Canagliflozin Compared with Sitagliptin For

Clinical Care/Education/Nutrition/Psychosocial Research ORIGINAL ARTICLE

Canagliﬂozin Compared With Sitagliptin for Patients With Type 2 Diabetes Who Do Not Have Adequate Glycemic Control With Metformin Plus Sulfonylurea A 52-week randomized trial

1 5 GUNTRAM SCHERNTHANER, MD JACQUELINE YEE, MS (2). With further decline in glycemic con- 2 5 JORGE L. GROSS, MD MASATO KAWAGUCHI, MD 3 5 trol (3,4), the addition of a third oral agent JULIO ROSENSTOCK, MD WILLIAM CANOVATCHEL, MD 4 5 is increasingly common. Currently avail- MICHAEL GUARISCO, MD GARY MEININGER, MD 5 able classes of AHAs, such as dipeptidyl MIN FU, MS peptidase-4 inhibitors, peroxisome proliferator–activated receptor (PPAR)g agonists, and sulfonylureas, have distinct OBJECTIVEdTo evaluate the efficacy and safety of canagliflozin, a sodium glucose cotrans- fi fi porter 2 inhibitor, compared with sitagliptin in subjects with type 2 diabetes inadequately risk/bene tpro les (2,5). A recent posi- controlled with metformin plus sulfonylurea. tion statement by the American Diabetes Association and the European Associa- RESEARCH DESIGN AND METHODSdIn this 52-week, randomized, double-blind, tion for the Study of Diabetes recom- active-controlled, phase 3 study, subjects using stable metformin plus sulfonylurea (N =755) mends individualization of treatment received canagliflozin 300 mg or sitagliptin 100 mg daily. Primary end point was change from for patients and suggests the use of phar- baseline in A1C at 52 weeks. Secondary end points included change in fasting plasma glucose macologic agents with complemen- (FPG) and systolic blood pressure (BP), and percent change in body weight, triglycerides, and tary mechanisms of action in triple HDL cholesterol. Safety was assessed based on adverse event (AE) reports. therapy combinations if A1C targets are RESULTSdAt 52 weeks, canagliflozin 300 mg demonstrated noninferiority and, in a sub- not attained with dual combination ther- sequent assessment, showed superiority to sitagliptin 100 mg in reducing A1C (21.03% [211.3 apy (2). mmol/mol] and 20.66% [27.2 mmol/mol], respectively; least squares mean difference between Canagliflozin is an inhibitor of the groups, 20.37% [95% CI, 20.50 to 20.25] or 24.0 mmol/mol [25.5 to 22.7]). Greater sodium glucose cotransporter 2 (SGLT2) reductions in FPG, body weight, and systolic BP were observed with canagliflozin versus sita- in development for the treatment of pa- P , fl gliptin ( 0.001). Overall AE rates were similar with canagli ozin (76.7%) and sitagliptin tients with type 2 diabetes (6–10). SGLT2 (77.5%); incidence of serious AEs and AE-related discontinuations was low for both groups. is responsible for the majority of glucose Higher incidences of genital mycotic infections and osmotic diuresis–related AEs were observed with canagliflozin, which led to one discontinuation. Hypoglycemia rates were similar in both reabsorption in the kidney (11). Almost groups. all glucose is reabsorbed from the tubules until renal tubular resorptive capacity is CONCLUSIONdFindings suggest that canagliflozin may be a new therapeutic tool providing exceeded and urinary glucose excretion better improvement in glycemic control and body weight reduction than sitagliptin, but with (UGE) ensues; the glucose concentration increased genital infections in subjects with type 2 diabetes using metformin plus sulfonylurea. at which this occurs is referred to as the renal threshold for glucose. Canagliflozin lowers the renal threshold for glucose, markedly increasing UGE and thereby re- atients with type 2 diabetes often is the recommended first-line pharmaco- ducing blood glucose concentrations in Prequire combinations of antihyper- logic therapy for type 2 diabetes (1,2). For patients with hyperglycemia. The in- glycemic agents (AHAs) to maintain patients who do not achieve or sustain crease in UGE results in a mild osmotic glycemic control because of the progres- sufficient glycemic control with met- diuresis and also provides a net caloric loss sive nature of the disease (1,2). Metformin formin, a second AHA is often added (with most patients with type 2 diabetes losing an average of 80–120 g/day) (12). ccccccccccccccccccccccccccccccccccccccccccccccccc This mechanism of action, distinct from From the 1Rudolfstiftung Hospital-Vienna, Vienna, Austria; 2Department of Internal Medicine, Federal Uni- the mechanisms of glucose-lowering of versity of Rio Grande do Sul, Porto Alegre, Brasil; 3Dallas Diabetes and Endocrine Center at Medical City, 4 5 current AHA classes and independent of Dallas, Texas; Stanocola Medical Clinic, Baton Rouge, Louisiana; and Janssen Research and Development, insulin, should provide additive glycemic LLC, Raritan, New Jersey. Corresponding author: Guntram Schernthaner, [email protected]. control across stages of type 2 diabetes and Received 30 November 2012 and accepted 21 February 2013. range of classes, including add-on to the DOI: 10.2337/dc12-2491. Clinical trial