Current Medical Research and Opinion
ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20
Efficacy and Safety of Canagliflozin in Patients With Type 2 Diabetes Mellitus From Latin America Fernando J. Lavalle-González, Freddy G. Eliaschewitz, Sonia Cerdas, Maria Del Pilar Chacon, Cindy Tong & Maria Alba To cite this article: Fernando J. Lavalle-González, Freddy G. Eliaschewitz, Sonia Cerdas, Maria Del Pilar Chacon, Cindy Tong & Maria Alba (2015): Efficacy and Safety of Canagliflozin in Patients With Type 2 Diabetes Mellitus From Latin America, Current Medical Research and Opinion, DOI: 10.1185/03007995.2015.1121865 To link to this article: http://dx.doi.org/10.1185/03007995.2015.1121865
Accepted author version posted online: 18 Nov 2015.
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Just Accepted by Current Medical Research & Opinion ORIGINAL ARTICLE Efficacy and Safety of Canagliflozin in Patients With Type 2 Diabetes Mellitus From Latin America Fernando J. Lavalle-González, Freddy G. Eliaschewitz, Sonia Cerdas, Maria Del Pilar Chacon, Cindy Tong, Maria Alba doi: 10.1185/03007995.2015.1121865 Abstract
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Objective: This post hoc analysis evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) from Latin America. Research design and methods: Analyses were performed in subgroups of patients from Latin America based on data from 3 individual, 26-week, placebo-controlled studies of canagliflozin (monotherapy [n = 116/584], add-on to metformin [n = 199/918], and add-on to metformin plus sulfonylurea [n = 76/469]) and 3 individual, 52-week, active-controlled studies of canagliflozin (add-on to metformin versus sitagliptin [n = 240/1,101], add-on to metformin versus glimepiride [n = 155/1,450], and add-on to metformin plus sulfonylurea versus sitagliptin [n = 156/755]). Main outcome measures: Changes from baseline in HbA1c, body weight, and systolic blood pressure (BP) with canagliflozin 100 and 300 mg versus placebo or active comparator (ie, sitagliptin or glimepiride) were evaluated in the overall study populations and Latin American subgroups. Safety was assessed based on adverse event (AE) reports. Results: Canagliflozin 100 and 300 mg provided reductions in HbA1c, body weight, and systolic BP across studies in patients from Latin America that were generally similar to those seen in the overall populations of patients with T2DM. The AE profile in patients from Latin America was equivalent to that in the overall populations; higher rates of genital mycotic infections and osmotic diuresis–related AEs were seen with canagliflozin versus comparators. Limitations of this study include the post hoc analysis of data and the small sample size of patients from Latin America. Conclusion: Canagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM from Latin America. Clinical trial registration: NCT01081834; NCT01106677; NCT01106625; NCT00968812; NCT01137812.
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ORIGINAL ARTICLE Efficacy and Safety of Canagliflozin in Patients With Type 2 Diabetes Mellitus From Latin America
Fernando J. Lavalle-González,1 Freddy G. Eliaschewitz,2 Sonia Cerdas,3 Maria Del Pilar Chacon,4 Cindy
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Tong,5 Maria Alba5
1
Universidad Autonoma de Nuevo Leon, Monterrey, Mexico; 2Hospital Israelita Albert Einstein and
CPClin Clinical Research Center, São Paulo, Brazil; 3Hospital Cima, Centro de Investigacíon Clínica San Agustín, San José, Costa Rica; 4Endocrinología, Medicina Interna, Bogota, Colombia; 5Janssen Research & Development, LLC, Raritan, NJ, USA.
Address for correspondence: Fernando J. Lavalle-González, MD, Universidad Autonoma de Nuevo Leon, Avenida Madero y Gonzalitos, S/N Col. Mitras Centro, C.P. 64460 Monterrey, Nuevo León, México. Telephone: (+52) 81-83487871; Fax: (+52) 81-83479010; [email protected]
Key words: phase 3 study, SGLT2 inhibitor, antihyperglycemic agent, canagliflozin, type 2 diabetes, Latin America
[Short title: Canagliflozin in patients from Latin America]
Abstract Objective: This post hoc analysis evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) from Latin America. Research design and methods: Analyses were performed in subgroups of patients from Latin America based on data from 3 individual, 26-week, placebo-controlled studies of canagliflozin (monotherapy [n = 116/584], add-on to metformin [n = 199/918], and add-on to metformin plus
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sulfonylurea [n = 76/469]) and 3 individual, 52-week, active-controlled studies of canagliflozin (addon to metformin versus sitagliptin [n = 240/1,101], add-on to metformin versus glimepiride [n = 155/1,450], and add-on to metformin plus sulfonylurea versus sitagliptin [n = 156/755]). Main outcome measures: Changes from baseline in HbA1c, body weight, and systolic blood pressure (BP) with canagliflozin 100 and 300 mg versus placebo or active comparator (ie, sitagliptin or glimepiride) were evaluated in the overall study populations and Latin American subgroups. Safety was assessed based on adverse event (AE) reports. Results: Canagliflozin 100 and 300 mg provided reductions in HbA1c, body weight, and systolic BP across studies in patients from Latin America that were generally similar to those seen in the overall populations of patients with T2DM. The AE profile in patients from Latin America was equivalent to that in the overall populations; higher rates of genital mycotic infections and osmotic diuresis– related AEs were seen with canagliflozin versus comparators. Limitations of this study include the post hoc analysis of data and the small sample size of patients from Latin America. Conclusion: Canagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM from Latin America. Clinical trial registration: NCT01081834; NCT01106677; NCT01106625; NCT00968812; NCT01137812.
