The Journal of Clinical Hypertension Vol 16 No 12 December

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1 ORIGINAL PAPER Effect of Canagliflozin on Blood Pressure and Adverse Events Related to Osmotic Diuresis and Reduced Intravascular Volume in Patients With Type 2 Diabetes Mellitus Matthew R. Weir, MD; 1 Andrzej Januszewicz, MD; 2 Richard E. Gilbert, MD, PhD; 3 Ujjwala Vijapurkar, PhD; 4 Irina Kline, MD; 4 Albert Fung, BS; 4 Gary Meininger, MD 4 From the Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD; 1 Department of Hypertension, Institute of Cardiology, Warsaw, Poland; 2 University of Toronto, St. Michael s Hospital, Toronto, ON, Canada; 3 and Janssen Research & Development, LLC, Raritan, NJ 4 The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on blood pressure (BP) and osmotic diuresis and intravascular volume reduction related adverse events (AEs) were evaluated using pooled data from four placebo-controlled, phase 3 studies in patients with type 2 diabetes mellitus (T2DM; N=2313). At baseline, 1332 (57.6%) patients were taking an antihypertensive medication. Canagliflozin 1 mg and 3 mg provided reductions (95% confidence interval [CI]) from baseline in systolic BP (SBP) compared with placebo ( 4.3 mm Hg [ 5. to 3.5], 5. mm Hg [ 5.8 to 4.2], and.3 mm Hg [ 1.2 to.5], respectively) and in diastolic BP (DBP; 2.5 mm Hg [ 2.9 to 2.], 2.4 mm Hg [ 2.9 to 1.9], and.6 mm Hg [ 1.1 to.2], respectively). Placebosubtracted reductions (95% CI) in SBP with canagliflozin 1 mg and 3 mg were 4. mm Hg ( 5.1 to 2.8) and 4.7 mm Hg ( 5.8 to 3.5) and reductions in DBP were 1.9 mm Hg ( 2.6 to 1.2) and 1.9 mm Hg ( 2.6 to 1.1), respectively. Compared with the overall population, patients with elevated baseline SBP ( 14 mm Hg) had numerically greater absolute SBP reductions (95% CI) with canagliflozin 1 mg and 3 mg and placebo ( 12.8 mm Hg [ 15.2 to 1.5], 14.2 mm Hg [ 16.4 to 12.], and 6.8 mm Hg [ 9.1 to 4.5], respectively). Numerically greater DBP reductions were seen in patients with DBP 9 mm Hg at baseline ( 5.9 mm Hg [ 8.2 to 3.6], 9. mm Hg [ 11.1 to 6.9], and 7.4 mm Hg [ 9.6 to 5.1], respectively). In patients with elevated SBP at baseline, placebo-subtracted reductions (95% CI) in SBP with canagliflozin 1 mg and 3 mg were 6. mm Hg ( 9.1 to 2.9) and 7.4 mm Hg ( 1.4 to 4.4), respectively. Placebo-subtracted changes in DBP were 1.5 mm Hg ( 1.6 to 4.5) and 1.6 mm Hg ( 4.5 to 1.2), respectively, in those with elevated DBP at baseline. Canagliflozin 1 mg and 3 mg were associated with increased incidence of osmotic diuresis related AEs (eg, pollakiuria [increased urine volume] and polyuria [increased urine frequency]) vs placebo (6.7%, 5.6%, and.8%). The incidence of intravascular volume reduction related AEs (eg, orthostatic hypotension and postural dizziness) was low across groups (1.2%, 1.3%, and 1.1%). In summary, canagliflozin was associated with reduced BP in patients with T2DM across a range of baseline BPs, with increased incidence of AEs related to osmotic diuresis but not intravascular volume reduction. J Clin Hypertens (Greenwich). 214;16: ª 214 Wiley Periodicals, Inc. Hypertension is a common comorbidity in patients with type 2 diabetes mellitus (T2DM), with approximately 67% of adults with T2DM having blood pressure (BP) 14/9 mm Hg or taking antihypertensive medication. 1 Lowering BP could help reduce the risk of cardiovascular disease in patients with T2DM. 1,2 Current guidelines from the American Diabetes Association recommend a systolic BP (SBP) goal of <14 mm Hg for patients with diabetes and hypertension (or <13 mm Hg for certain individuals, including younger patients) and a diastolic BP (DBP) goal of <8 mm Hg for patients with diabetes. 