Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Experimental setup.

<p>(<b>A</b>) Anatomical landmarks (i.e., sacrum, iliac crest, and spinous processes) for localization of the lumbar spine (L2–S1); (<b>B</b>) Lateral view of anatomical motion analysis markers (1-Lateral iliac crest, 2-Trochanter major, 3-Patella, 4-Lateral malleolus, 5-Fourth metatarsal); (<b>C</b>) Pre-operative computed tomography: Lower thoracic vertebrae, lumbar vertebrae and sacrum; (<b>D</b>) Exposure of the lumbar spine; (<b>E</b>) Laminotomy at L5-left (circle) and epidural electrode (arrow); (<b>F</b>) Exposure of the spinal cord for intraspinal microstimulation; (<b>G</b>) Typical microelectrode implantation in the left hemicord (arrow). Insulating adhesive tape was used for protection of the electrode during forceps-insertion and color-coded to determine insertion depth (e.g., blue tape corresponded to an electrode depth of 6 mm). A reference ruler (centimeters) was used to determine cord dimensions and estimate electrode location.</p

Targeting analysis and functional outcomes.

<p>(<b>A</b>) Epidural electrode placement confirmed by lateral intra-operative fluoroscopy; (<b>B</b>) Posterior-anterior intra-operative fluoroscopy; (<b>C</b>) <i>Ex-vivo</i> axial MRI of spinal cord showing ISMS electrode tract (arrow); (<b>D</b>) Experimental setup for kinematic analysis; (<b>E–F</b>) Typical hip extension evoked by ISMS at L5-segment; (<b>G</b>) Normalized intramuscular EMG amplitude as a function of spinal cord segment evoked by ISMS at 300 µA (n = 3); (<b>H</b>) Kinematic analysis of joint angle change evoked by ISMS as a function of spinal cord segment (n = 3). Abbreviations: G.M. = Gluteus medius, H = Hamstrings, B.F. = Biceps femoris, G = Gastrocnemius, Q.F. = quadriceps femoris.</p