INTRODUCTION Type 2 diabetes mellitus (T2DM) is one of the leading health problems in Latin America.1 It was estimated that nearly 30 million people in this region had T2DM in 2013; this number is expected to rise to almost 50 million by 2035.2 Individuals with Hispanic/Latino ethnicity have double the risk of developing T2DM and have higher rates of complications compared with people of non-Hispanic/Latino origin. Diabetes-related vascular complications, in particular chronic kidney
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disease and retinopathy, are more common in the Hispanic/Latino population.3 The prevalence of end stage renal disease has been shown to be nearly 60% higher among Hispanic/Latino patients compared with the non-Hispanic/Latino population; rates of diabetic retinopathy are estimated to be 8% and 5%, respectively.4,5 The increased incidence of T2DM and associated complications are, in part due to a higher prevalence of risk factors for T2DM, such as obesity, metabolic syndrome, and decreased insulin sensitivity, in the Hispanic/Latino population.6,7 Changes in urbanization, economic growth, and lifestyle also contribute to the high prevalence of T2DM in Latin America.8 Canagliflozin is a sodium glucose co-transporter 2 (SGLT2) inhibitor developed for the treatment of adults with T2DM.9-21 Canagliflozin inhibits renal glucose reabsorption by lowering the renal threshold for glucose (RTG) and increasing urinary glucose excretion (UGE), which results in lowered plasma glucose levels and a net caloric loss.22,23 Across Phase 3 studies, canagliflozin improved glycemic control, reduced body weight and blood pressure (BP), and was generally well tolerated in a broad range of patients with T2DM inadequately controlled by their current treatment regimens.1021
A previous pooled analysis demonstrated that the efficacy and safety profile of canagliflozin was
comparable in a global population of Hispanic/Latino and non-Hispanic/Latino patients with T2DM.24 In this post hoc analysis based on data from individual randomized controlled trials, the effects of canagliflozin on HbA1c, body weight, and systolic BP were assessed in subgroups of patients living in Latin American countries.
PATIENTS AND METHODS Study design, patient populations, and treatments This post hoc analysis was based on data from patients with T2DM enrolled in 3 individual 26-week, double-blind, placebo-controlled, Phase 3 studies (canagliflozin as monotherapy,10 add-on to metformin,18 and add-on to metformin plus sulfonylurea19) and 3 individual, 52-week, double-blind, active-controlled, Phase 3 studies (canagliflozin as add-on to metformin versus sitagliptin,18 add-on
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to metformin versus glimepiride,16 and add-on to metformin plus sulfonylurea versus sitagliptin21). Patients were randomized to receive canagliflozin 100 or 300 mg or placebo/active comparator once daily in all studies except the active-controlled, add-on to metformin plus sulfonylurea study, in which patients received canagliflozin 300 mg or sitagliptin 100 mg once daily.21 In the placebocontrolled, add-on to metformin study, patients in the placebo group switched to sitagliptin after 26 weeks in a blinded fashion; thus, this study was active-controlled at Week 52.18 Key inclusion criteria common to most studies included HbA1c ≥7.0% and ≤10.5% at screening, fasting plasma glucose (FPG) 1.5 times ULN at screening. Details of the study design, including randomization and blinding, and glycemic rescue therapy have been previously reported for the individual studies included in this analysis.10,16,18,19,21 These studies were conducted in accordance with ethical principles that comply with the Declaration of Helsinki, and were consistent with Good Clinical Practices and applicable regulatory requirements. Study protocols and amendments were approved by institutional review boards and independent ethics committees at participating institutions. All patients provided written informed consent prior to participation in the studies.
Study endpoints and assessments Changes from baseline in HbA1c, body weight, and systolic BP were evaluated at Week 26 (placebocontrolled trials) or Week 52 (active-controlled trials) in the overall study populations and in subgroups of patients from Latin America (ie, Argentina, Brazil, Colombia, Costa Rica, Guatemala, Mexico, and Peru). Note that the overall populations included patients of Hispanic/Latino ethnicity
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living in countries outside of Latin America at the time of the study. Safety and tolerability were assessed based on adverse event (AE) reports in the overall safety populations and Latin American subgroups through Week 26 or 52. The overall incidence of AEs and the incidence of specific AEs, including genital mycotic infections, urinary tract infections (UTIs), and AEs related to osmotic diuresis and volume depletion, were evaluated. An AE was considered serious if it was associated with clinical signs or symptoms judged by the investigator to have a significant clinical impact, or if it resulted in death, inpatient hospitalization or prolongation of existing hospitalization, or persistent or significant disability or incapacity.
Statistical analyses Efficacy analyses were conducted using the modified intent-to-treat (mITT) population, which included all randomized patients who received 1 dose of double-blind study drug. The last observation carried forward (LOCF) approach was used to impute missing data. For patients who received glycemic rescue therapy, the last post-baseline value prior to initiation of rescue therapy was used for the analysis. Endpoints were assessed using an analysis of covariance (ANCOVA) model with treatment and stratification factors as fixed effects and the corresponding baseline value for each endpoint as a covariate. Statistical testing of canagliflozin versus placebo/active comparator was not prespecified for analyses of efficacy parameters in the Latin American subgroups; therefore, P values are not provided for these post hoc analyses. The least squares (LS) mean differences between groups and 2-sided 95% confidence intervals (CIs) were estimated. Safety analyses
included all reported AEs, regardless of rescue therapy, and included all randomized patients who received 1 dose of double-blind study drug.
RESULTS Patient characteristics Baseline demographic and disease characteristics were generally similar across treatment groups
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within the overall populations and Latin American subgroups of the placebo- and active-controlled studies (Tables 1 and 2). In the Latin American subgroups of the monotherapy and add-on to metformin studies, there was a higher proportion of female patients in the canagliflozin 100 and 300 mg groups versus the placebo and sitagliptin groups. The majority of patients from Latin America identified themselves as Latino or Hispanic. Of note, the proportion of Hispanic/Latino patients in the Latin American subgroup of the add-on to metformin plus sulfonylurea versus sitagliptin study, which only included patients from Brazil, was smaller compared with other studies.
Efficacy Glycemic efficacy In the placebo-controlled studies, canagliflozin 100 and 300 mg provided significant reductions in HbA1c compared with placebo in the overall populations and numerical reductions in HbA1c in the Latin American subgroups over 26 weeks (Figure 1A and Supplemental Table 1). In the activecontrolled studies, canagliflozin 100 mg demonstrated noninferiority and canagliflozin 300 mg demonstrated superiority in lowering HbA1c compared with sitagliptin or glimepiride in the overall populations over 52 weeks (Figure 1B and Supplemental Table 2). Similar or greater numerical reductions in HbA1c were seen with canagliflozin versus sitagliptin or glimepiride in the Latin American subgroups over 52 weeks. A numeric dose response was observed with canagliflozin in both populations in most studies; however, in the Latin American subgroups of the monotherapy and add-on to metformin versus sitagliptin studies, LS mean (95% CI) reductions in HbA1c with
canagliflozin 100 mg exceeded numerically those observed in the overall population for this dose (– 1.37% (–1.79, –0.96) and – 0.91% [–1.09, –0.73] versus placebo, and –0.22% (–0.48, 0.05) and 0.00% [–0.12, 0.12] versus sitagliptin, respectively). Consequently, in these two studies, the reductions of HbA1c between 100 mg and 300 mg were similar in patients from Latin America.
