Heterosexually active and practicing highly effective method of birth control.Surgically sterile (have had hysterectomy or bilateral oophorectomy, tubal ligation) or incapable of pregnancy.Age ≥ years with 2+ following risk factors at screening: duration of T2DM ≥10 years, SBP>140 mmHg, while on ≥1 BP-lowering Tx, current daily cigarette smoker, documented microalbuminuria or macroalbuminuria, or documented HDL 45 years with amenorrhea ≥18 mos, or >45 years with amenorrhea ≥6 mos and less than 18 mos and FSH>40 IU/ml, or.Age ≥30 yrs with documented symptomatic atherosclerotic CV disease: including stroke MI hospitalization for UA CABG PCI peripheral revascularization symptomatic with documented hemodynamically-significant carotid or peripheral vascular disease or amputation secondary to vascular disease.History or high risk of CV disease defined on basis of either:.Not currently on antihyperglycemic agent therapy or on antihyperglycemic monotherapy or combination therapy with approved class of agents: e.g., sulfonylurea, metformin, PPAR-gamma agonist, alpha-glucosidase inhibitor, GLP-1 analog, DPP-4 inhibitor, or insulin.T2DM with HbA1c ≥7.0% to ≤10.5% at screening.Primary outcome: CV mortality, nonfatal MI, or nonfatal stroke.Median follow-up: 126 weeks mean follow-up: 188 weeks.Setting: 667 centers in 30 countries involved in two trials.Canagliflozin 100mg then 300mg daily vs.
OPEN CANVAS 6 TRIAL TRIAL
Two multicenter, randomized, double-blind, placebo-controlled trial.Of note, the 2019 CREDENCE trial evaluated renal outcomes with SGL2 inhibitors.Īs of August 2017, no guidelines have been published that reflect the results of this trial. Given that multiple previous clinical trials ( ACCORD 2008, ADVANCE 2008, VADT 2009) did not demonstrate a reduction in major adverse CV events with intensive glucose-lowering therapy, it remains unclear what mechanisms drive the CV benefits seen with empagliflozin and canagliflozin. Interestingly, the HbA1c reduction with empagliflozin and canagliflozin was modest at best (0.5% and 0.58%, respectively). patient-years HR 1.97 95% CI, 1.41 to 2.75), primarily of the toe or metatarsal. However, canagliflozin was associated with a significant doubling in the risk of amputations (6.3 vs. As with empagliflozin, there was a greater incidence of genital infections. 31.5 per 1,000 patient-years HR 0.86 95% CI 0.75-0.97) with a possible benefit with respect to the progression of albuminuria (HR 0.73 95% CI 0.67-0.79), the composite outcome of reduction in GFR, need for renal-replacement therapy or death from renal causes (HR 0.60 95% CI 0.47-0.77), and hospitalization for heart failure (HR 0.67 95% CI, 0.52-0.87). At mean follow-up of 188 weeks, canagliflozin was associated with a reduction in death from CV causes, nonfatal MI, or nonfatal stroke (26.9 vs. The CANVAS patients were randomized 1:1:1 to canagliflozin 100 mg/d or 300 mg/d or placebo, and the CANVAS-R patients were randomized to receive canagliflozin at an initial dose of 100 mg/d with an option to increase to 300 mg/d at week 13 or matching placebo.
The multicenter Canagliflozin Cardiovascular Assessment Study (CANVAS) program is comprised of data from two sister trials involving a total of 10,142 patients with T2DM at high risk of CV complications. The thiazolidinedione pioglitazone in PROactive (2005) and the DDP4 inhibitors alogliptin in EXAMINE (2013) and saxagliptin in SAVOR-TIMI 53 (2013) and TECOS (2015) have all failed to demonstrate cardiovascular benefits or improved survival in this patient population. While standard medications such as insulin, sulphonylureas, and DPP4 inhibitors all effectively reduce blood glucose, these agents have not been associated with improvements in a cardiovascular disease or survival. Mortality in T2DM is mainly related to an increased incidence of CV disease. Among patients with T2DM at high risk for CV events, does daily canagliflozin reduce CV mortality, nonfatal MI, or nonfatal strokes when compared to placebo?Īmong patients with T2DM at high risk for CV events, canagliflozin had a lower risk of cardiovascular events and reduced the rate of renal decline and heart failure hospitalization compared to those who received placebo but a greater risk of amputation.
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