Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes

Julio Rosenstock, Naresh Aggarwal, David Polidori, Yue Zhao, Deborah Arbit, Keith Usiskin, George Capuano, William Canovatchel, Canagliflozin DIA 2001 Study Group, Paula Antunez, Maurico Jadzinsky, Laura Maffei, Fabio Massari, Alfredo Halpern, Freddy Eliaschewitz, Flavio Guerra, Ivan Cinlikov, Mihail Protich, Tsvetalina Tankova, Naresh Aggarwal, Dan Dattani, Anthony Dowell, Iris Gorfinkel, Kay Ho, Subodh Kanani, Lawrence Leiter, Michael O'Mahony, Daniel Shu, Camil Vallieres, Jana Vojtiskova, Bohumil Seifert, Lenka Dohnalova, Cyril Mucha, Tomas Brychta, Miloslava Komrskova, Richard Ceska, Alena Andresova, P V Rao, Paramesh Shamanna, Pramod Gandhi, Shailaja Kale, Shailesh Pitale, Nor Azmi Kamaruddin, Siew Pheng Chan, Mafauzy Mohamed, Esteban Rios, Eduardo Elizondo, Melchor Alpizar, Armando Vargas, Cesar Calvo, Jerzy Loba, Lucyna Hotlos, Krystyna Jedenasty, Miroslawa Polaszewska-Muszynska, Janusz Schabowski, Maciej Foczpaniak, Teresa Stasinska, Ewa Semetkowka, Adrian Albota, Anca Ileana Coman, Ioan Andrei Veresiu, Lavinia Pop, Maevery dayalena Morosanu, Alexandrina Popescu, Alexandr Ametov, Irina Ulyanova, Sergey Shustov, Elena Grineva, Andrey Verbovoy, Nina Nosova, Elena Sivkova, Natalia Vorokhobina, Patrick Bell, Geoffrey Butcher, Ken MacLeod, Ian Caldwell, Keith Sands, Elizabeth Barranco, Steven Chrysant, Kenneth Cohen, Martin Conway, Christian Gallery, Ronald K Garcia, Kenneth S Hershon, Robert Hudrick, Randal Jacks, Rajeev Jain, Mark King, Steven Landgarten, Andrew Lewin, Stefanie Lundell, Michael McCartney, Brock McConnehey, Robert McNeill, Nicholas Messina, Jerry R Mitchell, William Jonakin, James Quigley, Daniel Urbach, Karin Rock, Julio Rosenstock, Scott Sanford, Erich Schramm, Sherwyn Schwartz, Gregory Serfer, Russell Simpson, Miguel Sosa- Padilla, Stanley Stringam, James Wallace, Jeffrey Wayne, Alan Wynne, Julio Rosenstock, Naresh Aggarwal, David Polidori, Yue Zhao, Deborah Arbit, Keith Usiskin, George Capuano, William Canovatchel, Canagliflozin DIA 2001 Study Group, Paula Antunez, Maurico Jadzinsky, Laura Maffei, Fabio Massari, Alfredo Halpern, Freddy Eliaschewitz, Flavio Guerra, Ivan Cinlikov, Mihail Protich, Tsvetalina Tankova, Naresh Aggarwal, Dan Dattani, Anthony Dowell, Iris Gorfinkel, Kay Ho, Subodh Kanani, Lawrence Leiter, Michael O'Mahony, Daniel Shu, Camil Vallieres, Jana Vojtiskova, Bohumil Seifert, Lenka Dohnalova, Cyril Mucha, Tomas Brychta, Miloslava Komrskova, Richard Ceska, Alena Andresova, P V Rao, Paramesh Shamanna, Pramod Gandhi, Shailaja Kale, Shailesh Pitale, Nor Azmi Kamaruddin, Siew Pheng Chan, Mafauzy Mohamed, Esteban Rios, Eduardo Elizondo, Melchor Alpizar, Armando Vargas, Cesar Calvo, Jerzy Loba, Lucyna Hotlos, Krystyna Jedenasty, Miroslawa Polaszewska-Muszynska, Janusz Schabowski, Maciej Foczpaniak, Teresa Stasinska, Ewa Semetkowka, Adrian Albota, Anca Ileana Coman, Ioan Andrei Veresiu, Lavinia Pop, Maevery dayalena Morosanu, Alexandrina Popescu, Alexandr Ametov, Irina Ulyanova, Sergey Shustov, Elena Grineva, Andrey Verbovoy, Nina Nosova, Elena Sivkova, Natalia Vorokhobina, Patrick Bell, Geoffrey Butcher, Ken MacLeod, Ian Caldwell, Keith Sands, Elizabeth Barranco, Steven Chrysant, Kenneth Cohen, Martin Conway, Christian Gallery, Ronald K Garcia, Kenneth S Hershon, Robert Hudrick, Randal Jacks, Rajeev Jain, Mark King, Steven Landgarten, Andrew Lewin, Stefanie Lundell, Michael McCartney, Brock McConnehey, Robert McNeill, Nicholas Messina, Jerry R Mitchell, William Jonakin, James Quigley, Daniel Urbach, Karin Rock, Julio Rosenstock, Scott Sanford, Erich Schramm, Sherwyn Schwartz, Gregory Serfer, Russell Simpson, Miguel Sosa- Padilla, Stanley Stringam, James Wallace, Jeffrey Wayne, Alan Wynne