3 Clinical trials registration numbers: ClinicalTrials.gov, NCT181834; NCT116677; NCT116625; NCT11669 Address for correspondence: Matthew R. Weir, MD, Division of Nephrology, University of Maryland Medical Center, 22 South Greene Street, Room N3W143, Baltimore, MD mweir@medicine.umaryland.edu Manuscript received: July 2, 214; revised: August 22, 214; accepted: August 25, 214 DOI: /jch Canagliflozin is a sodium glucose co-transporter 2 (SGLT2) inhibitor developed for the treatment of T2DM Canagliflozin inhibits renal glucose reabsorption and increases urinary glucose excretion (UGE), 13 thus reducing plasma glucose concentration in individuals with hyperglycemia. Increased UGE may lead to osmotic diuresis and intravascular volume reduction. In phase 3 studies, canagliflozin improved glycemic control and lowered body weight and BP in patients with T2DM on a variety of diabetes treatment regimens. 4 6,8,9,11,12 Higher incidence of adverse events (AEs) related to osmotic diuresis (eg, pollakiuria [increased urine volume], polyuria [increased urine frequency]) and intravascular volume reduction (eg, orthostatic hypotension, postural dizziness) have been observed with canagliflozin vs placebo. 4,6,9,11,12 To evaluate the effects of canagliflozin on BP and AEs related to osmotic diuresis and intravascular volume reduction in a general population of patients with T2DM, an analysis was performed based on pooled data from four randomized, double-blind, placebo-controlled The Journal of Clinical Hypertension Vol 16 No 12 December

2 TABLE I. Study Design and Patient Populations 6,1 12,14 Inclusion Criteria Patients Contributing Data to Pooled Analysis, No. Study a Duration, wk b Age, y HbA 1c, % egfr, ml/min/1.73 m 2 Placebo CANA 1 mg CANA 3 mg Total Monotherapy to 8 7. and Add-on to MET to 8 7. and Add-on to MET+SU to 8 7. and Add-on to MET+PIO to 8 7. and Overall total, No Abbreviations: CANA, canagliflozin; egfr, estimated glomerular filtration rate; HbA 1c, glycated hemoglobin; MET, metformin; PIO, pioglitazone; SU, sulfonylurea. a During the double-blind treatment period, patients meeting prespecified glycemic criteria received glycemic rescue therapy with MET (monotherapy study), glimepiride (add-on to MET and add-on to MET+PIO studies), or insulin (add-on to MET+SU study). b Primary assessment time point. phase 3 studies, as well as from subgroups of patients with elevated baseline SBP ( 14 mm Hg) or DBP ( 9 mm Hg) and those who were or were not taking antihypertensive medication at baseline. METHODS Study Design and Patient Population This pooled analysis included patients with T2DM from four placebo-controlled, phase 3 studies (Table I). 6,1 12,14 Each study evaluated canagliflozin 1 mg and 3 mg vs placebo over a 26-week, doubleblind core treatment period followed by a 26-week extension period; data from the 26-week core treatment periods are included in this analysis. The mean duration of exposure to study drug in the pooled dataset was approximately 24 weeks in each canagliflozin group and 22 weeks in the placebo group. Key inclusion criteria for each study are shown in Table I. Key exclusion criteria common to the four studies included repeated fasting plasma glucose (FPG) generally 15. mmol/l (27 mg/dl) during the pretreatment phase; history of type 1 diabetes; history of myocardial infarction, unstable angina, revascularization procedure, or cerebrovascular accident with 3 months of screening; and uncontrolled hypertension (ie, the average of three seated BP readings with SBP 16 mm Hg or DBP 1 mm Hg). Details of individual study designs, including randomization, blinding, and glycemic rescue therapy have been previously reported. 6,1 12 These studies were conducted in accordance with the ethical principles originating in the Declaration of Helsinki and are consistent with Good Clinical Practices and applicable regulatory requirements. Approval was obtained from institutional review boards and independent ethics committees for participating centers, and written informed consent was provided by patients prior to participation. Endpoints and Assessments Efficacy endpoints evaluated at week 26 in the overall population included change from baseline in SBP and TABLE II. Baseline Demographic and Disease Characteristics of the Overall Population a Characteristic Placebo (n=646) CANA 1 mg (n=833) CANA 3 mg (n=834) Sex, No. (%) Male 334 (51.7) 48 (49.) 