Clinical trial NCT01032629: CANVAS - CANagliflozin cardioVascular Assessment Study
Official title: A Randomized, Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of the Effects of JNJ-28431754 on Cardiovascular Outcomes in Adult Subjects With Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2
Cardiovascular Diseases
Risk Factors
Keywords: Diabetes
Type 2 diabetes mellitus
Cardiovascular risk
Cardiovascular outcomes
Canagliflozin (JNJ-28431754)
Placebo
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
Collaborators: name: The George Institute for Global Health, Australia
First posted: 2009-12-15
Enrollment: 4330
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study will assess canagliflozin (JNJ-28431754) in the treatment of patients with type 2 diabetes mellitus (T2DM) with regard to cardiovascular (CV) risk for major adverse cardiac events (MACE). Other objectives include evaluating the overall safety, tolerability, and effectiveness of canagliflozin.

The data from this study will be combined with the data from CANVAS-R study (Study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects with T2DM, NCT01989754) in a pre-specified integrated analysis of CV safety outcomes to satisfy US FDA post-marketing requirements for canagliflozin.

Detailed description: The study will evaluate canagliflozin compared to placebo on CV events including CV death, heart attack, and stroke in patients with T2DM, whose diabetes is not well controlled at the beginning of the study and who have a history of CV events or have a high risk for CV events. The study includes 3 substudies which will compare the effectiveness of lowering blood glucose and assess the safety of canagliflozin relative to placebo in patients receiving specific commonly-used diabetes agents. 4,330 participants will be randomly assigned to treatment with 1 of 2 doses of canagliflozin (100 or 300 mg) or placebo, in a 1:1:1 ratio. This study was originally designed to last for up to 9 years. As per FDA post-marketing requirements for canagliflozin, the study's last subject last visit will now occur when enough MACE events (ie, CV death, nonfatal myocardial infarction, nonfatal stroke) are accumulated between the CANVAS (this study) and CANVAS-R studies. The completion target was reached in February 2017.

Eligibility criteria: Inclusion Criteria:

* Patients must have a diagnosis of type 2 diabetes mellitus and greater than or equal to (\>=) 30 yrs old with history of cardiovascular (CV) event, or \>= 50 yrs old with high risk of CV events
* Patients must have inadequate diabetes control (as defined by glycosylated hemoglobin greater than or equal to 7.0% to less than or equal to 10.5% at screening) and be either (1) not currently on diabetes drug therapy or (2) on therapy with any approved class of diabetes drugs

Exclusion Criteria:

* A history of diabetic ketoacidosis, type 1 diabetes mellitus, pancreas or beta-cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy
* History of one or more severe hypoglycemic (ie, very low blood sugar) episode within 6 months before screening