Body weight
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In the placebo-controlled studies, canagliflozin 100 and 300 mg provided significant body weight reductions compared with placebo in the overall populations and numerical reductions in body weight in the Latin American subgroups over 26 weeks (Figure 2A and Supplemental Table 1). Canagliflozin also provided significant reductions in body weight versus sitagliptin and glimepiride in the overall populations of the active-controlled studies at Week 52; numerical reductions in body weight versus sitagliptin and glimepiride were seen in the Latin American subgroups (Figure 2B and Supplemental Table 2).
Systolic BP Canagliflozin was associated with significant reductions in systolic BP compared with placebo in the overall populations in most placebo-controlled studies over 26 weeks; numerical reductions in systolic BP were seen with canagliflozin versus placebo in the Latin American subgroups (Figure 3A and Supplemental Table 1). Canagliflozin also provided significant reductions in systolic BP versus sitagliptin and glimepiride in the overall populations of most active-controlled studies at Week 52; numerical reductions in systolic BP were seen with canagliflozin versus sitagliptin and glimepiride in the Latin American subgroups (Figure 3B and Supplemental Table 2). Safety and tolerability The overall incidence of AEs was generally similar across treatment groups in the overall populations and in the Latin American subgroups of both the placebo- and active-controlled studies, with a higher overall incidence in patients from Latin America in the active-controlled studies (Tables 3 and
4); rates of AEs leading to discontinuation were low and balanced across treatment groups. Overall, rates of serious AEs were low; in Latin American patients, serious AEs were generally higher with canagliflozin versus comparators, except in the add-on to metformin plus sulfonylurea versus sitagliptin study. The increase in serious AEs with canagliflozin in patients from Latin America was not associated with any pattern of specific AEs. The safety profile with canagliflozin in the Latin American subgroups was comparable to that seen in the overall populations.
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The incidence of male and female genital mycotic infections was higher with canagliflozin 100 and 300 mg compared with comparators across studies in patients from Latin America (Tables 3 and 4); these AEs were generally mild or moderate in intensity, and few led to study discontinuation. In most studies, circumcision rates were lower in patients from Latin America than in the overall population, which may have contributed to the higher incidence of male genital mycotic infections seen in the Latin American subgroups compared with the overall populations. Consistent with data from the overall populations, the trends in UTIs varied between studies in Latin American patients. The incidence of UTIs was generally higher with canagliflozin in the placebo-controlled monotherapy and add-on to metformin studies and lower with canagliflozin in the placebo- and active-controlled, add-on to metformin plus sulfonylurea studies. Rates of UTIs were generally comparable across treatment groups in the active-controlled, add-on to metformin studies. The incidence of AEs related to osmotic diuresis (eg, polyuria, pollakiuria) was generally higher with canagliflozin 100 and 300 mg compared with placebo, sitagliptin, or glimepiride in patients from Latin America across studies. The incidence of AEs related to volume depletion (eg, postural dizziness, orthostatic hypotension) was generally low and similar across treatment groups in the patients from Latin America across studies.
Discussion Findings from this post hoc analysis of individual Phase 3 studies demonstrated that canagliflozin treatment improved glycemic control and reduced body weight and systolic BP in patients from Latin America with T2DM. Canagliflozin provided dose-dependent reductions in HbA1c across most studies in both the overall populations and Latin American subgroups. In the monotherapy and add-on to metformin versus sitagliptin studies, mean changes in HbA1c were similar with canagliflozin 100 and
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300 mg in patients from Latin America, likely due to the small sample size; dose-dependent reductions in HbA1c were seen in the overall populations of these studies. HbA1c reductions with canagliflozin were generally similar in patients from Latin America compared with the overall population in each of the studies. Hispanic/Latino patients demonstrate reduced insulin sensitivity6; thus, canagliflozin, which lowers plasma glucose levels through an insulin-independent mechanism, may be particularly beneficial in this patient population and in patients from Latin America. Canagliflozin was associated with reductions in body weight and systolic BP that were generally comparable in the overall populations and Latin American subgroups of the placebo- and activecontrolled studies. In the placebo-controlled, add-on to metformin plus sulfonylurea study, a notable reduction in systolic BP was seen with placebo in both the overall population and Latin American subgroup, which led so smaller, placebo-subtracted reductions than observed in other studies. Overall, canagliflozin was generally well tolerated in patients with T2DM from Latin America in the individual placebo- and active-controlled studies, with a safety profile equivalent to the overall study populations. The incidence of male and female genital mycotic infections and AEs related to osmotic diuresis was generally higher with canagliflozin compared with placebo, sitagliptin, and glimepiride in the Latin American subgroups and overall populations across studies. The incidence of UTIs with canagliflozin versus comparator varied the Latin American subgroups and overall populations, with no clear trend across studies. The incidence of AEs related to volume depletion was low and similar across treatment groups across studies in the overall populations and Latin American subgroups.
The results from this analysis in patients from Latin America, the majority of which were of Hispanic/Latino ethnicity, are consistent with findings from pooled analysis of four, 26-week, placebo-controlled, Phase 3 studies of canagliflozin in Hispanic/Latino patients with T2DM, which also demonstrated reductions in HbA1c, body weight, and systolic BP.24 An analogous AE profile, with increases in genital mycotic infections and osmotic diuresis–related AEs, was seen with canagliflozin compared with placebo.
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Limitations of this study include the post hoc analysis of data and relatively small sample size of patients from Latin America in each study (n = 76-240), which made it difficult draw any meaningful conclusions regarding the true differences in efficacy and safety parameters between treatment groups. Larger prospective studies would be needed to verify that the efficacy and safety findings from studies of canagliflozin in broader patient populations apply to patients with T2DM from Latin America.
Conclusions Canagliflozin improved glycemic control and reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM from Latin America. The efficacy of canagliflozin in patients from Latin America was similar to that observed in the broader overall populations of patients with T2DM across Phase 3 studies of canagliflozin. Overall, findings from this analysis further support canagliflozin as monotherapy or part of a dual or triple therapy regimen for patients with T2DM in
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Latin America.