reg. no. NCT01137812, clinicaltrials.gov. combination of metformin and a sulfonyl- This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10 urea agent. This 52-week Canagliflozin .2337/dc12-2491/-/DC1. – © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly Treatment and Trial Analysis dipeptidyl cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ peptidase-4 inhibitor (CANTATA-D2; sec- licenses/by-nc-nd/3.0/ for details. ond comparator trial) study evaluated the care.diabetesjournals.org DIABETES CARE 1 Diabetes Care Publish Ahead of Print, published online April 5, 2013 Canagliflozin vs. sitagliptin add-on to MET plus SU efficacy and safety of canagliflozin 300 mg At week 22, all subjects received single- efficacy end points included change from compared with sitagliptin 100 mg as add- blind placebo capsules matching the baseline in FPG and systolic blood pres- on therapy in subjects with type 2 diabetes double-blind study drug for once-daily sure (BP), and percent change from base- inadequately controlled with metformin administration. After the placebo run-in line in body weight, triglycerides, and plus a sulfonylurea agent. period, subjects were randomly assigned HDL cholesterol (HDL-C). Additional to receive oral doses of canagliflozin 300 efficacy measures included proportion RESEARCH DESIGN AND mg or sitagliptin 100 mg once daily (1:1) of subjects reaching A1C ,7.0% (53 METHODS using an Interactive Voice Response System/ mmol/mol) and ,6.5% (48 mmol/mol), Interactive Web Response System. The change in diastolic BP, and percent Subjects and study design computer-generated randomization change in other fasting plasma lipids. This randomized, double-blind, active- schedule was prepared by the sponsor Indices of b-cell function (bCF) were controlled, phase 3 study was conducted before the study, and randomization evaluated. Homeostasis model assess- at 140 centers in 17 countries. The study was balanced using permuted blocks ment of b-cell function (HOMA2-%B), consisted of a 2-week single-blind pla- with the following two stratification cri- proinsulin/insulin ratio, and proinsulin/ cebo run-in period, a 52-week double- teria: whether the prerandomization A1C C-peptide ratio (post hoc analysis) were blind treatment phase, and a 4-week was $9.0% (75 mmol/mol) and whether assessed in the overall study population. follow-up period. a subject underwent the frequently The ratio of C-peptide area under the Eligible subjects were men and sampled mixed-meal tolerance test curve (AUCC) to glucose AUC (AUCG) women 18 years of age or older with (FS-MMTT). was assessed in a subset of subjects who type 2 diabetes using stable metformin After randomization, A1C and FPG underwent a FS-MMTT (;700 kcal and and sulfonylurea therapy. Subjects at values and all glucose levels from the FS- 100 g carbohydrates) on day 1 and at screening already using the combination MMTT were masked to the study centers, week 52. Postprandial glucose measure- of metformin and sulfonylurea with both unless FPG/A1C values met specificstudy ments were also performed in these sub- agents at maximally or near-maximally criteria for discontinuation; similarly, jects. For FS-MMTT end points, blood effective doses (metformin $2,000 urine glucose results were not reported samples were collected 15 min before mg/day [or $1,500 mg/day if unable to for urine dipsticks. Subjects, investiga- and immediately before the meal (time tolerate a higher dose]; sulfonylurea at tors, and local sponsor personnel re- 0), and 30, 60, 90, 120, and 180 min after half-maximal labeled dose or more), who mained blinded to treatment assignment the meal. had A1C $7.0% (53 mmol/mol) and and urine samples for glucosuria until all Safety evaluations included adverse #10.5% (91 mmol/mol), and who subjects completed the study (week 52 events (AEs), clinical laboratory tests, met all other enrollment criteria directly visit) and the final database was locked. vital sign measurements, physical exami- entered the 2-week single-blind placebo Subjects meeting prespecified glyce- nations, self-monitored blood glucose, run-in period before randomization. miccriteria(FPG.15.0 mmol/L [270 12-lead electrocardiograms, and docu- All other subjects underwent an AHA ad- mg/dL] after day 1 to week 6, .13.3 mentation of hypoglycemic episodes. justment period of up to 12 weeks (in- mmol/L [240 mg/dL] after week 6 to AEs prespecified for additional data col- cluding an 8-week dose-stable period) to week 12, .11.1 mmol/L [200 mg/dL] af- lection and analysis included genital my- use maximally or near-maximally ef- ter week 12 to week 26, and A1C .8.0% cotic infections and urinary tract fective doses of metformin and a sulfonyl- [64 mmol/mol] after week 26) were dis- infections (UTIs). The incidence of hypo- urea agent. These subjects then entered continued (no rescue therapy was imple- glycemia was assessed by the number of the 2-week single-blind placebo run-in mented). Subjects with serum creatinine subjects with documented events (i.e., period if