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Initial Combination Therapy with Canagliflozin Plus Metformin Versus Each Component As Monotherapy for Drug-Naïve Type 2 Diabe

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Initial Combination Therapy with Canagliflozin Plus Metformin Versus Each Component As Monotherapy for Drug-Naïve Type 2 Diabe Diabetes Care Volume 39, March 2016 353 Julio Rosenstock,1 Leonard Chuck,2 Initial Combination Therapy With Manuel Gonzalez-Ortiz,´ 3 Kate Merton,4 CLIN CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL Jagriti Craig,4 George Capuano,4 and Canagliflozin Plus Metformin Rong Qiu4 Versus Each Component as Monotherapy for Drug-Na¨ıve Type 2 Diabetes Diabetes Care 2016;39:353–362 | DOI: 10.2337/dc15-1736 OBJECTIVE This study assessed the efficacy/safety of canagliflozin (CANA), a sodium–glucose cotransporter 2 (SGLT2) inhibitor, plus metformin extended-release (MET) initial therapy in drug-na¨ıve type 2 diabetes. RESEARCH DESIGN AND METHODS This 26-week, double-blind, phase 3 study randomized 1,186 patients to CANA 100 mg (CANA100)/MET, CANA 300 mg (CANA300)/MET, CANA100, CANA300, or MET. Primary end point was change in HbA1c at week 26 for combinations versus monotherapies. Secondary end points included noninferiority in HbA1c lowering with CANA monotherapy versus MET; changes in fasting plasma glucose, body weight, and blood pressure; and proportion of patients achieving HbA1c <7.0% (<53 mmol/mol). RESULTS From mean baseline HbA1c of 8.8% (73 mmol/mol), CANA100/MET and CANA300/ MET significantly lowered HbA1c versus MET (median dose, 2,000 mg/day) by –1.77%, –1.78%, and –1.30% (–19.3, –19.5, and –14.2 mmol/mol; differences of 1Dallas Diabetes and Endocrine Center at Medi- 2 – – – P cal City, Dallas, TX 0.46% and 0.48% [ 5.0 and 5.2 mmol/mol]; = 0.001) and versus CANA100 2 – – – – Diablo Clinical Research, Walnut Creek, CA and CANA300 by 1.37% and 1.42% ( 15.0 and 15.5 mmol/mol; differences of 3Institute of Experimental and Clinical Therapeu- –0.40% and –0.36% [–4.4 and –3.9 mmol/mol]; P = 0.001). CANA100 and CANA300 tics, Physiology Department, Health Science Uni- versity Center, University of Guadalajara, monotherapy met noninferiority for HbA1c lowering and had significantly more weight loss versus MET (–2.8, –3.7, and –1.9 kg [–3.0%, –3.9%, and –2.1%]; Guadalajara, Mexico 4Janssen Research & Development, LLC, Raritan, P P < = 0.016 and = 0.002). Greater attainment of HbA1c 7.0% (50%, 57%, and NJ fi – – – – – 43%) and signi cantly more weight loss ( 3.2, 3.9, and 1.9 kg [ 3.5%, 4.2%, Corresponding author: Julio Rosenstock, and –2.1%]; P = 0.001) occurred with CANA100/MET and CANA300/MET versus [email protected]. MET. The incidence of adverse events (AEs) related to SGLT2 inhibition (genital Received 7 August 2015 and accepted 17 De- mycotic infections, osmotic diuresis– and volume depletion–related AEs) was cember 2015. higher in the CANA arms (0.4–4.4%) versus MET (0–0.8%). AE-related discontinu- Clinical trial reg no. NCT01809327, clinicaltrials ation rates were 1.3–3.0% across groups. The incidence of hypoglycemia was .gov. 3.0–5.5% in the CANA arms and 4.6% with MET. This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/ CONCLUSIONS suppl/doi:10.2337/dc15-1736/-/DC1. Initial therapy with CANA plus MET was more effective and generally well toler- © 2016 by the American Diabetes Association. Readers may use this article as long as the work is ated versus each monotherapy in drug-na¨ıve type 2 diabetes. CANA monotherapy properly cited, the use is educational and not for demonstrated noninferior HbA1c lowering versus MET. profit, and the work is not altered. 354 Canagliflozin/Metformin Initial Therapy Diabetes Care Volume 39, March 2016 The American Diabetes Association efficacy and safety profile (1). Canagli- taking any AHA within 12 weeks before (ADA) and the European Association flozin (CANA) is an SGLT2 inhibitor de- screening or during the placebo run-in pe- for the Study of Diabetes (EASD) recom- veloped for the treatment of adults with riod. Patients were discontinued from the mend individualized HbA1c targets of ap- type 2 diabetes (10–23). CANA lowers study if they had fasting plasma glucose proximately ,7.0% (,53 mmol/mol) the renal threshold for glucose, thereby (FPG) values meeting prespecified glyce- for patients with type 2 diabetes (1,2) increasing urinary glucose excretion mic withdrawal criteria (FPG .270 mg/dL if this target can be achieved safely with- (UGE); increased UGE results in insulin- [.15.0 mmol/L] after day 1 through week 6; out unwanted side effects, as glycemic independent glucose-lowering effects, .240 mg/dL [.13.3 mmol/L] after week control can lower the risk of diabetes- as well as a mild osmotic diuresis and 6 through week 12; .200 mg/dL related complications (3,4). A range of net caloric loss that can lead to weight [.11.1 mmol/L] after week 