44 (48.4) Female 312 (48.3) 425 (51.) 43 (51.6) Age, y 56.3 (9.8) 55.9 (1.1) 55.7 (9.5) Race, No. (%) White 47 (72.8) 591 (7.9) 61 (73.1) Black or African 28 (4.3) 43 (5.2) 48 (5.8) American Asian 82 (12.7) 13 (12.4) 1 (12.) Other b 66 (1.2) 96 (11.5) 76 (9.1) Region, No. (%) c North America 33 (46.9) 381 (45.7) 369 (44.2) Central/South 61 (9.4) 9 (1.8) 88 (1.6) America Europe 16 (24.8) 176 (21.1) 185 (22.2) Asia/Pacific 75 (11.6) 14 (12.5) 15 (12.6) Other d 47 (7.3) 82 (9.8) 87 (1.4) SBP, mm Hg (13.2) 128. (12.8) (12.8) DBP, mm Hg 77.9 (8.3) 77.5 (8.) 78.2 (8.3) BMI, kg/m (6.4) 32.3 (6.4) 32. (6.5) HbA 1c, % 8. (.9) 8. (.9) 8. (1.) Duration of T2DM, y 7.5 (6.2) 7.2 (5.8) 7.4 (6.2) egfr, ml/min/1.73 m (19.8) 88.3 (19.) 88.8 (18.9) Taking antihypertensive medication at baseline, No. (%) e 376 (58.2) 494 (59.3) 462 (55.4) Abbreviations: BMI, body mass index; CANA, canagliflozin; DBP, diastolic blood pressure; egfr, estimated glomerular filtration rate; HbA 1c, glycated hemoglobin; SBP, systolic blood pressure; T2DM, type 2 diabetes mellitus. a Data are mean (standard deviation) unless otherwise indicated. b Includes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, multiple, other, unknown, and not reported. c Percentages may not total 1.% due to rounding. d Includes Russian Federation, Turkey, Ukraine, and South Africa. e Including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and/or diuretics. 876 The Journal of Clinical Hypertension Vol 16 No 12 December 214

3 DBP. Change in SBP and the proportion of patients achieving SBP <14 mm Hg and <13 mm Hg were assessed in a subset of patients with baseline SBP 14 mm Hg. Change in SBP was also assessed in 6 subgroups by baseline SBP (<11, 11 <12, 12 <13, 13 <14, 14 <15, and 15 mm Hg). Change in DBP and the proportion of patients achieving DBP <9 mm Hg and <8 mm Hg were assessed in a subset of patients with baseline DBP 9 mm Hg. A subgroup analysis assessed changes in SBP and DBP in the overall population by baseline use of antihypertensive medications (ie, angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], and diuretics). A stable antihypertensive medication regimen was required for 4 weeks prior to randomization; adjustments to antihypertensive medication considered clinically necessary were to be made during the pretreatment phase in order to avoid adjustments during the double-blind period. In the subgroups with elevated baseline SBP or DBP, sensitivity analyses assessed the change from baseline in SBP or DBP prior to postrandomization adjustment in antihypertensive medication. A responder/nonresponder analysis examined characteristics of patients with an SBP reduction of 5 mmhgor<5 mm Hg. Three BP readings were taken manually with a mercury sphygmomanometer or an automated BP monitor at intervals of 1 minute. Patients were to be seated with their legs uncrossed and back and arm supported so that the upper arm was at the level of the right atrium (midpoint of the sternum). Cuff size was chosen based on the upper arm circumference so that A Overall population SBP 14 mm Hg No. Baseline (mm Hg) LS mean change (±SE) in SBP from baseline (mm Hg) mm Hg (95% CI: 5.1 to 2.8) mm Hg (95% CI: 5.8 to 3.5) mm Hg (95% CI: 9.1 to 2.9) B Overall population 7.4 mm Hg (95% CI: 1.4 to 4.4) DBP 9 mm Hg No. Baseline (mm Hg) LS mean change (±SE) in DBP from baseline (mm Hg) mm Hg (95% CI: 2.6 to 1.2) mm Hg 9. (95% CI: 2.6 to 1.1) 1.5 mm Hg (95% CI: 1.6 to 4.5) 1.6 mm Hg (95% CI: 4.5 to 1.2) PBO CANA 1 mg CANA 3 mg FIGURE 1. Change in (A) systolic blood pressure (SBP) and (B) diastolic blood pressure (DBP) for the overall population and for patients with SBP 14 mm Hg and DBP 9 mm Hg (last observation carried forward [LOCF]). LS indicates least-squares; SE, standard error; CI, confidence interval; PBO, placebo; CANA, canagliflozin. The Journal of Clinical Hypertension Vol 16 No 12 December

