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. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).
|Family Medicine (FM)/General Practice (GP)|
|General Internal Medicine-Primary Care(US)|
This may be a ground-breaking study with immediate implications for managing a large sub-population of persons with Type 2 diabetes (e.g, those with moderate CKD and who are at high risk for CV complications).
This study shows that canagliflozin reduces bad kidney outcomes over 2-3 years of use. The outcome curves between treatment and placebo don't diverge for 12-18 months, which is clinically plausible. The amputation increase seen in a previous study did not materialize here, and they aren't sure why. The benefit is apparently independent of glucose control, and they aren't sure why.
It seems reasonably clear that this class of medications will help patients with diabetes in important patient-oriented outcomes. A few reservations: 1. The editorialists refer to "tight control" and their reference is UKPDS....from 1998 - a trial that compared diet with insulin or SU and certainly was not "tight control"; 2. I do not find any evidence that "tight control" reduces patient-oriented renal outcomes; 3. I am not thrilled about a composite outcome of "lots of stuff" being a primary outcome; 5. Although diabetes is a leading cause of renal failure, it is not conversely true that renal failure is a common outcome of diabetes - I believe the lifetime risk is about 1%.
The results are expected to be practice-changing.
The sodium wasting / volume depletion and lower BP can explain some of the results. The BP was not controlled in this study! The control group had a higher systolic BP.
A highly relevant RCT in the field of diabetic nephropathy for which there are few treatment options. In this study, canagliflozin reduced rates of primary outcome (end-stage kidney disease, doubling of the serum creatinine level, or renal or cardiovascular death) vs placebo by 30% in patients with diabetic nephropathy (eGFR > 30) and at least 300mg albuminuria. There was also a significant reduction in ESRD, primary renal outcome, and albuminuria. All patients were on maximally tolerated ARB/ACEI. The study was terminated prematurely after an interim analysis. No increased rates of amputation were seen as with another trial of canagliflozin, and no increase in AKI. This adds to burgeoning evidence that SGLT2 inhibitors should be a cornerstone of diabetes management. Patients on aldosterone blockade were excluded, and it is unclear whether this medication should be used in patients with both ACEI/ARB + aldosterone blockade.
Most studies previously focused on mortality and cardiovascular outcome. This study clearly shows benefit to decreasing proteinuria due to change in renal hemodynamics. With SGLT-2 inhibition, there is more sodium going to the macula densa leading to decreased tubuloglomerular feedback mechanism causing less vasodilatation of the afferent arteriole. When these patients are on ACE inhibitors, there is less vasoconstriction or more vasodilation in the afferent arteriole. So with both ACEi and SGLT-2 inhibition, there is less vasodilation of the afferent and more vasodilation of the afferent contributing to decreased glomerular hyperfiltration and decreasing proteinuria. From the Kaplan-Meir curve, it looks like a renal benefit starts after 12 months compared with placebo. African Americans (AAs) are very under-represented and pose the highest risk for CKD progression. There is also increased natriuresis and lowering of blood pressure with these drugs. Would need another study with AAs.