CREDENCE - canagliflozin and renal outcomes in type 2 diabetes (diabetic) and nephropathy

Last edited 04/2019 and last reviewed 06/2023

CREDENCE - Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

• description of study
  • double-blind, randomized trial
    • 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
    • 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 and premature termination of study

• 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
  • 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)
  • 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)
    • most significant effect seen in 45 to <60 ml/min/1.73 m2
      • 33.4 versus 63.1 events per 1000 patient-years respectively for canagliflozin group and placebo (hazard ratio 0.52 (0.38-0.72))
  • 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)
  • were no significant differences in rates of amputation or fracture

Study authors concluded that 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.

A review of this study (2) noted possible mechanism for improved outcomes with SGLT2 versus placebo seen in this study:

• underlying mechanisms of canagliflozin activity probably both renal and systemic
  • SGLT2 inhibition increases glucose and sodium delivery to the distal renal tubule, which is sensed by the juxtaglomerular apparatus as increased glomerular perfusion
  • consequent increased vasoconstriction of the afferent arteriole, which decreases glomerular perfusion and intraglomerular pressure - note that these effects decrease the estimated GFR in the short term - as seen in first weeks of the CREDENCE trial - however over time effect stabilizes
  • level of angiotensin II in the circulation decreases, as does the level of atrial natriuretic peptide, with a subsequent decrease in inflammation and an increase in intrarenal oxygenation
  • decreased body weight and sympathetic output, decreased uric acid, and perhaps an increase in glucagon may also contribute

The study authors estimated projected effects (1)

• on the basis of our trial data, estimated that among 1000 patients in trial treated for 2.5 years
  • the primary composite outcome of endstage kidney disease, doubling of the serum creatinine level, or renal or cardiovascular death would occur in
    • 47 fewer patients in the canagliflozin group than in the placebo group (number needed to treat [NNT], 22; 95% CI, 15 to 38)
      • including 36 fewer composite renal outcomes of end-stage kidney disease, doubling of the serum creatinine level, or renal death (NNT, 28; 95% CI, 19 to 54) and
      • 24 fewer end-stage kidney disease events (NNT, 43; 95% CI, 26 to 121)
  • canagliflozin treatment would also prevent 22 hospitalizations for heart failure (NNT, 46; 95% CI, 29 to 124) and 25 composite events of cardiovascular death, myocardial infarction, or stroke (NNT, 40; 95% CI, 23 to 165).

Commentary:

"This is a significant addition to the evidence base in the treatment of renal disease in type 2 diabetes. All the patients had included in the study had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria. The study results showed a number needed to treat of 22 to prevent an episode of the primary composite outcome of endstage kidney disease, doubling of the serum creatinine level, or renal or cardiovascular death in comparison of those treated with canagliflozin 100mg per day versus placebo for 2.5 years.

Could this improvement be related to improved glycaemic control in the canagliflozin arm? There has been no definititive evidence of a glucose-lowering medication being, in effect, renoprotective previously. Also HbA1c average difference between the two groups was 0.25% lower in the canagliflozin arm over the trial period - and so the mechanism of effect is not glucose lowering. The efficacy of SGLT2 inhibitors is reduced as a glucose lowering medication with reducing eGFR; but it is probably the renal and systemic effects of the sodium delivery to the distal renal tubule that is the contributor to the renoprotective effect seen in the canagliflozin arm.

There are questions from this study. Would a 300mg dose have had a greater renoprotective effect? If there is evidence of CKD in a type 2 diabetic on canagiflozin - especially in the eGFR range of < 60 to 45 ml per minute where the evidence of effect of canagliflozin in this study was most pronounced - should we be continuing canagiflozin but at a 100mg dose? Also why is the effect of canagliflozin in this study most pronounced in the 45 to <60 ml per minute range? What about the use of SGLT inhibitors in non-diabetic renal disease? - studies are underway to answer this question and may increase the scope of use of SGLT inhbitors again.

In conclusion, this is indeed an important study, revealing an SGLT2 inhibitor (canagliflozin) having a renoprotective effect in patients with diabetic renal disease." Dr Jim McMorran, Editor in Chief GPnotebook (April 20th 2019)

Reference:

• Perkovic V et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy.N Engl J Med. 2019 Apr 14. doi: 10.1056/NEJMoa1811744
• Ingelfinger JR, Rosen CJ. Clinical Credence - SGLT2 Inhibitors, Diabetes, and Chronic Kidney Disease. N Engl J Med. 2019 Apr 14. doi: 10.1056/NEJMe1904740.