Transparency Declaration of funding This study was sponsored by Janssen Research & Development, LLC. The sponsor had a role in the study design and conduct, and in data collection, analysis, and interpretation. The authors prepared the report with editorial assistance funded by the sponsor. All authors had full access to study data; were responsible for the integrity of the data and the accuracy of the data analysis; and reviewed, edited, and approved the report for publication.
Declaration of financial/other relationships F.J.L-G. has received sponsorship from Sanofi and Janssen; has received grant/research support from Boehringer Ingelheim and Janssen; has served as a consultant/advisor for Sanofi, Boehringer Ingelheim, Merck Sharpe and Dohme, Janssen, Novo Nordisk, Eli Lilly, and AstraZeneca; and has participated in speakers bureaus for Sanofi, Boehringer Ingelheim, Eli Lilly, AstraZeneca, Novo Nordisk, Novartis, Janssen, and Merck Sharpe and Dohme. F.G.E. has served as a consultant/advisor for Sanofi, Eli Lilly, Novo Nordisk, AstraZeneca, and Boehringer Ingelheim; and has participated in speakers bureaus for Sanofi, AstraZeneca, and Novo Nordisk. S.C. has served as a consultant/advisor to Novo Nordisk, Sanofi, Merck Sharpe and Dohme, AstraZeneca, and Janssen. M.D.P.C. has no financial disclosures to report. C.T. and M.A. are full-
time employees of Janssen Research & Development, LLC. CMRO Peer Reviewer 1 has disclosed that he has received consulting and/or speaker fees from Eli Lilly, Sanofi, Novo Nordisk, Glaxo-SmithKline, Taisho pharmaceutical, Astellas Pharma, BD, Boehringer Ingelheim, Johnson & Johnson and Takeda. He has also received grants from Boehringer Ingelheim, Eli Lilly and MSD. CMRO Peer Reviewer 2 has disclosed that he is on the Speakers’ Bureau for MSD, Novo Nordisk and Sanofi.
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CMRO Peer reviewer 3 has no relevant financial relationships to disclose.
Acknowledgments This study was sponsored by Janssen Research & Development, LLC. Editorial support was provided by Kimberly Fuller, PhD, of MedErgy, and was funded by Janssen Global Services, LLC. The authors thank all investigators, study teams, and patients for participating in these studies.
Canagliflozin was developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation.
References 1. Guzman JR, Lyra R, Aguilar-Salinas CA, et al. Treatment of type 2 diabetes in Latin America: a consensus statement by the medical associations of 17 Latin American countries. Latin American Diabetes Association. Rev Panam Salud Publica 2010;28:463-71 2. Guariguata L, Whiting DR, Hambleton I, et al. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014;103:137-49
Downloaded by [NUS National University of Singapore] at 10:12 30 November 2015
3. Caballero AE. Type 2 diabetes in the Hispanic or Latino population: challenges and opportunities. Curr Opin Endocrinol Diabetes Obes 2007;14:151-7 4. The National Institutes of Health, National Eye Institute. Diabetic Retinopathy [online]. Available at: https://nei.nih.gov/eyedata/diabetic#2 [Last accessed 24 Sept. 2015] 5. United States Renal Data System. 2014 Annual Data Report. 2014 6. Cusi K, Ocampo GL. Unmet needs in Hispanic/Latino patients with type 2 diabetes mellitus. Am J Med 2011;124:S2-S9 7. Lorenzo C, Hanley AJ, Wagenknecht LE, et al. Relationship of insulin sensitivity, insulin secretion, and adiposity with insulin clearance in a multiethnic population: the insulin Resistance Atherosclerosis study. Diabetes Care 2013;36:101-3 8. Escalante M, Gagliardino JJ, Guzman JR, Tschiedel B. Call-to-action: Timely and appropriate treatment for people with type 2 diabetes in Latin America. Diabetes Res Clin Pract 2014;104:343-52 9. Rosenstock J, Aggarwal N, Polidori D, et al. Dose-ranging effects of canagliflozin, a sodiumglucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care 2012;35:1232-8 10. Stenlöf K, Cefalu WT, Kim K-A, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 2013;15:372-82 11. Stenlöf K, Cefalu WT, Kim KA, et al. Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: findings from the 52-week CANTATA-M study. Curr Med Res Opin 2014;30:163-75 12. Bode B, Stenlöf K, Sullivan D, et al. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract 2013;41:72-84 13. Bode B, Stenlöf K, Harris S, et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55 to 80 years with type 2 diabetes. Diabetes Obes Metab 2015;17:294-303 14. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 2013;15:463-73 15. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes Metab 2014;16:101627
16. Cefalu WT, Leiter LA, Yoon K-H, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 2013;382:941-50 17. Leiter LA, Yoon K-H, Arias P, et al. Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, Phase 3 study. Diabetes Care 2015;38:355-64
Downloaded by [NUS National University of Singapore] at 10:12 30 November 2015
18. Lavalle-González FJ, Januszewicz A, Davidson J, et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia 2013;56:2582-92 19. Wilding JP, Charpentier G, Hollander P, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract 2013;67:1267-82 20. Forst T, Guthrie R, Goldenberg R, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes Metab 2014;16:467-77 21. Schernthaner G, Gross JL, Rosenstock J, et al. 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. Diabetes Care 2013;36:2508-15 22. Sha S, Devineni D, Ghosh A, et al. Canagliflozin, a novel inhibitor of sodium glucose cotransporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes Metab 2011;13:669-72 23. Polidori D, Sha S, Ghosh A, et al. Validation of a novel method for determining the renal threshold for glucose excretion in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab 2013;98:E867-E871 24. Davidson J, Aguilar R, Lavalle-Gonzalez F, et al. Efficacy and safety of canagliflozin (CANA) in patients with type 2 diabetes mellitus (T2DM) by Hispanic/Latino ethnicity. Poster presented at: Association of Clinical Endocrinologists (AACE) 23rd Annual Scientific & Clinical Congress; May 14-18, 2014; Las Vegas, NV 2014;
FIGURE LEGENDS
Figure 1. Changes in HbA1c for the overall populations and Latin American subgroups of the (A) PBO-controlled studies at Week 26 and (B) active-controlled studies at Week 52. PBO, placebo; MET, metformin; SU, sulfonylurea; LS, least squares; SE, standard error; CI, confidence interval; CANA, canagliflozin; SITA, sitagliptin; GLIM, glimepiride. *
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ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20
Efficacy and Safety of Canagliflozin in Patients With Type 2 Diabetes Mellitus From Latin America Fernando J. Lavalle-González, Freddy G. Eliaschewitz, Sonia Cerdas, Maria Del Pilar Chacon, Cindy Tong & Maria Alba To cite this article: Fernando J. Lavalle-González, Freddy G. Eliaschewitz, Sonia Cerdas, Maria Del Pilar Chacon, Cindy Tong & Maria Alba (2015): Efficacy and Safety of Canagliflozin in Patients With Type 2 Diabetes Mellitus From Latin America, Current Medical Research and Opinion, DOI: 10.1185/03007995.2015.1121865 To link to this article: http://dx.doi.org/10.1185/03007995.2015.1121865
Accepted author version posted online: 18 Nov 2015.