they had A1C of $7.0% (53 $133 mmol/L (men) or $124 mmol/L concurrent finger stick glucose #3.9 mmol/mol) and #10.5% (91 mmol/mol) (women), eGFR ,50 mL/min/1.73 m2, mmol/L [70 mg/dL]) and severe events and met all enrollment criteria before be- or with eGFR values that constituted con- (i.e., requiring the assistance of another ing randomized. traindications to metformin use in the or resulting in seizure or loss of con- Exclusion criteria included the fol- country of the investigational site (,60 sciousness). lowing: repeated fasting plasma glucose mL/min/1.73 m2 in some countries) also (FPG) or fasting self-monitored blood were discontinued from the study. Statistical analyses glucose measurements $16.7 mmol/L The study was conducted in accor- The primary hypothesis for this study was (300 mg/dL), or both, during the pretreat- dance with ethical principles that comply that canagliflozin 300 mg was noninferior ment phase; history of type 1 diabetes, with the Declaration of Helsinki and is to sitagliptin 100 mg in reducing A1C cardiovascular disease, or uncontrolled consistent with Good Clinical Practices from baseline to week 52. The primary hypertension; treatment with either a and applicable regulatory requirements. analysis was based on the modified in- PPARg agonist, ongoing insulin therapy, Approval was obtained from Institutional tent-to-treat population (all randomized another SGLT2 inhibitor, or any other Review Boards and independent Ethics subjects who received one or more doses AHA (other than metformin and a sulfo- Committees for participating centers. All of study drug) with a last observation nylurea) within 12 weeks before screen- participants provided written informed carried forward approach to impute miss- ing; or estimated glomerular filtration rate consent. ing data at the end point. Assuming no (eGFR) ,55 mL/min/1.73 m2 (or ,60 difference between canagliflozin and sita- mL/min/1.73 m2 ifbasedonrestriction Study end points and assessments gliptin in A1C-lowering efficacy and a of metformin use in the metformin local The prespecified primary efficacy end common SD of 1.0% with respect to label); or serum creatinine $124 mmol/L point was change in A1C from baseline change in A1C, it was estimated that (men) and $115 mmol/L (women). through week 52. Prespecified secondary 234 subjects per treatment group would

2 DIABETES CARE care.diabetesjournals.org Schernthaner and Associates provide ;90% power to demonstrate the RESULTS similar with canagliflozin and sitagliptin noninferiority of canagliflozin compared (Table 1). Baseline mean A1C was 8.1% with sitagliptin. In addition, per-protocol Subject disposition and baseline (65 mmol/mol [A1C values in mmol/mol analysis (subjects completing the characteristics were directly converted from values in 52-week study and without protocol de- This study was conducted from 30 June percent]) and mean known duration of viations that could impact efficacy assess- 2010 through 9 March 2012. Of 1,672 type 2 diabetes was 9.6 years. Details of ment) was conducted to further support subjects screened, 916 (54.8%) were ex- background sulfonylurea therapies are the noninferiority assessment. To provide cluded from the study (Fig. 1). Of 756 shown in Supplementary Fig. 1. 90% power for the per-protocol analysis, randomized subjects, 755 received one assuming a discontinuation rate of 35% or more doses of study drug and were in- Efficacy over 52 weeks, the sample size was included in the modified intent-to-treat At 52 weeks, canagliflozin 300 mg dem- creased to 360 subjects per treatment analysis set; 464 (61%) completed the onstrated noninferiority to sitagliptin 100 group. 52-week treatment period. A higher rate mg in A1C lowering (LS mean change Safety analyses and the primary effi- of discontinuation was observed with si- of 21.03% [211.3 mmol/mol] and cacy analysis were conducted using the tagliptin 100 mg (44.4%) than with can- 20.66% [27.2 mmol/mol], respec- modified intent-to-treat population. The agliflozin 300 mg (32.6%); the largest tively), with a difference in LS means of last observation carried forward approach contribution was the discontinuation of 20.37% (95% CI, 20.50 to 20.25) or was used for the primary analysis of subjects who met glycemic withdrawal 24.0 mmol/mol (25.5 to 22.7); upper efficacy data. All statistical tests were criteria (22.5% [sitagliptin] and 10.6% limit of the 95% CI was less than the pre- interpreted at a two-sided significance [canagliflozin]), because glycemic rescue specified margin of 0.3% and thus met the level of 5%, and all CIs were interpreted therapy was not provided in this study, primary hypothesis of the study. Further, at a two-sided confidence level of 95%. with the majority (88%) of these subjects canagliflozin demonstrated superiority in Primary and continuous secondary end discontinued after week 26. After meeting reducing A1C compared with sitagliptin points were assessed using an ANCOVA glycemic withdrawal criteria, the most (upper limit of the 95% CI ,0.0%) (Fig. model, including treatment and stratifi- common reasons for withdrawal were 2A, B). A smaller between-group differ- cation factors as fixed effects and the meeting creatinine or eGFR withdrawal ence was observed for the per-protocol corresponding baseline value as a cova- criteria or AEs (Fig. 1). Subject demo- analysis (20.21% [95% CI, 20.34 to riate. The least squares (LS) mean differ- graphic and baseline characteristics were 20.08] or 22.3 mmol/mol [23.7 to ences and two-sided 95% CIs were estimated for the comparisons of canagliflozin versus sitagliptin. Noninferiority of canagliflozin to sitagliptin was assessed based on a prespecified margin of 0.3% for the upper limit of the two-sided 95% CI for the comparison in the primary last observation carried forward analysis. If noninferiority was demonstrated, then superiority was assessed, as determined by an upper bound of the 95% CI around the between-group difference (canagliflozin minus sitagliptin) of ,0.0%. A prespecified hierarchical testing sequence was implemented to strongly control overall type I error attributable to multi- plicity; P values are reported for prespecified comparisons only. For subgroup analysis, descriptive statistics and 95% CIs for the change from baseline in A1C were provided for subgroups of subjects with baseline A1C of ,8.0% (64 mmol/mol), $8.0% (64 mmol/mol) to ,9.0% (75 mmol/mol), and $9.0% (75 mmol/mol). For indices of bCF, descriptive statistics and 95% CIs for the changes from baseline were provided; comparisons of canagliflozin with sitagliptin for changes from baseline at week 52 were assessed using an ANCOVA model with treatment and stratification factors as fixed effects and the corresponding baseline value as a covariate. Figure 1dStudy flow diagram. SITA, sitagliptin; CANA, canagliflozin. care.diabetesjournals.org DIABETES CARE 3 Canagliflozin vs. sitagliptin add-on to MET plus SU

Table 1dBaseline demographics and disease characteristics

SITA 100 mg (n = 378) CANA 300 mg (n = 377) Total (N = 755) Age, years 56.7 6 9.3 56.6 6 9.6 56.7 6 9.5 Sex, n (%) Male 215 (56.9) 207 (54.9) 422 (55.9) Female 163 (43.1) 170 (45.1) 333 (44.1) Race, n (%)* White 240 (63.5) 245 (65.0) 485 (64.2) Black or African American 45 (11.9) 43 (11.4) 88 (11.7) Asian 65 (17.2) 67 (17.8) 132 (17.5) Other† 28 (7.4) 22 (5.8) 50 (6.6) Ethnicity, n (%)* Hispanic or Latino 80 (21.2) 79 (21.0) 159 (21.1) Not Hispanic or Latino 296 (78.3) 298 (79.0) 594 (78.7) Other‡ 2 (0.5) 0 2 (0.3) Body weight, kg 89.1 6 23.2 87.4 6 23.2 88.3 6 23.2 BMI, kg/m2 31.7 6 6.9 31.5 6 6.9 31.6 6 6.9 A1C, % (mmol/mol) 8.1 6 0.9 (65 6 9.8) 8.1 6 0.9 (65 6 9.8) 8.1 6 0.9 (65 6 9.8) FPG, mmol/L (mg/dL) 9.2 6 2.5 (165.8 6 44.9) 9.4 6 2.6 (169.4 6 47.4) 9.3 6 2.6 (167.6 6 46.1) Duration of type 2 diabetes, years 9.7 6 6.3 9.4 6 6.1 9.6 6 6.2

Data are mean 6 SD unless otherwise indicated. SITA, sitagliptin; CANA, canagliﬂozin. *Percentages may not total 100% because of rounding. †Includes American Indian or Alaska Native, Native Hawaiian or other Paciﬁc islander, multiple, other, unknown, or not reported. ‡Includes unknown or not reported.

20.9]) (Supplementary Fig. 1), but can- respectively; difference in LS means, hoc analysis showed a decrease in the agliflozin met both noninferiority to sita- 25.9 mmHg [95% CI, 27.6 to 24.2]; proinsulin/C-peptide ratio with canagli- gliptin (upper limit of the 95% CI P , 0.001) (Supplementary Table 2). Di- flozin, whereas an increase was seen ,0.3%) and superiority to sitagliptin astolic BP also was reduced with canagli- with sitagliptin. Both groups showed (upper limit of the 95% CI ,0.0%) in flozin compared with sitagliptin (23.0 similar increases from baseline in the this analysis. and 2 0.3 mmHg, respectively; difference AUCC/AUCG ratio. A greater proportion of subjects treated in LS means, 22.7 mmHg [95% CI, 23.8 with canagliflozin compared with sitaglip- to 21.7]). No meaningful change in heart Safety tin achieved A1C ,7.0% (53 mmol/mol; rate was observed with canagliflozin or The overall incidences of AEs, serious 47.6 vs. 35.3%, respectively) and A1C sitagliptin (mean change of 20.1 and AEs, and study discontinuations attrib- ,6.5% (48 mmol/mol; 22.5 vs. 18.9%, re- 0.7 bpm, respectively). An increase in utable to AEs were similar for canagli- spectively) at week 52. HDL-C was seen with canagliflozin flozin 300 mg and sitagliptin 100 mg Subgroup analyses showed stepwise and a minimal change was seen with sita- (Table 2). Canagliflozin was associated greater A1C reductions from baseline for gliptin (LS mean percent change of 7.6 with higher rates of genital mycotic infec- canagliflozin relative to sitagliptin with and 0.6%, respectively; difference in LS tions in females (e.g., vulvovaginitis) and increasing categories of baseline A1C as means, 7.0% [95% CI, 4.6 to 9.3]); in- males (e.g., balanitis) compared with si- follows: ,8.0% (64 mmol/mol); $8.0% creases in LDL-C were seen in both tagliptin, which led to one study discon- (64 mmol/mol) to ,9.0% (75 mmol/mol); groups, with