SUMMARY  

• Canagliflozin (CANA) increases urinary glucose excretion (UGE) via sodium-glucose cotransporter-2 (SGLT2) inhibition. The caloric waste arising from UGE is likely attributing to weight loss.¹ Percent change in body weight (BW) was a prespecified secondary endpoint in phase 3 glycemic control studies of INVOKANA.^1-9
• In the CREDENCE study, in patients with type 2 diabetes mellitus (T2DM) and albuminuric chronic kidney disease (CKD), INVOKANA demonstrated greater mean change in BW (-0.80 kg) vs PBO.^10-12
• In the CANVAS program, in patients with T2DM and CVD or ≥2 risk factors for CVD, INVOKANA demonstrated statistically significant reductions in BW vs placebo (PBO) (-0.80 kg; 95% confidence interval [CI]: -0.92 to -0.69 kg).¹³
• Significantly greater reductions in BW were observed with INVOKANA vs. comparator in phase 3 PBO-controlled glycemic control studies^{2-9, 14} during the core study periods and at week 52 in the active-controlled studies.^{1, 3, 4}
  • BW reductions with INVOKANA during core study periods were maintained during extension periods, with total durations up to 52 weeks^{3, 5, 7, 8, 15, 16} or 104 weeks.^{17, 18}
• In a subset of patients from two phase 3 studies^4,9 evaluating body composition using dual energy x-ray absorptiometry (DXA), ~2/3 of weight loss with INVOKANA was due to loss of body fat mass and ~1/3 from total lean mass, including water.¹⁹
• A post hoc analysis of pooled data from two phase 3 trials^1,3 comparing efficacy of INVOKANA vs sitagliptin (SITA) reported superior attainment of individual diabetes-related quality measures, including body mass index (BMI) and change in BW through week 52.²⁰
• An analysis was conducted for INVOKANA randomized controlled trials with at least one year of follow up reporting % change in BW or change in BP. Six studies were analyzed (including the integration of the two CANVAS program studies: CANVAS and CANVAS-R).^{1, 7, 8, 13, 18} BW reduction was significantly greater with INVOKANA vs comparator.²¹
• A quality of life analysis, including four phase 3 glycemic control trials, showed improvements in BW and weight-related quality of life measures in INVOKANA-treated patients compared to PBO/SITA.²²
• Additional citations identified during a literature search are included in the REFERENCES section for your review.^23-45

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 effects of INVOKANA (100 mg) vs PBO on clinically important renal outcomes in people with T2DM and (estimated glomerular filtration rate [eGFR] 30 to <90 mL/min/1.73 m²) and albuminuria (urine albumin:creatinine ratio [UACR] >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).^{10-12, 46-48}

• 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 mean BW change from baseline.

Baseline Characteristics^10-12

• 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, and mean BMI 31.1 kg/m². Across both treatment groups, mean exposure to study drug was 115 weeks.

Results¹⁰

• 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. At study conclusion, the median follow-up time was 2.62 years (range 0.02-4.53 years).
• INVOKANA demonstrated a greater mean change in BW (-0.80 kg; 95% confidence interval [CI] -0.92, -0.69 kg) compared to PBO.

CANVAS Program

• The efficacy and safety of INVOKANA were evaluated in the CANVAS Program.¹³
• A statistically significant mean difference in BW of -1.60 kg (95% CI -1.70 to -1.51; P<0.001) between INVOKANA and PBO was seen in the CANVAS Program, comprised of two large INVOKANA cardiovascular (CV) outcome studies [CANagliflozin cardioVascular Assessment Study (CANVAS) and CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R)].¹³ The mean follow-up in the CANVAS Program was 188.2 weeks.¹³ See Figure: CANVAS Program – Adjusted Mean Body Weight Over Time.

Phase 3 Glycemic Control Studies

• Efficacy and safety of INVOKANA were evaluated in several phase 3 studies which included core 26 weeks,^{2, 3, 7-9, 14} 52 weeks,^{1, 4} 18 weeks,^{5, 6} and extension study periods (52-104 weeks).
• Percent change in BW was a prespecified secondary endpoint in phase 3 glycemic control studies of INVOKANA.^1-9 BW reductions observed with INVOKANA during core study periods were maintained during extension periods, with total study durations up to 52 weeks^{3, 5, 7, 8, 15, 16} or 104 weeks^{17, 18} (see Table: Percent Change in Body Weight).
• Across phase 3, glycemic, PBO-controlled studies,^{2, 3, 5-8} a greater BW reduction was seen with INVOKANA 300 mg relative to 100 mg, with observed incremental differences in the PBO-subtracted BW reduction from baseline of ~1.1% in the monotherapy study and ranging from 0.5% to 1.2% in add-on combination add-on to current therapy studies.⁴⁹
• In phase 3 glycemic active-controlled studies, in which both INVOKANA and comparator were added to metformin (MET)-based background therapy (INVOKANA in an add-on to [1] metformin vs SITA study³, [2] add-on to MET plus sulfonylurea [SU] vs SITA study¹, and [3] add-on to MET vs glimepiride [GLIM] study⁴) INVOKANA was associated with significantly greater reductions in BW than comparator at week 52.
• The pattern of weight loss with INVOKANA was generally consistent across studies, with a reduction seen as early as week 6^2,3,14 in some studies, and was generally maintained through 104 weeks in other studies.^17,18