4 1 PBO CANA 1 mg CANA 3 mg Percentage of patients SBP <14 mm Hg SBP <13 mm Hg FIGURE 2. Proportion of patients with baseline systolic blood pressure (SBP) 14 mm Hg reaching SBP targets (last observation carried forward [LOCF]). PBO indicates placebo; CANA, canagliflozin. Patients with baseline SBP 14 mm Hg (PBO, n=134; CANA 1 mg, n=146; CANA 3 mg, n=166). 8% of the arm circumference was encircled by the bladder of the cuff (arm circumference ranges: 22 cm to 26 cm [small adult cuff], 27 cm to 34 cm [adult cuff], 35 cm to 44 cm [large adult cuff], and 45 cm to 52 cm [adult thigh cuff]). For patients with an arm circumference >52 cm, an appropriately sized cuff was to be placed on the patient s forearm (supported at heart level), and the radial pulse at the wrist was used. Site staff performing BP measurements received training by the sponsor based on the American Heart Association BP recommendations specified in the protocol and received ongoing reminders of the methodology via newsletters. The investigator was responsible for documenting site staff training and for delegation of responsible individuals trained to perform the vital sign assessments. Safety analyses were performed in the overall population. Assessments of AEs related to osmotic diuresis and intravascular volume reduction were based on prespecified Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (Table S1), which were grouped for analysis. Safety data are reported for regardless of initiation of glycemic rescue medication. Statistical Analyses BP analyses were performed using the modified intentto-treat (mitt) population, consisting of randomized patients who received 1 dose of study drug. The lastobservation-carried-forward (LOCF) approach was used to impute missing data; if a patient received glycemic rescue therapy, the last post-baseline value prior to the initiation of rescue medication was used. Changes in SBP and DBP in the mitt population and subgroups, based on use of antihypertensive medications, were assessed using an analysis of covariance (ANCOVA) model with treatment and study as factors and the respective baseline value as a covariate. Changes in SBP and DBP in patients with SBP 14 mm Hg and DBP 9 mm Hg, respectively, were assessed using the same ANCOVA model, with an additional factor adjusting for baseline antihypertensive medication use. Least-squares (LS) means and the two-sided 95% confidence intervals (CIs) for the comparison of each canagliflozin dose vs placebo were determined. The proportions of patients achieving target BP values were analyzed using a logistic model with treatment and study as factors and baseline BP as a covariate. For sensitivity analyses, the last observation prior to adjustment in antihypertensive medication regimen (ie, prior to the addition of a new ACE inhibitor, ARB, or diuretic) was carried forward. Given the post hoc nature of these analyses, no P values are reported. RESULTS Patients Of the 2313 patients in the overall population who were randomized and dosed, 1984 (85.8%) completed the 26-week treatment periods of their respective studies. In the overall population, 1332 (57.6%) patients were taking antihypertensive medication at baseline, most commonly ACE inhibitors (37.