12 through antihyperglycemic agents (AHAs) is loss and blood pressure (BP) reductions week 26), serum creatinine $1.5 mg/dL available to manage hyperglycemia in (24,25). Across phase 3 studies in a ($133 mmol/L) for men or $1.4 mg/dL patients with type 2 diabetes (1). Met- broad range of patients with type 2 di- ($124 mmol/L) for women, or eGFR formin (MET) monotherapy is the stan- abetes, CANA provided reductions in ,50 mL/min/1.73 m2. fi dard rst-line AHA; however, its use is HbA1c, body weight, and BP and was The study was conducted in accor- limited in some patients due to poor generally well tolerated as monother- dance with the ethical principles that gastrointestinal tolerability (1). In addi- apy and in combination with other have their origin in the Declaration of – tion, patients with elevated baseline AHAs, including MET (11 23). This study Helsinki and are consistent with Good fi fi HbA1c may have dif culty meeting gly- evaluated the ef cacy and safety of ini- Clinical Practice and applicable regula- cemic targets with a single AHA (5,6). tial combination therapy with CANA tory requirements. Regulatory approval Thus, many people will require combi- 100 mg (CANA100) or CANA 300 mg for the conduct of the trial was obtained ¨ı nation therapy with two or three AHAs (CANA300) plus MET in drug-na ve pa- in each country, and ethics approval was to achieve individualized glycemic tients with type 2 diabetes over 26 received at every site before initiation. targets (1). weeks. In addition, changes in HbA 1c Patients provided written informed con- Early intervention with combination and body weight with CANA monother- sent before participation. therapy has been successful in the man- apy versus MET monotherapy were as- agement of chronic conditions such as sessed with sufficient statistical power. Randomization and Blinding hypertension, and a similar approach is Patients were randomized (1:1:1:1:1) to RESEARCH DESIGN AND METHODS recommended for patients with type 2 receive CANA100/MET extended-release diabetes (7). Physicians are increasingly Study Design and Patients (XR), CANA300/MET XR, CANA100, fi initiating dual therapy as the prelimi- This double-blind, ve-arm, parallel- CANA300, or MET XR over 26 weeks nary treatment strategy in patients group, phase 3 study was conducted at using a computer-generated randomization who would benefit from a more proactive 158 centers in 12 countries from 16 May schedule that was prepared by the sponsor approach to glycemic control (i.e., those 2013 to 1 December 2014. The study before the study. Randomization was bal- with HbA $9.0% [$75 mmol/mol]). consisted of a 2-week, single-blind, pla- 1c anced using permuted blocks and stratified The ADA/EASD support initiation of cebo run-in period, followed by a 26-week, by HbA values at screening (i.e., ,9.0% dual therapy in newly diagnosed pa- double-blind treatment phase and 1c or $9.0% [,75 or $75 mmol/mol]). FPG tients with type 2 diabetes and 4 weeks of follow-up for all patients. and HbA1c values were masked to the study HbA1c $9.0% ($75 mmol/mol) (1). Eligible patients were $18 and ,75 Similarly, combination therapy is rec- years of age with drug-na¨ıve type 2 sites and to the sponsor, unless an FPG ommended in Canada for patients with diabetes (i.e., not on AHA therapy or value met glycemic discontinuation criteria. At week –2, all patients received pla- HbA1c $8.5% ($69 mmol/mol) (8). In con- off for $12 weeks before screening) trast, the American Association of Clinical that was inadequately controlled with cebo tablets matching MET XR 500 mg and placebo capsules matching CANA. Endocrinologists supports initiation of dual diet and exercise (HbA1c $7.5% and therapy in patients with a lower baseline #12.0% [$58 and #108 mmol/mol] at Patients were instructed to take three pills each day during the 2-week, single- HbA1c (i.e., $7.5% [$58 mmol/mol]) (9), screening). Patients were excluded if but there are no randomized controlled they had a history of type 1 diabetes; blind, placebo run-in period: one pla- studies at that early stage to substantiate repeated fasting self-monitored blood cebo capsule matching CANA before such an aggressive approach for relatively glucose .300 mg/dL (.16.7 mmol/L); the morning meal, then one placebo cap- sule matching CANA and one placebo mild HbA1c elevations that can be poten- myocardial infarction, unstable angina, tially controlled by a single agent. There- revascularization procedure, or cerebro- tablet matching MET XR 500 mg with fore, an evaluation of the efficacy and vascular accident #12 weeks before the evening meal. MET XR was adminis- safety of initial combinations of newer screening; history of New York Heart As- tered in the evening to minimize adverse AHA classes with established therapies, sociation Functional Classification III gastrointestinal effects.
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