Impact of Baseline Factors on BW Reductions

• In a subgroup analysis of phase 3 PBO-controlled studies^{2, 3, 5-8}, treatment with INVOKANA lowered BW in a dose-related manner at the primary assessment time point, with mean % reductions in BW consistently larger than those observed with PBO regardless of demographic characteristics (age, sex, race, ethnicity), baseline BMI, baseline disease severity (i.e., severity of hyperglycemia), or degree of underlying renal impairment.⁴⁹
• In addition, as baseline BMI increased, increases in a stepwise manner in absolute mean BW reductions were observed with INVOKANA compared to PBO, and for baseline eGFR, greater % reductions in BW were reported in patients with an eGFR ≥90 mL/min/1.73m² compared to those that had an eGFR of <60 mL/min/1.73m².⁴⁹

Composition of Weight Loss

• Body composition using DXA was evaluated in two phase 3 studies (one active GLIM-controlled add-on to MET study⁴ and one PBO-controlled study in older patients).^9,19
• Approximately 2/3 of the weight loss with INVOKANA were due to loss of body fat mass and ~1/3 from total lean mass, including water.
• Results showed a slightly greater % reduction in visceral adipose tissue (VAT) than subcutaneous adipose tissue (SAT) following treatment with INVOKANA.¹⁹
  • In the 52 week GLIM-controlled add-on to MET study⁴, % change between INVOKANAand GLIM was slightly greater for VAT (least squares mean (LSM) difference vs GLIM of –7.4% and –8.3%, for INVOKANA 100 mg and 300 mg, respectively) compared with SAT (LSM difference of –7.2% and –7.4%, for INVOKANA 100 mg and 300 mg, respectively).¹⁹

Blonde et al (2014)⁵³ conducted a post hoc analysis to evaluate the proportion of T2DM patients achieving BW reduction ≥ 5% with INVOKANA treatment based on the pool of four phase 3, 26-week, PBO-controlled studies.^2,3,7,8

• Baseline characteristics included patients with mean BW 89.2 kg.
• At baseline, 95% of patients were taking ≥1 medication, including antihyperglycemic agents (AHAs) (75%), antihypertensive agents (i.e., ACEi, ARBs, and diuretics; 58%), and/or lipid-modifying agents (47%).
• At week 26, a higher proportion of INVOKANA-treated patients achieved BW reduction ≥5% vs PBO (25.3%, 32.9%, and 6.1% with INVOKANA 100 mg, 300 mg, and PBO, respectively).

Blonde et al (2014)⁵⁴ conducted a post hoc analysis of four pooled, 26-week, PBO-controlled studies^2,3,7,8 to compare INVOKANA 100 mg and 300 mg to PBO for changes in BW stratified by baseline BMI in patients with T2DM (N=2,312). See Table: Percent Change in Body Weight by Baseline BMI for INVOKANA 100 mg and 300 mg Relative to Placebo.

Bailey et al (2014)²⁰ conducted a post hoc analysis of pooled data from two randomized, double-blind, phase 3 clinical trials^1,3 comparing efficacy of INVOKANA vs SITA in which individual diabetes-related quality measures, including BMI and change in BW, were evaluated through week 52.

• At 52 weeks, a greater proportion of patients experienced change in BW evaluated as: proportion of patients with BMI ≥ 25 kg/m² who have lost >10 pounds (lbs) (4.5 kg) at any time during the past 12 months. The difference of INVOKANA 100 mg vs SITA 100 mg was 19.6% (95% CI: 14.3-24.9) and the difference with INVOKANA 300 mg vs SITA 100 mg was 15.2% (95% CI: 11.3-19.1).
• At 52 weeks, a greater proportion of patients experienced a change in BW: evaluated as a BMI <30 kg/m² with INVOKANA 300 mg vs SITA 100 mg (difference: 10.4% [95% CI: 5.1-15.6]). The proportion of patients with BMI <30 kg/m² was similar with INVOKANA 100 mg vs SITA 100 mg (difference: 2.0% [95% CI: -4.5 to 8.5]).

Khan et al (2019)²¹ conducted a pooled analysis evaluating six^{1, 7, 8, 13, 18} INVOKANA randomized, controlled trials (including the integration of the two CANVAS program studies: CANVAS and CANVAS-R) with at least one year of follow up reporting % change in BW or change in BP. The weighted mean different for BW reduction was significantly greater with INVOKANA compared with controls: -3.32%; 95% CI (-4.04, -2.60); p<0.001. Significant weight reduction was seen with INVOKANA 100 mg and 300 mg doses and was not shown to be dose dependent.

MECHANISM

CANAis an inhibitor of SGLT2.¹ By inhibiting SGLT2, CANAreduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RT_G), and thereby increases UGE. The reductions in RT_G led to increases in mean UGE of ~100 g/day in patients with T2DM treated with either CANA 100 mg or 300 mg in phase 1 studies^55-58, which is equivalent to ~400 kcal/day (calculated based on 1 g glucose = 4 kcal).^59,26 The caloric waste arising from UGE is likely attributing to weight loss.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 29 March 2023.