%). Of the 1268 patients taking ACE inhibitor/arb therapy at baseline, 1194 (94.2%) were still taking ACE inhibitors/arbs throughout the 26-week double-blind period. Similarly, 519 of the 554 patients taking diuretics at baseline (93.7%) were still taking these agents throughout the 26-week double-blind period. Patients in this population had normal renal function or mild renal impairment, with a mean estimated glomerular filtration rate of 88.1 ml/min/1.73 m 2. Baseline characteristics were similar across treatment groups in the overall population (Table II). Baseline characteristics in the subgroups of patients with baseline SBP 14 mm Hg and baseline DBP 9 mm Hg are shown in Table S2. Canagliflozin significantly improved glycemic control over 26 weeks in each of the four studies included in the pooled dataset, as previously reported. 6,1 12 Briefly, placebo-subtracted LS mean differences from baseline in glycated hemoglobin with canagliflozin 1 mg and 878 The Journal of Clinical Hypertension Vol 16 No 12 December 214

5 3 mg were.91% and 1.16%, respectively, as monotherapy 6 ;.62% and.77%, respectively, as add-on to metformin 1 ;.71% and.92%, respectively, as add-on to metformin plus sulfonylurea 11 ;and.62% and.76%, respectively, as add-on to metformin plus pioglitazone. 12 Blood Pressure In the overall population, canagliflozin 1 mg and 3 mg were associated with reductions relative to placebo in SBP and DBP (Figure 1). SBP was reduced across treatment groups among patients with elevated baseline SBP ( 14 mm Hg), with greater decreases observed with both canagliflozin doses compared with placebo (Figure 1A). In patients with elevated baseline DBP ( 9 mm Hg), decreases in DBP were observed across treatment groups; a reduction relative to placebo was seen with canagliflozin 3 mg, whereas an increase was observed with canagliflozin 1 mg relative to placebo (Figure 1B). The placebo-subtracted increase in DBP with canagliflozin 1 mg may reflect the presence of outliers given that median changes were 7 mm Hg, 8 mm Hg, and 6 mm Hg with canagliflozin 1 mg and 3 mg and placebo, respectively. Absolute reductions from baseline in SBP and DBP were greater with canagliflozin in patients with higher baseline BP compared with the overall population (Figure 1). Placebo-subtracted reductions in SBP were generally larger for greater baseline SBP (Figure S1). A greater proportion of patients with baseline SBP 14 mm Hg A On antihypertensives at baseline Not on antihypertensives at baseline No. Baseline (mm Hg) LS mean change (±SE) in SBP from baseline (mm Hg) mm Hg (95% CI: 5.9 to 2.8) mm Hg (95% CI: 6.2 to 3.) mm Hg 5.2 (95% CI: 5.1 to 1.8) 4.7 mm Hg (95% CI: 6.3 to 3.1) B On antihypertensives at baseline Not on antihypertensives at baseline No. Baseline (mm Hg) LS mean change (±SE) in DBP from baseline (mm Hg) mm Hg (95% CI: 2.7 to.8) mm Hg (95% CI: 2.7 to.7) mm Hg (95% CI: 3.2 to 1.) mm Hg (95% CI: 3.1 to.9) PBO CANA 1 mg CANA 3 mg FIGURE 3. Change in (A) systolic blood pressure (SBP) and (B) diastolic blood pressure (DBP) for patients taking antihypertensive medications (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and/or diuretics) and not taking antihypertensive medications at baseline (last observation carried forward [LOCF]). LS indicates least-squares; SE, standard error; CI, confidence interval; PBO, placebo; CANA, canagliflozin. The Journal of Clinical Hypertension Vol 16 No 12 December

6 who received canagliflozin achieved SBP <14 mm Hg or <13 mm Hg compared with patients who received placebo (Figure 2). Among patients with baseline DBP 9 mm Hg, a greater proportion of those who received canagliflozin 3 mg achieved DBP <9 mm Hg or <8 mm Hg compared with those who received canagliflozin 1 mg and placebo (Figure S2). Among patients taking background antihypertensive medication (n=1332), decreases in SBP and DBP with canagliflozin 1 mg and 3 mg compared with placebo were generally comparable to those observed in patients not taking these agents (n=981; Figures 3A and B). The sensitivity analysis in patients with elevated baseline BP, using the last observation prior to adjustment in antihypertensive medication regimen carried forward, showed that, relative