1. Canagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, significantly reduced the risk of the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke in patients with type 2 diabetes when compared to placebo.
2. Patients treated with canagliflozin experienced significantly higher rates of amputation, fracture, and genitourinary infections compared to those treated with placebo.
Evidence Rating Level: 1 (Excellent)
Study Rundown: SGLT2 inhibitors are a newer class of medication that has been developed for managing type 2 diabetes. They inhibit the SGLT2 protein located in the kidneys and reduce glucose reabsorption from the renal tubules, thereby increasing urinary glucose excretion. The idea of SGLT inhibition has been around for a long time. Phlorizin, the first SGLT inhibitor discovered, was isolated over 150 years ago from the root bark of apple trees and there is documentation of its use in humans as far back as 1933. Phlorizin derivates were subsequently developed with greater specificity to SGLT2, and several such drugs have been approved for diabetes management in the past few years. Canagliflozin, dapagliflozin, and empagliflozin are the SGLT2 inhibitors that have been approved by the U.S. Food and Drug Administration (FDA) for clinical use.
Two years ago, a large randomized trial demonstrated that empagliflozin therapy significantly reduced the risk of cardiovascular events and mortality in patients with type 2 diabetes when compared with placebo. The Canagliflozin Cardiovascular Assessment Study (CANVAS) sought to determine the effects of canagliflozin on cardiovascular outcomes. In summary, the trial found that canagliflozin treatment significantly reduced the risk of the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke in diabetic patients when compared to placebo. There were no significant differences between the two groups in the rates of the individual components of the primary outcome. Those treated with canagliflozin, however, experienced significantly higher rates of amputation, fracture, and genitourinary infection.
In-Depth [randomized controlled trial]: This trial was conducted at 667 sites in 30 countries and was led by an academic steering committee, in conjunction with Janssen Pharmaceuticals, and George Clinical. Patients were included in the trial if they had type 2 diabetes with HbA1c ≥7.0% and ≤10.5%, and were either ≥30 years of age with symptomatic atherosclerotic cardiovascular disease or ≥50 years of age with 2 or more cardiovascular risk factors (i.e., diabetes >10 years, systolic blood pressure (sBP) >140 mmHg on antihypertensives, current smoker, micro- or macroalbuminuria, HDL <1 mmol/L). Exclusion criteria included history of DKA or type 1 diabetes, fasting glucose >15 mmol/L at baseline, ≥1 severe hypoglycemic episode, and impaired renal function (estimated glomerular filtration rate <30 mL/min/1.73 m2). Patients were enrolled into either the CANVAS arm or the CANVAS-Renal arm. In the CANVAS arm, patients were randomized in 1:1:1 ratio to canagliflozin 300 mg daily, canagliflozin 100 mg daily, or placebo. In the CANVAS-Renal arm, patients were randomized 1:1 to canagliflozin 100 mg daily (with the option to increase to 300 mg at week 13) or placebo. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Sequential hypothesis testing was performed, as non-inferiority testing with a hazard ratio margin of 1.3 was performed first, and superiority testing was completed afterwards.
A total of 10 142 participants took part in the trial, and drug discontinuation rates were similar in the canagliflozin (29.2%) and placebo (29.9%) groups. Median follow-up was about 126.1 weeks. Of note, approximately 65.6% of patients had a known history of cardiovascular disease. Patients taking canagliflozin experienced significant reductions in their HbA1c (-0.58%, 95%CI -0.61 to -0.56%), body weight (-1.6 kg, 95%CI -1.70 to -1.51 kg), sBP (-3.93 mmHg, 95%CI -4.30 to -3.56 mmHg) and diastolic BP (-1.39 mmHg, 95%CI -1.61 to -1.17 mmHg).
Patients in the canagliflozin group experienced significantly lower rates of the primary composite outcome, compared to those taking placebo (HR 0.86, 95%CI 0.75-0.97, p < 0.001 for non-inferiority, p = 0.02 for superiority). There were no differences between the groups in rates of the individual components of the primary outcome – cardiovascular death (HR 0.87, 95%CI 0.72-1.06), nonfatal myocardial infarction (HR 0.85, 95%CI 0.69-1.05), and nonfatal stroke (HR 0.90, 95%CI 0.71-1.15). There were no differences between the two groups in the rates of diabetic ketoacidosis (p = 0.14). Patients taking canagliflozin were at significantly higher risk of amputation (6.3% vs. 3.4%, p < 0.001), fracture (15.4% vs. 11.9%, p = 0.02), and genitourinary infections (p < 0.001).