Abstract

Objective: To evaluate the effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in type 2 diabetes mellitus inadequately controlled with metformin monotherapy.

Research design and methods: This was a double-blind, placebo-controlled, parallel-group, multicenter, dose-ranging study in 451 subjects randomized to canagliflozin 50, 100, 200, or 300 mg once daily (QD) or 300 mg twice daily (BID), sitagliptin 100 mg QD, or placebo. Primary end point was change in A1C from baseline through week 12. Secondary end points included change in fasting plasma glucose (FPG), body weight, and overnight urinary glucose-to-creatinine ratio. Safety and tolerability were also assessed.

Results: Canagliflozin was associated with significant reductions in A1C from baseline (7.6-8.0%) to week 12: -0.79, -0.76, -0.70, -0.92, and -0.95% for canagliflozin 50, 100, 200, 300 mg QD and 300 mg BID, respectively, versus -0.22% for placebo (all P < 0.001) and -0.74% for sitagliptin. FPG was reduced by -16 to -27 mg/dL, and body weight was reduced by -2.3 to -3.4%, with significant increases in urinary glucose-to-creatinine ratio. Adverse events were transient, mild to moderate, and balanced across arms except for a non-dose-dependent increase in symptomatic genital infections with canagliflozin (3-8%) versus placebo and sitagliptin (2%). Urinary tract infections were reported without dose dependency in 3-9% of canagliflozin, 6% of placebo, and 2% of sitagliptin arms. Overall incidence of hypoglycemia was low.

Conclusions: Canagliflozin added onto metformin significantly improved glycemic control in type 2 diabetes and was associated with low incidence of hypoglycemia and significant weight loss. The safety/tolerability profile of canagliflozin was favorable except for increased frequency of genital infections in females.

Trial registration: ClinicalTrials.gov NCT00642278.

Figures

Figure 1
Figure 1
Effects of canagliflozin from baseline to week 12 in subjects with type 2 diabetes on metformin. Mean change in A1C (A), FPG (B), body weight (C), and UGlucose-to-UCreatinine ratio (D) from baseline to week 12. Data are observed mean changes from baseline. Error bars show SE of the mean (last observation carried forward). *P < 0.001 vs. placebo calculated using least squares means. PBO, placebo; CANA, canagliflozin; SITA, sitagliptin.
Figure 1
Figure 1
Effects of canagliflozin from baseline to week 12 in subjects with type 2 diabetes on metformin. Mean change in A1C (A), FPG (B), body weight (C), and UGlucose-to-UCreatinine ratio (D) from baseline to week 12. Data are observed mean changes from baseline. Error bars show SE of the mean (last observation carried forward). *P < 0.001 vs. placebo calculated using least squares means. PBO, placebo; CANA, canagliflozin; SITA, sitagliptin.

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Source: PubMed

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