to placebo, decreases in TABLE III. Summary of AEs Related to Osmotic Diuresis and Intravascular Volume Reduction a Patients, No. (%) Placebo (n=646) CANA 1 mg (n=833) CANA 3 mg (n=834) Osmotic diuresis related AEs Any AE 5 (.8) 56 (6.7) 47 (5.6) AEs leading to 1 (.1) 2 (.2) discontinuation AEs related to study drug b 5 (.8) 41 (4.9) 41 (4.9) Serious AEs Specific terms Dry mouth 6 (.7) 2 (.2) Micturition urgency 2 (.2) 3 (.4) Nocturia 1 (.2) 3 (.4) 1 (.1) Pollakiuria c 4 (.6) 35 (4.2) 26 (3.1) Polydipsia 6 (.7) 2 (.2) Polyuria d 6 (.7) 12 (1.4) Thirst 1 (.2) 11 (1.3) 16 (1.9) Urine output 1 (.1) 1 (.1) increased Intravascular volume reduction AEs Any AE 7 (1.1) 1 (1.2) 11 (1.3) AEs leading to 1 (.2) discontinuation AEs related to study 2 (.3) 4 (.5) 6 (.7) drug b Serious AEs 1 (.2) Specific terms Dehydration 1 (.1) Hypotension 4 (.6) 6 (.7) 2 (.2) Orthostatic 1 (.2) 4 (.5) hypotension Postural dizziness 2 (.3) 3 (.4) 4 (.5) Syncope e 1 (.1) a All adverse events (AEs) are reported for regardless of rescue medication. b Possibly, probably, or very likely related to study drug. c Increased urine frequency. d Increased urine volume. e A nonserious, mild, isolated syncopal episode with canagliflozin (CANA) 1 mg did not lead to treatment interruption. SBP with both canagliflozin doses, and in DBP with canagliflozin 3 mg, were observed in patients who maintained a stable antihypertensive medication regimen (Figure S3). Placebo-subtracted reductions in SBP with both canagliflozin doses were modestly lower and the placebo-subtracted reduction in DBP with canagliflozin 3 mg was modestly higher compared with those seen in the overall elevated SBP and DBP subgroups (Figure 1). An analysis was performed to identify potential patient characteristics associated with greater canagliflozin-related BP reductions. With canagliflozin 1 mg and 3 mg and placebo, 44.9%, 48.3%, and 34.5% of patients, respectively, achieved an SBP reduction of 5 mm Hg (ie, responders). The mean baseline SBP in responders treated with canagliflozin 1 mg and 3 mg and placebo (132.3, 133.6, and mm Hg, respectively) was higher compared with patients in the nonresponder group (ie, SBP reduction <5 mm Hg; 124.5, 124.2, and mm Hg, respectively); baseline DBP was also higher in responders (78.8, 79.8, and 79.9 mm Hg, respectively) compared with nonresponders (76.5, 76.6, and 76.8 mm Hg, respectively). Other patient characteristics were similar between responders and nonresponders. Safety and Tolerability The incidence of AEs related to intravascular volume reduction was low and similar with canagliflozin and placebo (Table III), with events being generally mild or moderate in intensity, as assessed by the investigator. No patients had a serious AE or AE leading to study discontinuation with canagliflozin, compared with one each with placebo. Overall, the most common specific terms related to intravascular volume reduction were hypotension, postural dizziness, and orthostatic hypotension; one patient (canagliflozin 1 mg) reported an AE of syncope that was neither severe nor serious and did not lead to discontinuation. The median time to the first AE related to intravascular volume reduction was shorter in the canagliflozin 3 mg group than in the canagliflozin 1 mg and placebo groups (43., 11.5, and 78. days, respectively); however, the range was large in all groups. The mean duration of AEs related to intravascular volume reduction was longer in the canagliflozin 3 mg group compared with the canagliflozin 1 mg and placebo groups (33.4, 8.8, and 11.1 days, respectively). Treatment with canagliflozin 1 mg and 3 mg was associated with an increased incidence of osmotic diuresis related AEs compared with placebo (Table III). Most of these AEs were mild or moderate in intensity, as assessed by the investigator, and none were serious. The most common specific terms reported were pollakiuria, thirst, and polyuria. The majority of osmotic diuresis related AEs with canagliflozin occurred within the first 6 weeks of treatment (Figure 4). Minimal mean changes in pulse rate were observed in the overall population (.6,.4, and. beats per 88 The Journal of Clinical Hypertension Vol 16 No 12 December 214