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Just Accepted by Current Medical Research & Opinion ORIGINAL ARTICLE Efficacy and Safety of Canagliflozin in Patients With Type 2 Diabetes Mellitus From Latin America Fernando J. Lavalle-González, Freddy G. Eliaschewitz, Sonia Cerdas, Maria Del Pilar Chacon, Cindy Tong, Maria Alba doi: 10.1185/03007995.2015.1121865 Abstract
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Objective: This post hoc analysis evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) from Latin America. Research design and methods: Analyses were performed in subgroups of patients from Latin America based on data from 3 individual, 26-week, placebo-controlled studies of canagliflozin (monotherapy [n = 116/584], add-on to metformin [n = 199/918], and add-on to metformin plus sulfonylurea [n = 76/469]) and 3 individual, 52-week, active-controlled studies of canagliflozin (add-on to metformin versus sitagliptin [n = 240/1,101], add-on to metformin versus glimepiride [n = 155/1,450], and add-on to metformin plus sulfonylurea versus sitagliptin [n = 156/755]). Main outcome measures: Changes from baseline in HbA1c, body weight, and systolic blood pressure (BP) with canagliflozin 100 and 300 mg versus placebo or active comparator (ie, sitagliptin or glimepiride) were evaluated in the overall study populations and Latin American subgroups. Safety was assessed based on adverse event (AE) reports. Results: Canagliflozin 100 and 300 mg provided reductions in HbA1c, body weight, and systolic BP across studies in patients from Latin America that were generally similar to those seen in the overall populations of patients with T2DM. The AE profile in patients from Latin America was equivalent to that in the overall populations; higher rates of genital mycotic infections and osmotic diuresis–related AEs were seen with canagliflozin versus comparators. Limitations of this study include the post hoc analysis of data and the small sample size of patients from Latin America. Conclusion: Canagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM from Latin America. Clinical trial registration: NCT01081834; NCT01106677; NCT01106625; NCT00968812; NCT01137812.
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ORIGINAL ARTICLE Efficacy and Safety of Canagliflozin in Patients With Type 2 Diabetes Mellitus From Latin America
Fernando J. Lavalle-González,1 Freddy G. Eliaschewitz,2 Sonia Cerdas,3 Maria Del Pilar Chacon,4 Cindy
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Tong,5 Maria Alba5
1
Universidad Autonoma de Nuevo Leon, Monterrey, Mexico; 2Hospital Israelita Albert Einstein and
CPClin Clinical Research Center, São Paulo, Brazil; 3Hospital Cima, Centro de Investigacíon Clínica San Agustín, San José, Costa Rica; 4Endocrinología, Medicina Interna, Bogota, Colombia; 5Janssen Research & Development, LLC, Raritan, NJ, USA.
Address for correspondence: Fernando J. Lavalle-González, MD, Universidad Autonoma de Nuevo Leon, Avenida Madero y Gonzalitos, S/N Col. Mitras Centro, C.P. 64460 Monterrey, Nuevo León, México. Telephone: (+52) 81-83487871; Fax: (+52) 81-83479010; [email protected]
Key words: phase 3 study, SGLT2 inhibitor, antihyperglycemic agent, canagliflozin, type 2 diabetes, Latin America
[Short title: Canagliflozin in patients from Latin America]
Abstract Objective: This post hoc analysis evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) from Latin America. Research design and methods: Analyses were performed in subgroups of patients from Latin America based on data from 3 individual, 26-week, placebo-controlled studies of canagliflozin (monotherapy [n = 116/584], add-on to metformin [n = 199/918], and add-on to metformin plus
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sulfonylurea [n = 76/469]) and 3 individual, 52-week, active-controlled studies of canagliflozin (addon to metformin versus sitagliptin [n = 240/1,101], add-on to metformin versus glimepiride [n = 155/1,450], and add-on to metformin plus sulfonylurea versus sitagliptin [n = 156/755]). Main outcome measures: Changes from baseline in HbA1c, body weight, and systolic blood pressure (BP) with canagliflozin 100 and 300 mg versus placebo or active comparator (ie, sitagliptin or glimepiride) were evaluated in the overall study populations and Latin American subgroups. Safety was assessed based on adverse event (AE) reports. Results: Canagliflozin 100 and 300 mg provided reductions in HbA1c, body weight, and systolic BP across studies in patients from Latin America that were generally similar to those seen in the overall populations of patients with T2DM. The AE profile in patients from Latin America was equivalent to that in the overall populations; higher rates of genital mycotic infections and osmotic diuresis– related AEs were seen with canagliflozin versus comparators. Limitations of this study include the post hoc analysis of data and the small sample size of patients from Latin America. Conclusion: Canagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM from Latin America. Clinical trial registration: NCT01081834; NCT01106677; NCT01106625; NCT00968812; NCT01137812.