a larger increase seen with tinuation (male subject) and no serious and $9.0% (75 mmol/mol) (Supplemen- canagliflozin relative to sitagliptin (11.7 AEs, and responded to usual treatment tary Fig. 2). and 5.2%, respectively; difference in LS with antifungal agents. Among female Significantly greater reductions from means, 6.4% [95% CI, 1.7 to 11.2]). subjects with genital mycotic infections, baseline in FPG were observed at week 52 Smaller increases in non–HDL-C were 8 of 26 and 2 of 7 subjects in the canagli- with canagliflozin 300 mg compared with observed in both groups, with no notable flozin and sitagliptin groups, respec- sitagliptin 100 mg (P , 0.001; Fig. 2C). difference in the change from baseline in tively, had recurrences; 2 of 19 male Among subjects who underwent the the LDL-C/HDL-C ratio between groups. subjects with genital mycotic infections FS-MMTT, canagliflozin provided greater Modest increases in triglycerides, similar had recurrences in the canagliflozin reductions from baseline in 2-h postpran- in both groups, also were observed (Sup- group and no recurrences were reported dial glucose compared with sitagliptin plementary Table 2). in the sitagliptin group. Incidences of (difference in LS means: –1.0 mmol/L At week 52, a greater increase from UTIs were similar for canagliflozin and [95% CI, 21.9 to 20.1]) (Fig. 2D). baseline in HOMA2-%B was observed sitagliptin, with no serious AEs of UTI Canagliflozin 300 mg provided sig- with canagliflozin 300 mg compared with reported with canagliflozin. Low inci- nificant reductions in body weight at sitagliptin 100 mg (Supplementary Table 3). dences (,2%) of AEs related to osmotic week 52 relative to sitagliptin 100 mg Modest increases in the proinsulin/insulin diuresis (i.e., thirst, pollakiuria) were (P , 0.001; Fig. 2E). Canagliflozin signif- ratiowereobservedinbothgroups,witha seen with canagliflozin treatment. The icantly decreased systolic BP compared numerically greater increase seen with can- proportion of subjects having at least with sitagliptin (25.1 and 0.9 mmHg, agliflozin compared with sitagliptin. Post one documented hypoglycemic episode

4 DIABETES CARE care.diabetesjournals.org Schernthaner and Associates

Figure 2dChanges in efficacy parameters (last observation carried forward [LOCF]). Change in A1C (A), mean A1C over time (B), change in FPG (C), change in postprandial glucose (PPG) (D), and percent change in body weight (E). SITA, sitagliptin; CANA, canagliflozin. *Statistical comparison for CANA 300 mg versus SITA 100 mg not performed (not prespecified). was similar with canagliflozin (43.2%) increases in hemoglobin, bilirubin, and have side effects, including weight gain and sitagliptin (40.7%). Incidence of se- blood urea nitrogen were observed with or increased risk of hypoglycemia (2,3,13). vere hypoglycemic episodes was similar canagliflozin compared with sitagliptin. Inhibition of SGLT2 and increasing UGE with canagliflozin (4.0%) and sitagliptin Similar small reductions in eGFR were is a novel insulin-independent approach (3.4%). observed in both groups. to lowering plasma glucose in patients Overall, there were only minor differ- with type 2 diabetes that is associated ences observed in laboratory parameters CONCLUSIONSdFor patients with with caloric loss and low risk of hypogly- with canagliflozin 300 mg compared with type 2 diabetes to achieve and maintain cemia (14). SGLT2 inhibitors therefore sitagliptin 100 mg (Supplementary Table glycemic control, combination therapies may present a new therapeutic option 4). Small to moderate decreases in alanine with AHAs are often needed (1,2). How- that provides a mechanism of action aminotransferase, g-glutamyl transferase, ever, currently available AHAs have de- that is complementary to those of other and serum urate and small to moderate creased efficacy over time and some AHAs. care.diabetesjournals.org DIABETES CARE 5 Canagliflozin vs. sitagliptin add-on to MET plus SU

Table 2dSummary of overall safety and selected AEs related to the mild osmotic diuretic response and some natriuretic effect, but Subjects, n (%) SITA 100 mg (n = 378) CANA 300 mg (n =377) weight loss also may contribute. Canagliflozin and sitagliptin were as- Any AE 293 (77.5) 289 (76.7) sociated with improvements in HOMA2- AEs leading to discontinuation 11 (2.9) 20 (5.3) %B, an index of fasting insulin secretion, AEs related to study drug* 105 (27.8) 128 (34.0) with a numerically greater increase seen Serious AEs 21 (5.6) 24 (6.4) with canagliflozin. Postmeal improvement † Deaths 0 2 (0.5) in bCF based on the AUCC/AUCG ratio AEs of special interest (assessed during the FS-MMTT) also was Genital mycotic infection seen with both agents. Modest increases in Male‡,x 1 (0.5) 19 (9.2) the proinsulin/insulin ratio were observed Female|,{ 7 (4.3) 26 (15.3) with canagliflozin and sitagliptin. The UTI 21 (5.6) 15 (4.0) proinsulin/C-peptide ratio has been re- Osmotic diuresis–related AEs ported to be a more accurate reflection of Pollakiuria** 5 (1.3) 6 (1.6) the degree of disproportional hyperproin- Polyuria†† 0 3 (0.8) sulinemia (18); this was assessed in the Volume-related AEs current study and showed a reduction Postural dizziness 2 (0.5) 0 with canagliflozin, suggesting improved Orthostatic hypotension 1 (0.3) 0 insulin processing efficiency with no dis- SITA, sitagliptin; CANA, canagliflozin. *Possibly, probably, or very likely related to study drug, as assessed by cernible change seen with sitagliptin. Be- investigators. †One death was attributable to respiratory arrest and cardiac arrest, and the other death was cause b-cells are not known to express the attributable to cardiac arrest. Both deaths were considered by the investigator to be doubtfully related to SGLT2 transporter, an indirect mecha- the study drug. ‡SITA 100 mg, n = 215; CANA 300 mg, n =207.xIncluding balanitis, balanitis candida, nism of these improvements in bCF seems | n n balanoposthitis, genital candidiasis, and genital infection fungal. SITA 100 mg, = 163; CANA 300 mg, = 170. likely. Now classic studies of the nonselec- {Including vaginal infection, vulvovaginal candidiasis, vulvovaginal mycotic infection, and vulvovaginitis. **Increased urine frequency. ††Increased urine volume. tive SGLT inhibitor, phlorizin, by Rossetti and DeFronzo et al. (19) in a diabetic rodent model demonstrated marked bCF In this phase 3 study of subjects with In addition to improvements in gly- improvements considered to be related type 2 diabetes inadequately controlled cemic parameters, canagliflozin provided to reversal of glucotoxicity. The results of with metformin plus sulfonylurea, the statistically significant and clinically rele- these studies with phlorizin are supported addition of canagliflozin 300 mg vant reductions in body weight over 52 by experimental studies in mice har- provided a significantly greater reduc- weeks, whereas a slight increase was boring a gene knockout of SGLT2 (20), tion in A1C compared with sitagliptin observed with sitagliptin. The effect of preclinical studies of SGLT inhibitors in di- 100mgat52weeks.Significantly greater canagliflozin on body weight is likely abetic rodent models (21–23), and pre- reductions in FPG also were observed attributable to the marked increase in vious clinical studies of canagliflozin with canagliflozin compared with sita- UGE, because each gram of glucose lost demonstrating improvements in bCF gliptin. Both medications lowered post- equates to the loss of 4 kcal; previous (10). In addition to reversal of glucotoxic- meal glucose levels, with numerically studies of canagliflozin have demonstrated ity, by reducing plasma glucose concentra- greater reductions seen with canagliflo- that this agent leads to 80–120 g/day of tions through a noninsulin-dependent zin, as shown by similar decreases in UGE in subjects with type 2 diabetes, mechanism, the b cells may be “unloaded,” incremental glucose after the meal with or a deficit of ;400 kcal/day; note that also contributing to improved function both agents; however, canagliflozin pro- studies of canagliflozin have shown that (24). Furthermore, improvements in vided substantially greater premeal re- the augmentation of UGE with this agent b-cell function could be related to the ductions in glucose. The effects of is sustained (9,10). This caloric deficit sus- weight loss seen with canagliflozin, with canagliflozin in lowering A1C and FPG tained over 52 weeks might predict an potential improvements in insulin sensi- were sustained over 52 weeks of treat- even greater weight loss than observed, tivity reducing b-cell demand, thus im- ment, whereas increases from the ach- suggesting that compensatory mecha- proving insulin secretion (25,26). ievednadirsinA1CandFPGwere nisms (e.g., increased food intake) likely The overall rate of study discontinu- observed with sitagliptin. The results limit weight loss. An important observa- ation (38.5%) was high but consistent with sitagliptin in the current study, tion was that although the weight loss pla- with expectations given the absence of both with regard to the pattern of change teaued with canagliflozin, no meaningful glycemic rescue therapy in this study; over time and the extent of A1C-lowering weight regain occurred. Body composi- nearly 80% of subjects in both groups efficacy, are consistent with the 52-week tion analyses conducted in other phase 3 could have completed the study had results seen in a previous sitagliptin studies of subjects with type 2 diabetes rescue therapy rather than withdrawal study (in particular, comparing the pri- have shown that the weight loss observed been specified for poorer glycemic con- mary per-protocol analysis reported in with canagliflozin is predominantly (ap- trol. The higher discontinuation rate ob- the previous study with the per-protocol proximately two-thirds) from the loss of served with sitagliptin was primarily analysis results from the current study) fat mass (17). Canagliflozin also lowered attributable to the discontinuation of (Supplementary Fig. 1) considering systolic BP at week 52, with no meaning- subjects who met glycemic withdrawal baseline differences in glycemic control ful change seen with sitagliptin. The BP- criteria. Rates of discontinuation ob- (15,16). lowering effect with canagliflozin is likely served with sitagliptin are consistent