Primary outcomes:
measure: Major Adverse Cardiovascular Events (MACE) Composite of Cardiovascular (CV) Death, Non-Fatal Myocardial Infarction (MI), and Non-Fatal Stroke
timeFrame: Up to approximately 8 years
Secondary outcomes:
measure: Change From Baseline in Homeostasis Model Assessment 2 Steady-State Beta-Cell Function (HOMA2-%B) at the End-of-Treatment (EOT)
timeFrame: Baseline and end of treatment (approximately 338 weeks)
measure: Percentage of Participants With Progression of Albuminuria at the End-of-Treatment
timeFrame: End of treatment (approximately 338 weeks)
measure: Change From Baseline in Proinsulin/Insulin (PI/I) Ratio at the End-of-Treatment
timeFrame: Baseline and end of treatment (approximately 338 weeks)
measure: Change From Baseline in Urinary Albumin/Creatinine Ratio at End-of-Treatment
timeFrame: Baseline and End of treatment (approximately 338 weeks)
measure: Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at End-of-Treatment
timeFrame: Baseline and end of treatment (approximately 338 weeks)
measure: Change From Baseline in Glycated Hemoglobin (HbA1c) at End-of-Treatment
timeFrame: Baseline and end of treatment (approximately 338 weeks)
measure: Change From Baseline in Fasting Plasma Glucose (FPG) Levels at End-of-Treatment
timeFrame: Baseline and end of treatment (approximately 338 weeks)
measure: Percent Change From Baseline in Body Weight at End-of-Treatment
timeFrame: Baseline and end of treatment (approximately 338 weeks)
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End-of-Treatment
timeFrame: Baseline and end of treatment (approximately 338 weeks)
measure: Change From Baseline in Triglycerides Levels at End-of-Treatment
timeFrame: Baseline and end of treatment (approximately 338 weeks)
measure: Change From Baseline in Cholesterol, High-Density Lipoprotein Cholesterol (HDL-C) and Low Density Lipoprotein Cholesterol (LDL-C) Levels at End-of-Treatment
timeFrame: Baseline and end of treatment (approximately 338 weeks)
measure: Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) to High-Density Lipoprotein-Cholesterol (HDL-C) Ratio at End-of-Treatment
timeFrame: Baseline and end of treatment (approximately 338 weeks)
Other outcomes:
Locations:
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country: United States
state: Alabama
city: Mesa
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state: Arizona
city: Tucson
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state: Arizona
city: La Mesa
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city: Los Gatos
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state: California
city: Pismo Beach
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state: California
city: Stockton
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city: Walnut Creek
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state: Nebraska
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state: New Jersey
city: Bronx
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city: Flushing
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city: Chapel Hill
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state: North Carolina
city: Charlotte
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state: Ohio
city: Cleveland
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city: Mentor
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state: South Carolina
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state: Tennessee
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state: Texas
city: Houston
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city: Temple
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state: Utah
city: Salt Lake City
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state: Virginia
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state: Washington
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city: Capital Federal
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city: Ciudad Autonma Buenos Aires
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city: East Ringwood
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city: Elizabeth Vale
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city: Hornsby, Nsw 2077
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state: Alberta
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city: St. John'S
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state: Newfoundland and Labrador
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city: Moravsky Krumlov
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city: Prague 5
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city: Znojmo N/A
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city: Pärnu
country: Estonia
city: Tallinn
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country: Estonia
city: Viljandi
country: Estonia
city: Amiens
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city: Nimes Cedex 9
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city: Pessac
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city: Dortmund
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city: Budapest
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city: Kecskemet
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city: Mosonmagyaróvár
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city: Zalaegerszeg
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city: Ahemadabad
country: India
city: Ahmedabad
country: India
city: Ambawadi
country: India
city: Bangalore, Karnataka
country: India
city: Bangalore
country: India
city: Belgaum
country: India
city: Calicut
country: India
city: Chennai
country: India
city: Cochin
country: India
city: Coimbatore