INTRODUCTION Type 2 diabetes mellitus (T2DM) is one of the leading health problems in Latin America.1 It was estimated that nearly 30 million people in this region had T2DM in 2013; this number is expected to rise to almost 50 million by 2035.2 Individuals with Hispanic/Latino ethnicity have double the risk of developing T2DM and have higher rates of complications compared with people of non-Hispanic/Latino origin. Diabetes-related vascular complications, in particular chronic kidney
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disease and retinopathy, are more common in the Hispanic/Latino population.3 The prevalence of end stage renal disease has been shown to be nearly 60% higher among Hispanic/Latino patients compared with the non-Hispanic/Latino population; rates of diabetic retinopathy are estimated to be 8% and 5%, respectively.4,5 The increased incidence of T2DM and associated complications are, in part due to a higher prevalence of risk factors for T2DM, such as obesity, metabolic syndrome, and decreased insulin sensitivity, in the Hispanic/Latino population.6,7 Changes in urbanization, economic growth, and lifestyle also contribute to the high prevalence of T2DM in Latin America.8 Canagliflozin is a sodium glucose co-transporter 2 (SGLT2) inhibitor developed for the treatment of adults with T2DM.9-21 Canagliflozin inhibits renal glucose reabsorption by lowering the renal threshold for glucose (RTG) and increasing urinary glucose excretion (UGE), which results in lowered plasma glucose levels and a net caloric loss.22,23 Across Phase 3 studies, canagliflozin improved glycemic control, reduced body weight and blood pressure (BP), and was generally well tolerated in a broad range of patients with T2DM inadequately controlled by their current treatment regimens.1021
A previous pooled analysis demonstrated that the efficacy and safety profile of canagliflozin was
comparable in a global population of Hispanic/Latino and non-Hispanic/Latino patients with T2DM.24 In this post hoc analysis based on data from individual randomized controlled trials, the effects of canagliflozin on HbA1c, body weight, and systolic BP were assessed in subgroups of patients living in Latin American countries.
PATIENTS AND METHODS Study design, patient populations, and treatments This post hoc analysis was based on data from patients with T2DM enrolled in 3 individual 26-week, double-blind, placebo-controlled, Phase 3 studies (canagliflozin as monotherapy,10 add-on to metformin,18 and add-on to metformin plus sulfonylurea19) and 3 individual, 52-week, double-blind, active-controlled, Phase 3 studies (canagliflozin as add-on to metformin versus sitagliptin,18 add-on
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to metformin versus glimepiride,16 and add-on to metformin plus sulfonylurea versus sitagliptin21). Patients were randomized to receive canagliflozin 100 or 300 mg or placebo/active comparator once daily in all studies except the active-controlled, add-on to metformin plus sulfonylurea study, in which patients received canagliflozin 300 mg or sitagliptin 100 mg once daily.21 In the placebocontrolled, add-on to metformin study, patients in the placebo group switched to sitagliptin after 26 weeks in a blinded fashion; thus, this study was active-controlled at Week 52.18 Key inclusion criteria common to most studies included HbA1c ≥7.0% and ≤10.5% at screening, fasting plasma glucose (FPG) 1.5 times ULN at screening. Details of the study design, including randomization and blinding, and glycemic rescue therapy have been previously reported for the individual studies included in this analysis.10,16,18,19,21 These studies were conducted in accordance with ethical principles that comply with the Declaration of Helsinki, and were consistent with Good Clinical Practices and applicable regulatory requirements. Study protocols and amendments were approved by institutional review boards and independent ethics committees at participating institutions. All patients provided written informed consent prior to participation in the studies.
Study endpoints and assessments Changes from baseline in HbA1c, body weight, and systolic BP were evaluated at Week 26 (placebocontrolled trials) or Week 52 (active-controlled trials) in the overall study populations and in subgroups of patients from Latin America (ie, Argentina, Brazil, Colombia, Costa Rica, Guatemala, Mexico, and Peru). Note that the overall populations included patients of Hispanic/Latino ethnicity
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living in countries outside of Latin America at the time of the study. Safety and tolerability were assessed based on adverse event (AE) reports in the overall safety populations and Latin American subgroups through Week 26 or 52. The overall incidence of AEs and the incidence of specific AEs, including genital mycotic infections, urinary tract infections (UTIs), and AEs related to osmotic diuresis and volume depletion, were evaluated. An AE was considered serious if it was associated with clinical signs or symptoms judged by the investigator to have a significant clinical impact, or if it resulted in death, inpatient hospitalization or prolongation of existing hospitalization, or persistent or significant disability or incapacity.
Statistical analyses Efficacy analyses were conducted using the modified intent-to-treat (mITT) population, which included all randomized patients who received 1 dose of double-blind study drug. The last observation carried forward (LOCF) approach was used to impute missing data. For patients who received glycemic rescue therapy, the last post-baseline value prior to initiation of rescue therapy was used for the analysis. Endpoints were assessed using an analysis of covariance (ANCOVA) model with treatment and stratification factors as fixed effects and the corresponding baseline value for each endpoint as a covariate. Statistical testing of canagliflozin versus placebo/active comparator was not prespecified for analyses of efficacy parameters in the Latin American subgroups; therefore, P values are not provided for these post hoc analyses. The least squares (LS) mean differences between groups and 2-sided 95% confidence intervals (CIs) were estimated. Safety analyses
included all reported AEs, regardless of rescue therapy, and included all randomized patients who received 1 dose of double-blind study drug.
RESULTS Patient characteristics Baseline demographic and disease characteristics were generally similar across treatment groups
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within the overall populations and Latin American subgroups of the placebo- and active-controlled studies (Tables 1 and 2). In the Latin American subgroups of the monotherapy and add-on to metformin studies, there was a higher proportion of female patients in the canagliflozin 100 and 300 mg groups versus the placebo and sitagliptin groups. The majority of patients from Latin America identified themselves as Latino or Hispanic. Of note, the proportion of Hispanic/Latino patients in the Latin American subgroup of the add-on to metformin plus sulfonylurea versus sitagliptin study, which only included patients from Brazil, was smaller compared with other studies.
Efficacy Glycemic efficacy In the placebo-controlled studies, canagliflozin 100 and 300 mg provided significant reductions in HbA1c compared with placebo in the overall populations and numerical reductions in HbA1c in the Latin American subgroups over 26 weeks (Figure 1A and Supplemental Table 1). In the activecontrolled studies, canagliflozin 100 mg demonstrated noninferiority and canagliflozin 300 mg demonstrated superiority in lowering HbA1c compared with sitagliptin or glimepiride in the overall populations over 52 weeks (Figure 1B and Supplemental Table 2). Similar or greater numerical reductions in HbA1c were seen with canagliflozin versus sitagliptin or glimepiride in the Latin American subgroups over 52 weeks. A numeric dose response was observed with canagliflozin in both populations in most studies; however, in the Latin American subgroups of the monotherapy and add-on to metformin versus sitagliptin studies, LS mean (95% CI) reductions in HbA1c with
canagliflozin 100 mg exceeded numerically those observed in the overall population for this dose (– 1.37% (–1.79, –0.96) and – 0.91% [–1.09, –0.73] versus placebo, and –0.22% (–0.48, 0.05) and 0.00% [–0.12, 0.12] versus sitagliptin, respectively). Consequently, in these two studies, the reductions of HbA1c between 100 mg and 300 mg were similar in patients from Latin America.