6 DIABETES CARE care.diabetesjournals.org Schernthaner and Associates with those previously reported in the sitagliptin were associated with a higher with metformin plus a sulfonylurea for 52-week study comparing sitagliptin with incidence of female and male genital the treatment of patients with type 2 glipizide (15), discussed here, that also did infections and AEs related to osmotic di- diabetes. not provide rescue therapy. In that study, uresis. Thus, in selecting treatments, the rate of discontinuations attributable to physicians will have to weigh the benefits reasons other than meeting glucose dis- with the side effects, taking into account d continuation criteria was similar to that the needs and tolerances of the patient Acknowledgments This study was supported by Janssen Research & Development, observed in the current study. based on age and comorbidities. fi fl LLC. Editorial support was provided by Overall incidences of AEs were similar The overall pro le of canagli ozin in Kimberly Dittmar, PhD, of MedErgy, and was for canagliflozin and sitagliptin. Canagli- the current study of patients with type 2 funded by Janssen Global Services, LLC. flozin was associated with an increased diabetes inadequately controlled with Canagliflozin is being developed by Janssen incidence of genital mycotic infections; metformin plus sulfonylurea suggests Research & Development, LLC, in collabora- however, these were generally assessed that this agent may be a beneficial option tion with Mitsubishi Tanabe Pharma Corpo- by the investigators as mild to moderate in when a third agent is needed. Although ration. intensity, responded to usual antifungal the current study specifically evaluated G.S. has served on advisory boards for Eli therapy, and led to few discontinuations. the potential use of canagliflozin as an Lilly, AstraZeneca, Bristol-Myers Squibb, There was a higher rate of AEs related to add-on therapy to metformin plus a sul- Boehringer Ingelheim, Takeda, and Johnson & Johnson, and is a speaker for Eli Lilly, osmotic diuresis (i.e., polyuria) compared fonylurea, other studies have assessed the fi fl Boehringer Ingelheim, Takeda, AstraZeneca, with sitagliptin, with an overall low in- ef cacy and safety of canagli ozin in Bristol-Myers Squibb, Sanofi,Merck,and cidence and infrequently leading to dis- subjects inadequately controlled with Novo Nordisk. J.L.G. has received grants or continuation. Incidences of UTIs were diet or exercise (monotherapy) or met- research support from Eli Lilly, Bristol-Myers similar between groups. Despite greater formin (10,32,33). Canagliflozin also Squibb, Boehringer Ingelheim, GlaxoSmith- reductions in A1C and FPG with canagli- may represent an alternative to the addi- Kline, Novo Nordisk, and Janssen, and has flozin compared with sitagliptin, the in- tion of injectable AHAs that have shown served as a board member for Boehringer cidence of documented and severe efficacy as add-on therapies to metformin Ingelheim, Eli Lilly, and Novo Nordisk. J.R. has received grants or research support from hypoglycemia was similar in both groups plus sulfonylurea, such as glucagon-like fi and consistent with other studies conduc- peptide 1 receptor agonists (e.g., liraglu- Merck, Pfizer, Sano , Novo Nordisk, Roche, Bristol-Myers Squibb, Eli Lilly, GlaxoSmith- ted on the background of AHAs associated tide, exenatide) without gastrointestinal Kline, Takeda, Novartis, AstraZeneca, Amylin, with hypoglycemia (e.g., sulfonylureas, symptoms or insulin without weight Johnson & Johnson, Daiichi Sankyo, Mann- insulin) (27–31). In studies of subjects gain or frequent hypoglycemia (beyond Kind, Lexicon, and Boehringer Ingelheim, not using background AHAs associated that expected from improved glycemic and has served on advisory boards for and with hypoglycemia, the low risk of hypo- control) (29,34). received honoraria or consulting fees from glycemia observed with canagliflozin is A limitation of this study was its Novo Nordisk, Eli Lilly, Sanofi, MannKind, consistent with its mechanism of action, 1-year duration, because longer-term GlaxoSmithKline, Takeda, Daiichi Sankyo, because the renal threshold for glucose is studies will be needed to evaluate the Johnson & Johnson, Boehringer Ingelheim, – fl and Lexicon. M.G. has no proprietary interest typically reduced to 4.4 5.0 mmol/L durability of the effects of canagli ozin. fi (;80–90 mg/dL) in patients with type 2 This study enrolled subjects using back- in the tested product, does not have a signi - cant equity interest in the sponsor of the cov- diabetes, above the hypoglycemia thresh- ground therapy with metformin plus a fi fi ered study, and has not received signi cant old (9,10). A different pro le