Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)—A randomized placebo-controlled trial

Neal, Bruce; Perkovic, Vlado; Zeeuw, Dick de; Mahaffey, Kenneth W.; Fulcher, Greg; Stein, Peter; Desai, Mehul; Shaw, Wayne; Jiang, Joel; Vercruysse, Frank; Meininger, Gary; Matthews, David R.

doi:10.1016/j.ahj.2013.05.007

Cited by 301 publications

(252 citation statements)

References 12 publications

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“…62% (95% CI 20.69, 20.54; 26.8 mmol/mol [95% CI 27.5,25.9]; P < 0.001) and 20. 73% (95% CI 20.81, 20.65; 28.0 mmol/mol [95% CI 28.9,27.1]; P < 0.001) at 18 weeks and 20. 58% (95% CI 20.68, 20.48; 26.3 mmol/mol [95% CI 27.4, 25.2]) and 20.73% (95% CI 20.…”

Section: Resultsmentioning

confidence: 99%

Efficacy and Safety of Canagliflozin, an Inhibitor of Sodium–Glucose Cotransporter 2, When Used in Conjunction With Insulin Therapy in Patients With Type 2 Diabetes

et al. 2014

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OBJECTIVEThere are limited data about the effects of sodium-glucose cotransporter 2 inhibitors when used with insulin. We report the efficacy and safety of canagliflozin in patients with type 2 diabetes using insulin. RESEARCH DESIGN AND METHODSThe CANagliflozin CardioVascular Assessment Study is a double-blind, placebocontrolled study that randomized participants to placebo, canagliflozin 100 mg, or canagliflozin 300 mg once daily, added to a range of therapies. The primary end point of this substudy was the change in HbA 1c from baseline at 18 weeks among patients using insulin; 52-week effects were also examined. RESULTSIndividuals receiving insulin at baseline were randomized to receive placebo (n 5 690), canagliflozin 100 mg (n 5 692), or canagliflozin 300 mg (n 5 690). These individuals were 66% male and had a median age of 63 years, mean HbA 1c of 8.3% (67 mmol/mol), BMI of 33.1 kg/m 2 , estimated glomerular filtration rate of 75 mL/min/1.73 m 2 , fasting plasma glucose of 9.2 mmol/L, and a median daily insulin dose of 60 IU. Most individuals were using basal/bolus insulin. Reductions in HbA 1c with canagliflozin 100 and 300 mg versus placebo were 20. 62% (95% CI 20.69, 20.54; 26.8 mmol/mol [95% CI 27.5,25.9]; P < 0.001) and 20. 73% (95% CI 20.81, 20.65; 28.0 mmol/mol [95% CI 28.9,27.1]; P < 0.001) at 18 weeks and 20. 58% (95% CI 20.68, 20.48; 26.3 mmol/mol [95% CI 27.4, 25.2]) and 20.73% (95% CI 20. 83, 20.63; 28.0 mmol/mol [95% CI 29.1,26.9]) at 52 weeks. There were significant falls in fasting plasma glucose, body weight, and blood pressure at both time points and there was a greater incidence of hypoglycemia, genital mycotic infections, and hypovolemia with both canagliflozin doses. CONCLUSIONSCanagliflozin added to insulin therapy improved glycemic control and decreased body weight. There was a greater frequency of several anticipated side effects, although few led to discontinuation of treatment.

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Section: Resultsmentioning

confidence: 99%

Efficacy and Safety of Canagliflozin, an Inhibitor of Sodium–Glucose Cotransporter 2, When Used in Conjunction With Insulin Therapy in Patients With Type 2 Diabetes

et al. 2014

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“…Effects on macrovascular disease are also unknown; cardiovascular safety trials are currently in progress (22).…”

Section: Sodium-glucose Cotransporter 2 Inhibitorsmentioning

confidence: 99%

Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes

et al. 2014

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“…Of note, there is a numerical excess of bone fractures in some studies with canagliflozin and dapagliflozin (45,46). A more definitive answer to the deleterious effects of SGLT2 inhibitors on bone should become available from the results of the large cardiovascular outcome trials currently in progress (58)(59)(60).…”

Section: Skeletal Effectsmentioning

confidence: 99%

Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport

et al. 2015

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Type 2 diabetes is a chronic disease with disabling micro-and macrovascular complications that lead to excessive morbidity and premature mortality. It affects hundreds of millions of people and imposes an undue economic burden on populations across the world. Although insulin resistance and insulin secretory defects play a major role in the pathogenesis of hyperglycemia, several other metabolic defects contribute to the initiation/worsening of the diabetic state. Prominent among these is increased renal glucose reabsorption, which is maladaptive in patients with diabetes. Instead of an increase in renal glucose excretion, which could ameliorate hyperglycemia, there is an increase in renal glucose reabsorption, which helps sustain hyperglycemia in patients with diabetes. The sodium-glucose cotransporter (SGLT) 2 inhibitors are novel antidiabetes agents that inhibit renal glucose reabsorption and promote glucosuria, thereby leading to reductions in plasma glucose concentrations. In this article, we review the long journey from the discovery of the glucosuric agent phlorizin in the bark of the apple tree through the animal and human studies that led to the development of the current generation of SGLT2 inhibitors.It took nearly 200 years from the isolation of phlorizin, a chemical found in apple tree bark that inhibits sodium-glucose cotransporters (SGLTs) (1), to the approval of the first medications inhibiting SGLTs for treatment of type 2 diabetes (T2D). During this time, several SGLTs were discovered and the roles of SGLT1 and SGLT2 in intestinal and renal glucose reabsorption have been elucidated in studies in genetically manipulated rodents, humans with SGLT gene mutations, healthy humans, and humans with diabetes (Fig. 1). This review provides an overview of the basic and clinical research that led to the translation of the initial findings of increased glucosuria with phlorizin to the development and approval of SGLT inhibitors and a summary of the clinical trial results obtained to date. Identification, Distribution, and In Vitro Characterization of the SGLT InhibitorsIn the 1980s and 1990s, Wright and colleagues cloned SGLT1 (2) and SGLT2 (2,3) and did much of the in vitro characterization, demonstrating that SGLT1 has a higher affinity for glucose than SGLT2 (K m for glucose ;0.4 mmol/L and 2 mmol/L, respectively), whereas SGLT2 has a higher capacity (4). SGLT1 is expressed at high levels in the intestine and is also expressed in the kidney, heart, and skeletal muscle, whereas SGLT2 is expressed almost exclusively in the kidney (4). Renal SGLT2 expression is increased in hyperglycemic rodents (5,6) and in humans with T2D (7). Intestinal SGLT1 expression is regulated by diet and other factors (8) and is

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Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)—A randomized placebo-controlled trial

Cited by 301 publications

References 12 publications

Efficacy and Safety of Canagliflozin, an Inhibitor of Sodium–Glucose Cotransporter 2, When Used in Conjunction With Insulin Therapy in Patients With Type 2 Diabetes

Efficacy and Safety of Canagliflozin, an Inhibitor of Sodium–Glucose Cotransporter 2, When Used in Conjunction With Insulin Therapy in Patients With Type 2 Diabetes

Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes

Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport

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