Body weight
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In the placebo-controlled studies, canagliflozin 100 and 300 mg provided significant body weight reductions compared with placebo in the overall populations and numerical reductions in body weight in the Latin American subgroups over 26 weeks (Figure 2A and Supplemental Table 1). Canagliflozin also provided significant reductions in body weight versus sitagliptin and glimepiride in the overall populations of the active-controlled studies at Week 52; numerical reductions in body weight versus sitagliptin and glimepiride were seen in the Latin American subgroups (Figure 2B and Supplemental Table 2).
Systolic BP Canagliflozin was associated with significant reductions in systolic BP compared with placebo in the overall populations in most placebo-controlled studies over 26 weeks; numerical reductions in systolic BP were seen with canagliflozin versus placebo in the Latin American subgroups (Figure 3A and Supplemental Table 1). Canagliflozin also provided significant reductions in systolic BP versus sitagliptin and glimepiride in the overall populations of most active-controlled studies at Week 52; numerical reductions in systolic BP were seen with canagliflozin versus sitagliptin and glimepiride in the Latin American subgroups (Figure 3B and Supplemental Table 2). Safety and tolerability The overall incidence of AEs was generally similar across treatment groups in the overall populations and in the Latin American subgroups of both the placebo- and active-controlled studies, with a higher overall incidence in patients from Latin America in the active-controlled studies (Tables 3 and
4); rates of AEs leading to discontinuation were low and balanced across treatment groups. Overall, rates of serious AEs were low; in Latin American patients, serious AEs were generally higher with canagliflozin versus comparators, except in the add-on to metformin plus sulfonylurea versus sitagliptin study. The increase in serious AEs with canagliflozin in patients from Latin America was not associated with any pattern of specific AEs. The safety profile with canagliflozin in the Latin American subgroups was comparable to that seen in the overall populations.
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The incidence of male and female genital mycotic infections was higher with canagliflozin 100 and 300 mg compared with comparators across studies in patients from Latin America (Tables 3 and 4); these AEs were generally mild or moderate in intensity, and few led to study discontinuation. In most studies, circumcision rates were lower in patients from Latin America than in the overall population, which may have contributed to the higher incidence of male genital mycotic infections seen in the Latin American subgroups compared with the overall populations. Consistent with data from the overall populations, the trends in UTIs varied between studies in Latin American patients. The incidence of UTIs was generally higher with canagliflozin in the placebo-controlled monotherapy and add-on to metformin studies and lower with canagliflozin in the placebo- and active-controlled, add-on to metformin plus sulfonylurea studies. Rates of UTIs were generally comparable across treatment groups in the active-controlled, add-on to metformin studies. The incidence of AEs related to osmotic diuresis (eg, polyuria, pollakiuria) was generally higher with canagliflozin 100 and 300 mg compared with placebo, sitagliptin, or glimepiride in patients from Latin America across studies. The incidence of AEs related to volume depletion (eg, postural dizziness, orthostatic hypotension) was generally low and similar across treatment groups in the patients from Latin America across studies.
Discussion Findings from this post hoc analysis of individual Phase 3 studies demonstrated that canagliflozin treatment improved glycemic control and reduced body weight and systolic BP in patients from Latin America with T2DM. Canagliflozin provided dose-dependent reductions in HbA1c across most studies in both the overall populations and Latin American subgroups. In the monotherapy and add-on to metformin versus sitagliptin studies, mean changes in HbA1c were similar with canagliflozin 100 and
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300 mg in patients from Latin America, likely due to the small sample size; dose-dependent reductions in HbA1c were seen in the overall populations of these studies. HbA1c reductions with canagliflozin were generally similar in patients from Latin America compared with the overall population in each of the studies. Hispanic/Latino patients demonstrate reduced insulin sensitivity6; thus, canagliflozin, which lowers plasma glucose levels through an insulin-independent mechanism, may be particularly beneficial in this patient population and in patients from Latin America. Canagliflozin was associated with reductions in body weight and systolic BP that were generally comparable in the overall populations and Latin American subgroups of the placebo- and activecontrolled studies. In the placebo-controlled, add-on to metformin plus sulfonylurea study, a notable reduction in systolic BP was seen with placebo in both the overall population and Latin American subgroup, which led so smaller, placebo-subtracted reductions than observed in other studies. Overall, canagliflozin was generally well tolerated in patients with T2DM from Latin America in the individual placebo- and active-controlled studies, with a safety profile equivalent to the overall study populations. The incidence of male and female genital mycotic infections and AEs related to osmotic diuresis was generally higher with canagliflozin compared with placebo, sitagliptin, and glimepiride in the Latin American subgroups and overall populations across studies. The incidence of UTIs with canagliflozin versus comparator varied the Latin American subgroups and overall populations, with no clear trend across studies. The incidence of AEs related to volume depletion was low and similar across treatment groups across studies in the overall populations and Latin American subgroups.
The results from this analysis in patients from Latin America, the majority of which were of Hispanic/Latino ethnicity, are consistent with findings from pooled analysis of four, 26-week, placebo-controlled, Phase 3 studies of canagliflozin in Hispanic/Latino patients with T2DM, which also demonstrated reductions in HbA1c, body weight, and systolic BP.24 An analogous AE profile, with increases in genital mycotic infections and osmotic diuresis–related AEs, was seen with canagliflozin compared with placebo.
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Limitations of this study include the post hoc analysis of data and relatively small sample size of patients from Latin America in each study (n = 76-240), which made it difficult draw any meaningful conclusions regarding the true differences in efficacy and safety parameters between treatment groups. Larger prospective studies would be needed to verify that the efficacy and safety findings from studies of canagliflozin in broader patient populations apply to patients with T2DM from Latin America.
Conclusions Canagliflozin improved glycemic control and reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM from Latin America. The efficacy of canagliflozin in patients from Latin America was similar to that observed in the broader overall populations of patients with T2DM across Phase 3 studies of canagliflozin. Overall, findings from this analysis further support canagliflozin as monotherapy or part of a dual or triple therapy regimen for patients with T2DM in
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Latin America.