of lipid sulfonylurea and included subjects with a payments of other sorts from the sponsor. changes was observed with canagliflozin reasonably wide range of baseline A1C M.F., J.Y., M.K., W.C, and G.M. are full- relative to sitagliptin; there were increases values; therefore, the findings may not be time employees of Janssen Research & De- in HDL-C and LDL-C seen with canagli- generalizable to patients using other AHA velopment, LLC. No other potential conflicts flozin, and no change in HDL-C and a regimens or those with milder or more of interest relevant to this article were small increase in LDL-C seen with sitaglip- severe hyperglycemia at baseline. Addi- reported. tin, resulting in no difference in the change tionally, studies including other AHAs as G.S., J.L.G., J.R., M.G., J.Y., M.K., and G.M. from baseline in the LDL-C/HDL-C ratio active comparators will be useful for contributed to the conduct of the study, con- between treatment groups. evaluating the relative efficacy/safety pro- tributed to the acquisition, analysis, and in- fi fl terpretation of data, and reviewed and The recent American Diabetes Asso- le of canagli ozin compared with other approved the manuscript. M.F. contributed to ciation and European Association for the AHAs commonly used as third agents in the analysis and interpretation of data, and Study of Diabetes position statement rec- combination therapy with metformin reviewed and approved the manuscript. W.C. ommends that selection of AHA therapy plus sulfonylurea. contributed to the design and conduct of the should be individualized to meet the In conclusion, canagliflozin signifi- study, contributed to the acquisition, analysis, needs of each patient based on the risk/ cantly improved glycemic control and and interpretation of data, and reviewed and benefitprofiles of the various AHA classes reduced body weight and systolic BP approved the manuscript. G.S. and G.M. are (2). Findings from this study demon- compared with sitagliptin over 52 weeks, the guarantors of this work and, as such, had strated that in patients using metformin with an increase in genital infections and full access to all the data in the study and take and a sulfonylurea, relative to sitagliptin, osmotic diuresis–related AEs, but it was responsibility for the integrity of the data and fl the accuracy of the data analysis. canagli ozin provided a greater and more generally well-tolerated in subjects with Parts of this study were previously pre- sustained reduction in A1C, weight loss, a type 2 diabetes inadequately controlled sented in abstract form at the 72nd Scientific reduction in systolic BP, and a similar in- with metformin plus sulfonylurea. These Sessions of the American Diabetes Association, cidence of hypoglycemia. However, these results support the potential value of can- Philadelphia, Pennsylvania, 8–12 June 2012, benefits of canagliflozin relative to agliflozin in triple combination therapy and at the 48th Annual Meeting of the care.diabetesjournals.org DIABETES CARE 7 Canagliflozin vs. sitagliptin add-on to MET plus SU

European Association for the Study of Di- insulin. Diabetes Obes Metab 2012;14: tissue sensitivity to insulin in diabetic rats. abetes, Berlin, Germany, 1–5 October 2012. 539–545 J Clin Invest 1987;79:1510–1515 The authors acknowledge Sharmila Patel, 10. Rosenstock J, Aggarwal N, Polidori D, et al.; 20. Jurczak MJ, Lee HY, Birkenfeld AL, et al. PhD, Janssen Global Services, LLC, for her Canagliflozin DIA 2001 Study Group. SGLT2 deletion improves glucose ho- assistance and contribution to data review, Dose-ranging effects of canagliflozin, a meostasis and preserves pancreatic beta- clinical management, and the study report. sodium-glucose cotransporter 2 inhibitor, cell function. Diabetes 2011;60:890–898 The authors thank all investigators, study as add-on to metformin in subjects with 21. Yasuda K, Okamoto Y, Nunoi K, et al. teams, and patients for participating in this type 2 diabetes. 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Lower baseline peptidyl peptidase-4 inhibitor, sitagliptin, sodium-dependent glucose cotransporter 2 glycemia reduces apparent oral agent in patients with type 2 diabetes mellitus inhibitor for the treatment of type 2 di- glucose-lowering efficacy: a meta-regression inadequately controlled on glimepiride abetes mellitus. J Med Chem 2010;53: analysis. Diabetes Care 2006;29:2137–2139 alone or on glimepiride and metformin. – 6355 6360 17. Toubro S, Cefalu WT, Xie J, et al. Diabetes Obes Metab 2007;9:733–745 7. Sha S, Devineni D, Ghosh A, et al. Canagliflozin, a sodium glucose co- 29. Kendall DM, Riddle MC, Rosenstock J, fl Canagli ozin, a novel inhibitor of sodium transporter 2 inhibitor, reduces body et al. Effects of exenatide (exendin-4) on glucose co-transporter 2, dose dependently weight mainly through loss of fat mass glycemic control over 30 weeks in patients reduces calculated renal threshold for glu- in subjects with type 2 diabetes. 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