Introduction: Canagliflozin lowers the renal threshold for glucose and increases urinary glucose excretion (UGE), resulting in decreased plasma glucose in patients with hyperglycemia. Because the rate of UGE is proportional to the glomerular filtration rate (which is diminished in patients with renal impairment), this study was designed to investigate whether canagliflozin is effective and safe in augmenting UGE in subjects with chronic kidney disease.
Methods: The phase 3 trial involved 269 patients with type 2 diabetes and stage 3 chronic kidney disease who were randomized to 100 mg or 300 mg canagliflozin or placebo daily for 26 weeks. The patients had inadequate glycemic control despite use of previous antihyperglycemic agents, in some patients. They also had stage 3 chronic kidney disease and generally stable renal function. The primary outcome was change in hemoglobin A1C from baseline.
Results: Both the 100-mg and 300-mg canagliflozin doses were associated with significantly greater decreases in A1C compared with placebo (-0.33%, -0.44%, and -0.03%; P<0.05). Both doses also were linked to a greater proportion of patients achieving an A1C <7.0% (27.3%, 32.6%, and 17.2%) and a greater reduction in fasting plasma glucose level (-0.83, -0.65, and 0.03 mmol/L); measures of statistical significance were not performed for these comparisons because of multiplicity control. Body weight and blood pressure also were reduced in the canagliflozin groups compared with the placebo group.
The groups had a similar rate of adverse events (74.2%-78.9%) and the 300-mg canagliflozin group was linked to slightly higher rates of urinary tract infections and adverse events related to osmotic diuresis and reduced intravascular volume compared with the other groups. Both canagliflozin groups showed transient changes in renal function parameters that improved over the course of the study.
Conclusion: As expected, the efficacy of canagliflozin in this population of patients with chronic kidney disease was less than that found in patients with normal or only mildly impaired renal function. Nevertheless, this agent was significantly effective and generally well tolerated, offering a therapeutic option to a population with limited treatment options.
Commentary by J. Michael Gonzalez-Campoy MD, PhD, FACE
Chronic kidney disease (CKD) with loss of renal function affects a substantial number of people in the United States, and is classified into 5 stages corresponding to progressive disease. The 2001-2008 NHANES survey documented that 26% of the American population has stage 3 chronic kidney disease. For patients with CKD stages 3-5, the 1-year mortality for heart attack is 51%, compared to 36% in patients without CKD.
Diabetes remains the leading cause of CKD in the United States and in other developed countries. The diagnosis of diabetic kidney disease in clinical practice is made by documentation of albuminuria and progressively lower glomerular filtration rates (GFR). Unfortunately, many people with prediabetes and diabetes are not even aware that they have these conditions, which leads to kidney damage before the diagnosis of diabetes. Therefore, screening for diabetic kidney disease should begin 5 years after the diagnosis of type 1 diabetes, and at the time of diagnosis for type 2 diabetes.
Yale and colleagues studied the safety and efficacy of 2 doses of canagliflozin in patients with diabetes and CKD, stage 3 (estimate GFR, 30-50 mL/min/1.73 m2). In this patient population, canagliflozin effectively lowered the level of glycemia over 26 weeks, while achieving adverse event rates similar to placebo. Because of the osmotic diuresis produced by canagliflozin, transient drops in kidney function were seen. By week 26, these changes had trended to baseline.
Although not studied in CKD stages 4 or 5, canagliflozin is effective and safe to use at both the 100 mg and 300 mg doses in patients who have up to CKD stage 3. Of note, current labeling recommends that the 100 mg dose be used for patients with CKD. This labeling is due to the observation in this study that reduced intravascular volume from osmotic diuresis led to hypovolemic adverse events in patients with stage 3 CKD.