⁵ in patients inadequately controlled with metformin plus sulfonylurea, a higher proportion of patients in the INVOKANA 300 mg group achieved a BP <140/90 mm Hg, <140/80 mm Hg, and <130/80 mm Hg at week 52 (84.5%, 62.4%, and 53.3%, respectively) vs the sitagliptin 100 mg group (71.9%, 48.2%, and 38.4%, respectively).¹⁶

In a post hoc analysis of pooled data from two 52-week,^15,23 randomized, double-blind, phase 3 controlled studies, 13.4% more patients attained BP <130/80 mm Hg, 11.4% more patients attained BP <140/80 mm Hg, and 9.7% more patients attained BP <140/90 mm Hg in the INVOKANA 300 mg group compared to the sitagliptin 100 mg group.¹⁷

A post hoc analysis comparing efficacy of INVOKANA and glimepiride in attainment of T2DM-related quality measures has been included in the REFERENCES section for your review.⁴⁵

REAL WORLD EVIDENCE

Tanton et al (2018)⁴⁶ conducted a retrospective, multicenter, real-world study using US electronic medical records (January 1, 2012 – February 15, 2017). BP and other outcomes were evaluated at 3, 6, 9, and 12 months (N=1,259 in the study). Of those, 1,254 had ≥ 1 BP measurement, with 71.5% having SBP < 140 mm Hg (mean 130.0 mm Hg) and 90.9% having DBP < 90 mm Hg (mean 76.1 mm Hg). Significant BP reductions began around 3 months and were statistically significantly lower at all 4 time points for both SBP and DBP with INVOKANA compared to baseline.

A retrospective observational study conducted by Lefebvre et al (2016)²¹ utilized electronic health records from the Cegedim Strategic Data from March 2012 to September 2014 to describe the clinical characteristics and glycemic control quality measure of T2DM patients treated with INVOKANA in the US in a real-world setting (N=16,163).

The secondary objective was to describe other quality measures, including SBP and DBP control, in INVOKANA patients. Among patients with BP ≥140/90 at baseline, 60.0% and 75.6% attained SBP <140 mm Hg and DBP <90 mm Hg after 3 months, respectively, and these proportions of patients attaining BP control were similar after 6, 9, and 12 months.

Lefebvre et al (2016)⁴⁷ conducted a retrospective, observational study using data from the IMS Health Real-World Data Electronic Medical Records-US database from March 2012 to April 2015, to evaluate the proportion of patients with pre- and postindex SBP and DBP reductions at various time points among Whites and Blacks/African Americans with T2DM.

• Postindex SBP decreased among patients with preindex SBP ≥140 mm Hg (Whites: N=5,541, mean preindex=149.8 mm Hg; Blacks/African Americans: N=772, mean preindex=151.6 mm Hg). Most decrease occurred by 3 months and continued through 12 months postindex among samples of evaluable patients at each time point.
• Postindex DBP decreased among patients with preindex DBP ≥90 mm Hg (Whites: N=2,054, mean preindex=94.2 mm Hg; Blacks/African Americans: N=384, mean preindex=95.4 mm Hg). Most of the decrease happened at 3 months and continued through 12 months postindex among samples of evaluable patients at each time point.

Other relevant real-world evidence that report on INVOKANA-associated changes in BP and heart rate have been included in the REFERENCES section for your review.^48-53

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 21 March 2023.