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city: Karnal
country: India
city: Kerala
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city: Kochi
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city: Lucknow
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city: Nagpur
country: India
city: New Delhi
country: India
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country: India
city: Pune
country: India
city: Rajkot
country: India
city: Trivandrum, Kerala
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city: Vadodhara
country: India
city: Vijayawada
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city: Visakhapatnam
country: India
city: Beer Sheba
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city: Holon
country: Israel
city: Jerusalem
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city: Kfar Saba
country: Israel
city: Luxembourg
country: Luxembourg
city: Georgetown
country: Malaysia
city: Johor Bahru
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city: Kota Bharu
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city: Kuala Lumpur N/A
country: Malaysia
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country: Malaysia
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city: Celaya
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city: Ciudad De Mexico
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country: Mexico
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country: Mexico
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country: Mexico
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city: Almere
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country: Netherlands
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city: Christchurch
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city: Dunedin
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country: New Zealand
city: Wellington
country: New Zealand
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city: Asker
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city: Bekkestua
country: Norway
city: Elverum
country: Norway
city: Hamar
country: Norway
city: Lierskogen
country: Norway
city: Moss
country: Norway
city: Oslo
country: Norway
city: Skedsmokorset
country: Norway
city: Bialystok
country: Poland
city: Ciechocinek
country: Poland
city: Gniewkowo
country: Poland
city: Grudziadz
country: Poland
city: Katowice
country: Poland
city: Krakow
country: Poland
city: Lublin
country: Poland
city: Plock
country: Poland
city: Poznan
country: Poland
city: Rzeszow
country: Poland
city: Slawkow
country: Poland
city: Torun
country: Poland
city: Warszawa
country: Poland
city: Wroclaw
country: Poland
city: Arkhangelsk
country: Russian Federation
city: Chelyabinsk
country: Russian Federation
city: Ekaterinburg
country: Russian Federation
city: Kemerovo
country: Russian Federation
city: Kirov
country: Russian Federation
city: Kursk
country: Russian Federation
city: Moscow N/A
country: Russian Federation
city: Moscow
country: Russian Federation
city: Nizhny Novgorod
country: Russian Federation
city: Novosibirsk
country: Russian Federation
city: Omsk
country: Russian Federation
city: Penza
country: Russian Federation
city: Rostov-On-Don
country: Russian Federation
city: Russia
country: Russian Federation
city: Ryazan
country: Russian Federation
city: Saint Petersburg
country: Russian Federation
city: Saint-Petersburg
country: Russian Federation
city: Saratov
country: Russian Federation
city: Smolensk
country: Russian Federation
city: St Petersburg
country: Russian Federation
city: Tomsk
country: Russian Federation
city: Tula
country: Russian Federation
city: Tyumen
country: Russian Federation
city: Yaroslavl Nap
country: Russian Federation
city: Yaroslavl
country: Russian Federation
city: Alicante
country: Spain
city: Almeria
country: Spain
city: Barcelona
country: Spain
city: Figueres
country: Spain
city: Madrid
country: Spain
city: Málaga
country: Spain
city: Oviedo
country: Spain
city: Reus
country: Spain
city: Sabadell
country: Spain
city: San Juan De Alicante
country: Spain
city: Santiago De Compostela
country: Spain
city: Sevilla N/A
country: Spain
city: Valencia
country: Spain
city: Viladecans
country: Spain
city: Borås
country: Sweden
city: Göteborg
country: Sweden
city: Helsingborg
country: Sweden
city: Lund
country: Sweden
city: Malmö
country: Sweden
city: Oskarshamn N/A
country: Sweden
city: Piteå
country: Sweden
city: Stockholm
country: Sweden
city: Uddevalla
country: Sweden
city: Dnepropetrovsk
country: Ukraine
city: Donetsk
country: Ukraine
city: Kharkov
country: Ukraine
city: Kiev
country: Ukraine
city: Kyiv
country: Ukraine
city: Odessa
country: Ukraine
city: Ternopol
country: Ukraine
city: Uzhgorod
country: Ukraine
city: Vinnitsa
country: Ukraine
city: Zaporozhye
country: Ukraine
city: Belfast
country: United Kingdom
city: Blackburn
country: United Kingdom
city: Bolton
country: United Kingdom
city: Chorley
country: United Kingdom
city: Derby
country: United Kingdom
city: Glasgow
country: United Kingdom
city: Hull
country: United Kingdom
city: Leicester
country: United Kingdom
city: Liverpool
country: United Kingdom
city: Londonderry
country: United Kingdom
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
city: Randalstown
country: United Kingdom
city: Salford
country: United Kingdom
city: York
country: United Kingdom
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Ferrannini E, Baldi S, Scozzaro T, Tsimihodimos V, Tesfaye F, Shaw W, Rosenthal N, Figtree GA, Neal B, Mahaffey KW, Perkovic V, Hansen MK. Fasting Substrate Concentrations Predict Cardiovascular Outcomes in the CANagliflozin cardioVascular Assessment Study (CANVAS). Diabetes Care. 2022 Aug 1;45(8):1893-1899. doi: 10.2337/dc21-2398.