7 Estimated % of patients with an event PBO CANA 1 mg CANA 3 mg Time (wk) Patients at risk, No. PBO CANA 1 mg CANA 3 mg FIGURE 4. Kaplan-Meier plot of time to first osmotic diuresis related adverse event (AE). PBO indicates placebo; CANA, canagliflozin. minute with canagliflozin 1 mg and 3 mg and placebo, respectively). Canagliflozin 1 mg and 3 mg were associated with small mean increases in creatinine compared with placebo (2.8%, 4.%, and 1.5%, respectively). Small mean increases in hematocrit were also seen with canagliflozin 1 mg and 3 mg compared with placebo (5.8%, 6.3%, and.2%, respectively). DISCUSSION The majority of patients with T2DM have hypertension, which may contribute to increased risk of comorbidities, including cardiovascular disease. 1,2 In this pooled analysis of studies in a general population of patients with T2DM, treatment with canagliflozin 1 mg and 3 mg provided clinically meaningful reductions in SBP and smaller reductions in DBP relative to placebo, with no notable changes in pulse rate. Treatment with canagliflozin was associated with a higher incidence of AEs related to osmotic diuresis compared with placebo, but the incidence of AEs related to intravascular volume reduction was low across groups; these AEs were generally considered mild or moderate in intensity, as assessed by the investigator, and infrequently led to study discontinuation. Overall, these findings were generally consistent with previous studies of canagliflozin. 4 6,8 12 Patients with elevated SBP or DBP at baseline who received canagliflozin showed greater absolute reductions in SBP and DBP, respectively, compared with the overall population. Despite greater absolute reductions, the placebo-subtracted reductions in DBP with canagliflozin 3 mg were similar in the subgroup with elevated baseline DBP and in the overall population. Among patients with elevated baseline SBP, a greater proportion of canagliflozin-treated patients achieved SBP targets of <14 mm Hg and <13 mm Hg compared with patients who received placebo. Overall, the magnitude of the BP-lowering effect of canagliflozin was greater with SBP than with DBP. Canagliflozin was associated with similar placebosubtracted decreases in SBP and DBP in patients either taking or not taking antihypertensive medication at baseline. Thus, the BP-lowering effect of canagliflozin was not substantially altered by the concomitant use of antihypertensive medication. As adjustments in antihypertensive medication may have impacted the assessment of BP change in patients with elevated baseline BP, sensitivity analyses were performed in these patients to evaluate changes in SBP and DBP only among those on a stable antihypertensive medication regimen (ie, based on BP measurements prior to adjustment of antihypertensive medication). Findings from these sensitivity analyses were comparable to those observed in the elevated baseline BP subgroups, when data after adjustment of antihypertensive medications were included. These results support the finding that antihypertensive medication use does not notably alter the effects of canagliflozin on lowering BP. In addition to providing glycemic control, canagliflozin 1 mg and 3 mg were associated with body weight reductions across phase 3 studies in adults with T2DM. 4 6,8,9,11,12 Among the patients included in this analysis, body weight reductions were 2.8% and 3.5% with canagliflozin 1 mg and 3 mg, respectively (.6% with placebo). Some of the initial weight reduction with canagliflozin treatment may be related to fluid loss caused by increased UGE; however, plasma volume reduction associated with canagliflozin is transient and largely attenuates after several weeks on treatment. 