Transparency Declaration of funding This study was sponsored by Janssen Research & Development, LLC. The sponsor had a role in the study design and conduct, and in data collection, analysis, and interpretation. The authors prepared the report with editorial assistance funded by the sponsor. All authors had full access to study data; were responsible for the integrity of the data and the accuracy of the data analysis; and reviewed, edited, and approved the report for publication.
Declaration of financial/other relationships F.J.L-G. has received sponsorship from Sanofi and Janssen; has received grant/research support from Boehringer Ingelheim and Janssen; has served as a consultant/advisor for Sanofi, Boehringer Ingelheim, Merck Sharpe and Dohme, Janssen, Novo Nordisk, Eli Lilly, and AstraZeneca; and has participated in speakers bureaus for Sanofi, Boehringer Ingelheim, Eli Lilly, AstraZeneca, Novo Nordisk, Novartis, Janssen, and Merck Sharpe and Dohme. F.G.E. has served as a consultant/advisor for Sanofi, Eli Lilly, Novo Nordisk, AstraZeneca, and Boehringer Ingelheim; and has participated in speakers bureaus for Sanofi, AstraZeneca, and Novo Nordisk. S.C. has served as a consultant/advisor to Novo Nordisk, Sanofi, Merck Sharpe and Dohme, AstraZeneca, and Janssen. M.D.P.C. has no financial disclosures to report. C.T. and M.A. are full-
time employees of Janssen Research & Development, LLC. CMRO Peer Reviewer 1 has disclosed that he has received consulting and/or speaker fees from Eli Lilly, Sanofi, Novo Nordisk, Glaxo-SmithKline, Taisho pharmaceutical, Astellas Pharma, BD, Boehringer Ingelheim, Johnson & Johnson and Takeda. He has also received grants from Boehringer Ingelheim, Eli Lilly and MSD. CMRO Peer Reviewer 2 has disclosed that he is on the Speakers’ Bureau for MSD, Novo Nordisk and Sanofi.
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CMRO Peer reviewer 3 has no relevant financial relationships to disclose.
Acknowledgments This study was sponsored by Janssen Research & Development, LLC. Editorial support was provided by Kimberly Fuller, PhD, of MedErgy, and was funded by Janssen Global Services, LLC. The authors thank all investigators, study teams, and patients for participating in these studies.
Canagliflozin was developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation.
References 1. Guzman JR, Lyra R, Aguilar-Salinas CA, et al. Treatment of type 2 diabetes in Latin America: a consensus statement by the medical associations of 17 Latin American countries. Latin American Diabetes Association. Rev Panam Salud Publica 2010;28:463-71 2. Guariguata L, Whiting DR, Hambleton I, et al. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014;103:137-49
Downloaded by [NUS National University of Singapore] at 10:12 30 November 2015
3. Caballero AE. Type 2 diabetes in the Hispanic or Latino population: challenges and opportunities. Curr Opin Endocrinol Diabetes Obes 2007;14:151-7 4. The National Institutes of Health, National Eye Institute. Diabetic Retinopathy [online]. Available at: https://nei.nih.gov/eyedata/diabetic#2 [Last accessed 24 Sept. 2015] 5. United States Renal Data System. 2014 Annual Data Report. 2014 6. Cusi K, Ocampo GL. Unmet needs in Hispanic/Latino patients with type 2 diabetes mellitus. Am J Med 2011;124:S2-S9 7. Lorenzo C, Hanley AJ, Wagenknecht LE, et al. Relationship of insulin sensitivity, insulin secretion, and adiposity with insulin clearance in a multiethnic population: the insulin Resistance Atherosclerosis study. Diabetes Care 2013;36:101-3 8. Escalante M, Gagliardino JJ, Guzman JR, Tschiedel B. Call-to-action: Timely and appropriate treatment for people with type 2 diabetes in Latin America. Diabetes Res Clin Pract 2014;104:343-52 9. Rosenstock J, Aggarwal N, Polidori D, et al. Dose-ranging effects of canagliflozin, a sodiumglucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care 2012;35:1232-8 10. Stenlöf K, Cefalu WT, Kim K-A, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 2013;15:372-82 11. Stenlöf K, Cefalu WT, Kim KA, et al. Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: findings from the 52-week CANTATA-M study. Curr Med Res Opin 2014;30:163-75 12. Bode B, Stenlöf K, Sullivan D, et al. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract 2013;41:72-84 13. Bode B, Stenlöf K, Harris S, et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55 to 80 years with type 2 diabetes. Diabetes Obes Metab 2015;17:294-303 14. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 2013;15:463-73 15. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes Metab 2014;16:101627
16. Cefalu WT, Leiter LA, Yoon K-H, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 2013;382:941-50 17. Leiter LA, Yoon K-H, Arias P, et al. Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, Phase 3 study. Diabetes Care 2015;38:355-64
Downloaded by [NUS National University of Singapore] at 10:12 30 November 2015
18. Lavalle-González FJ, Januszewicz A, Davidson J, et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia 2013;56:2582-92 19. Wilding JP, Charpentier G, Hollander P, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract 2013;67:1267-82 20. Forst T, Guthrie R, Goldenberg R, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes Metab 2014;16:467-77 21. Schernthaner G, Gross JL, Rosenstock J, et al. 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. Diabetes Care 2013;36:2508-15 22. Sha S, Devineni D, Ghosh A, et al. Canagliflozin, a novel inhibitor of sodium glucose cotransporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes Metab 2011;13:669-72 23. Polidori D, Sha S, Ghosh A, et al. Validation of a novel method for determining the renal threshold for glucose excretion in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab 2013;98:E867-E871 24. Davidson J, Aguilar R, Lavalle-Gonzalez F, et al. Efficacy and safety of canagliflozin (CANA) in patients with type 2 diabetes mellitus (T2DM) by Hispanic/Latino ethnicity. Poster presented at: Association of Clinical Endocrinologists (AACE) 23rd Annual Scientific & Clinical Congress; May 14-18, 2014; Las Vegas, NV 2014;
FIGURE LEGENDS
Figure 1. Changes in HbA1c for the overall populations and Latin American subgroups of the (A) PBO-controlled studies at Week 26 and (B) active-controlled studies at Week 52. PBO, placebo; MET, metformin; SU, sulfonylurea; LS, least squares; SE, standard error; CI, confidence interval; CANA, canagliflozin; SITA, sitagliptin; GLIM, glimepiride. *
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P