citation: Vaduganathan M, Sattar N, Xu J, Butler J, Mahaffey KW, Neal B, Shaw W, Rosenthal N, Pfeifer M, Hansen MK, Januzzi JL Jr. Stress Cardiac Biomarkers, Cardiovascular and Renal Outcomes, and Response to Canagliflozin. J Am Coll Cardiol. 2022 Feb 8;79(5):432-444. doi: 10.1016/j.jacc.2021.11.027.
citation: Waijer SW, Sen T, Arnott C, Neal B, Kosterink JGW, Mahaffey KW, Parikh CR, de Zeeuw D, Perkovic V, Neuen BL, Coca SG, Hansen MK, Gansevoort RT, Heerspink HJL. Association between TNF Receptors and KIM-1 with Kidney Outcomes in Early-Stage Diabetic Kidney Disease. Clin J Am Soc Nephrol. 2022 Feb;17(2):251-259. doi: 10.2215/CJN.08780621. Epub 2021 Dec 7.
citation: Young TK, Li JW, Kang A, Heerspink HJL, Hockham C, Arnott C, Neuen BL, Zoungas S, Mahaffey KW, Perkovic V, de Zeeuw D, Fulcher G, Neal B, Jardine M. Effects of canagliflozin compared with placebo on major adverse cardiovascular and kidney events in patient groups with different baseline levels of HbA1c, disease duration and treatment intensity: results from the CANVAS Program. Diabetologia. 2021 Nov;64(11):2402-2414. doi: 10.1007/s00125-021-05524-1. Epub 2021 Aug 26.
citation: Yu J, Li J, Leaver PJ, Arnott C, Huffman MD, Udell JA, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Matthews DR, Shaw W, Rosenthal N, Neal B, Figtree GA. Effects of canagliflozin on myocardial infarction: a post hoc analysis of the CANVAS programme and CREDENCE trial. Cardiovasc Res. 2022 Mar 16;118(4):1103-1114. doi: 10.1093/cvr/cvab128.
citation: Yu J, Arnott C, Neuen BL, Heersprink HL, Mahaffey KW, Cannon CP, Khan SS, Baldridge AS, Shah SJ, Huang Y, Li C, Figtree GA, Perkovic V, Jardine MJ, Neal B, Huffman MD. Cardiovascular and renal outcomes with canagliflozin according to baseline diuretic use: a post hoc analysis from the CANVAS Program. ESC Heart Fail. 2021 Apr;8(2):1482-1493. doi: 10.1002/ehf2.13236. Epub 2021 Feb 17.
citation: Januzzi JL Jr, Butler J, Sattar N, Xu J, Shaw W, Rosenthal N, Pfeifer M, Mahaffey KW, Neal B, Hansen MK. Insulin-Like Growth Factor Binding Protein 7 Predicts Renal and Cardiovascular Outcomes in the Canagliflozin Cardiovascular Assessment Study. Diabetes Care. 2021 Jan;44(1):210-216. doi: 10.2337/dc20-1889. Epub 2020 Nov 6.
citation: Januzzi JL Jr, Xu J, Li J, Shaw W, Oh R, Pfeifer M, Butler J, Sattar N, Mahaffey KW, Neal B, Hansen MK. Effects of Canagliflozin on Amino-Terminal Pro-B-Type Natriuretic Peptide: Implications for Cardiovascular Risk Reduction. J Am Coll Cardiol. 2020 Nov 3;76(18):2076-2085. doi: 10.1016/j.jacc.2020.09.004.
citation: Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, Fulcher G, Blais J, Li Q, Jardine MJ, Perkovic V, Wheeler DC. Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories: Findings From the CANVAS Program. Am J Kidney Dis. 2021 Jan;77(1):23-34.e1. doi: 10.1053/j.ajkd.2020.06.018. Epub 2020 Sep 21.
citation: Oshima M, Neal B, Toyama T, Ohkuma T, Li Q, de Zeeuw D, Heerspink HJL, Mahaffey KW, Fulcher G, Canovatchel W, Matthews DR, Perkovic V. Different eGFR Decline Thresholds and Renal Effects of Canagliflozin: Data from the CANVAS Program. J Am Soc Nephrol. 2020 Oct;31(10):2446-2456. doi: 10.1681/ASN.2019121312. Epub 2020 Jul 21.
citation: Matthews DR, Wysham C, Davies M, Slee A, Alba M, Lee M, Perkovic V, Mahaffey KW, Neal B. Effects of canagliflozin on initiation of insulin and other antihyperglycaemic agents in the CANVAS Program. Diabetes Obes Metab. 2020 Nov;22(11):2199-2203. doi: 10.1111/dom.14143. Epub 2020 Aug 24.
citation: Zhou Z, Jardine M, Perkovic V, Matthews DR, Mahaffey KW, de Zeeuw D, Fulcher G, Desai M, Oh R, Simpson R, Watts NB, Neal B. Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program. Diabetologia. 2019 Oct;62(10):1854-1867. doi: 10.1007/s00125-019-4955-5. Epub 2019 Aug 10.
citation: Figtree GA, Radholm K, Barrett TD, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Matthews DR, Shaw W, Neal B. Effects of Canagliflozin on Heart Failure Outcomes Associated With Preserved and Reduced Ejection Fraction in Type 2 Diabetes Mellitus. Circulation. 2019 May 28;139(22):2591-2593. doi: 10.1161/CIRCULATIONAHA.119.040057. Epub 2019 Mar 17. No abstract available.
citation: Zhou Z, Lindley RI, Radholm K, Jenkins B, Watson J, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Shaw W, Oh R, Desai M, Matthews DR, Neal B. Canagliflozin and Stroke in Type 2 Diabetes Mellitus. Stroke. 2019 Feb;50(2):396-404. doi: 10.1161/STROKEAHA.118.023009.
citation: Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, Fulcher G, Desai M, Li Q, Deng H, Rosenthal N, Jardine MJ, Bakris G, Perkovic V. Cardiovascular and Renal Outcomes With Canagliflozin According to Baseline Kidney Function. Circulation. 2018 Oct 9;138(15):1537-1550. doi: 10.1161/CIRCULATIONAHA.118.035901.
citation: Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Erondu N, Shaw W, Barrett TD, Weidner-Wells M, Deng H, Matthews DR, Neal B. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol. 2018 Sep;6(9):691-704. doi: 10.1016/S2213-8587(18)30141-4. Epub 2018 Jun 21.
citation: Wittbrodt ET, Eudicone JM, Bell KF, Enhoffer DM, Latham K, Green JB. Eligibility varies among the 4 sodium-glucose cotransporter-2 inhibitor cardiovascular outcomes trials: implications for the general type 2 diabetes US population. Am J Manag Care. 2018 Apr;24(8 Suppl):S138-S145.
citation: Radholm K, Figtree G, Perkovic V, Solomon SD, Mahaffey KW, de Zeeuw D, Fulcher G, Barrett TD, Shaw W, Desai M, Matthews DR, Neal B. Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results From the CANVAS Program. Circulation. 2018 Jul 31;138(5):458-468. doi: 10.1161/CIRCULATIONAHA.118.034222.
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