15 Additionally, body composition assessments have shown that loss of fat mass accounts for approximately two thirds of the body weight reductions over 52 weeks. 5 Because the accumulation of adipose tissue is associated with hypertension, weight loss would result in BP reduction. 16,17 An analysis evaluating the contribution of weight loss with canagliflozin to SBP reduction showed that approximately 4% of the The Journal of Clinical Hypertension Vol 16 No 12 December

8 canagliflozin-associated reduction in SBP may be related to weight loss, with each 1% reduction in body weight associated with a.62 mm Hg reduction in SBP. 18 The mechanism of weight loss independent BP reductions with canagliflozin is not known, but may be related to the mild osmotic diuresis, which reduces intravascular volume. Of note, reductions in intravascular volume would be more likely to result in reductions in SBP compared with DBP. Changes in sodium excretion may also impact BP-lowering with canagliflozin. Consistent with the mechanism of action of canagliflozin and with previous findings, 4 6,8,9,11,12 a higher incidence of osmotic diuresis related AEs was observed with canagliflozin relative to placebo in this pooled analysis. These AEs were generally considered mild or moderate in intensity, as assessed by the investigator, and few were serious or led to study discontinuation. Increased incidence of AEs related to osmotic diuresis have also been observed with another SGLT2 inhibitor. 19 In the current analysis, the incidence of AEs related to intravascular volume reduction was low and similar across groups. CONCLUSIONS Overall, canagliflozin provided SBP and DBP reductions in a general population of patients with T2DM. Patients with elevated SBP or DBP had larger BP reductions compared with the overall population. Notably, SBP and DBP reductions with canagliflozin were similar regardless of background use of antihypertensive agents. Canagliflozin was generally well tolerated, with a low incidence of AEs related to intravascular volume reduction across groups and an increased incidence of osmotic diuresis related AEs. Therefore, canagliflozin may benefit patients with T2DM across a range of baseline BPs. Acknowledgments: The authors thank all investigators, study teams, and patients for participating in the studies contributing to this analysis. The authors acknowledge Keith Usiskin, MD; Gordon Law, PhD; and Jacqueline Yee, MS, of Janssen Research & Development, LLC, for their contributions to the analyses described in this manuscript. Canagliflozin was developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation. Disclosures: This study was sponsored by Janssen Research & Development, LLC. Editorial support was provided by Courtney St. Amour, PhD, of MedErgy, and was funded by Janssen Global Services, LLC. M.W. is a scientific consultant for Janssen; A.J. has received research funding from Janssen; R.G. has received research support, served on advisory panels, and participated in speaking engagements for Johnson & Johnson, Merck, Bristol-Myers Squibb, Astra-Zeneca, and Sanofi; U.V., I.K., A.F., and G.M. are full-time employees of Janssen Research & Development, LLC. References 1. Centers for Disease Control and Prevention. 211 National Diabetes Fact Sheet. 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Baseline Demographic and Disease Characteristics (SBP 14 mm Hg and DBP 9 mm Hg Subgroups) Figure S1. Change in SBP by baseline SBP (LOCF). Figure S2. Proportion of patients with baseline DBP 9 mm Hg reaching DBP targets (LOCF). Figure S3. Change in BP in patients with baseline SBP 14 mm Hg and DBP 9 mm Hg prior to adjustment in antihypertensive medication (LOCF). 882 The Journal of Clinical Hypertension Vol 16 No 12 December 214