CREDENCE

Published

Perkovic V, et al. "Canagliflozin and renal outcomes in diabetic nephropathy". The New England Journal of Medicine. 2019. 380(24):2295-2306.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

In patients with T2DM and diabetic nephropathy characterized by albuminuria (ACR >300-5000 mg/g) and reduced GFR (30-90 mL/min/1.73m2 BSA), does canagliflozin 100mg/d reduce the risk of end-stage kidney disease, doubling of serum creatinine from baseline, and death from renal or cardiovascular disease compared to placebo?

Bottom Line

Among patients with T2DM and diabetic nephropathy characterized by albuminuria and no more than a mild reduction in GFR, canagliflozin 100 mg/d reduces the risk of the composite end-point of end-stage kidney disease, doubling of serum creatinine from baseline, and death from renal or cardiovascular disease when compared to placebo (HR 0.70; 95% CI 0.59-0.82; p = 0.00001).

Between 22 to 25 patients would need to be treated for approximately 2.5 years in order to prevent one occurrence of the primary composite outcome.

Major Points

Initial management of type 2 diabetes consists of a combination of lifestyle modifications and metformin. SGLT2 inhibitors including canagliflozin have demonstrated reductions in HbA1c as well as improved cardiovascular mortality and morbidity in patients with type 2 diabetes and cardiovascular disease in CANVAS (2017). Whether SGLT2 inhibitors also improve kidney outcomes was limited to secondary analyses that were limited by small numbers of ESRD events.

Published in 2019, Canagliflozin and Renal Events in Diabetes and Nephropathy Clinical Evaluation (CREDENCE) randomized 4,401 patients with diabetes and albuminuria to canagliflozin 100 mg or placebo. The trial was halted at 2.6 years due to benefit with canagliflozin. The primary endpoint in this trial was mix of CVD and renal outcomes and there was a significant reduction in events with canagliflozin (43.2 vs. 61.2/1000 P-Y). Given the possibility for competing risk between CVD and renal endpoints, it was a reasonable approach to include CVD as an outcome. (I.e., had renal endpoints been the only outcome and more participants in the placebo group died from CVD and were therefore unable to develop renal outcomes, not including a CVD endpoint may have led canagliflozin to falsely appear to worsen renal function.) Importantly, there appeared to be reductions in several clinically-meaningful renal endpoints with canagliflozin, including doubling of creatinine (20.7 vs. 33.8/1000 P-Y) and ESRD (20.4 vs. 29.4/1000 P-Y).

SGLT2 inhibitors promote glucosuria and may lead to complications related to this mechanism of action. Recent reports have found an increased incidence of fatal genitourinary tract infections with SGLT2 inhibitors including Fournier’s gangrene. The study did not directly report mortality due to infection though it did demonstrate an increased incidence of genital mycotic infections particularly in males (8.4 vs. 0.9/1000 P-Y) and possibly females (12.6 vs. 6.1/1000 P-Y).

Overall, CREDENCE adds to the growing literature that SGLT2 inhibitors may prevent against diabetes-associated outcomes.

Guidelines

As of August 2019, no guidelines have been published that reflect the results of this trial.

Design

• Prospective, double-blind, randomized controlled trial
• N=4,401 patients with diabetes and albuminuria
  • Canagliflozin (n=2,202)
  • Placebo (n=2,199)
• Setting: 690 sites in 34 countries
• Enrollment: 2014-2017
• Median follow-up: 2.6 years
• Analysis: Intention-to-treat
• Primary outcome: ESRD, doubling of serum creatinine, renal mortality, or cardiovascular mortality

Population

Inclusion Criteria

• Age ≥30 years old with T2DM
• HbA1c 6.5-12.0% (6.5-10.5% in Germany)
• eGFR 30-89 mL/min/1.73 m²
• Urinary albumin:creatinine 300-5000 (mg/g)
• On an ACEi/ARB at the maximum labeled dose or a dose not associated with unacceptable side effect (at least 4 weeks before randomization). Dual therapy with ACEi/ARB OR MRA OR direct renin inhibitor was not allowed.

Exclusion Criteria

• Type 1 diabetes
• Suspected non-diabetic kidney disease
• Dialysis
• Kidney transplantation

Baseline Characteristics

From the canagliflozin group

• Demographics: Age 63 years, female 35%; race or ethnic group: White 68%, Black 5%, Asian 19%, other 8%
• Baseline health data:
  • eGFR: 56 mL/min/1.73 m²
  • Median urinary albumin-to-creatinine ratio: 923
  • Body-mass index: 31
  • Current smoker: 16%
  • Duration of diabetes: 16 years
  • Blood pressure: 140/78 mmHg
  • HbA1c: 8.3%
• PMH: Hypertension 97%, HF 15%, CVD 50%, amputation 5%
• Baseline Drug Therapy: Insulin 66%, sulfonylurea 28%, biguanides 58%, GLP-1 receptor agonist 4%, DPP-4 inhibitor 17%, statin 70%, antithrombotic 61%, RAAS inhibitor >99.9%, beta blocker 40%, diuretic 47%

Interventions

• Randomized to a group:
  • Canagliflozin (100mg PO qday)
  • Placebo
• Rate of adherence at follow-up: 84%

Outcomes

Comparisons are canagliflozin vs. placebo. P-Y is person-years.

Primary Outcomes

ESKD, doubling of baseline serum creatinine, renal mortality, or cardiovascular mortality

Canagliflozin 100 mg/d 43.2 events/1000 P-Y vs. placebo 61.2/1000 events/1000 P-Y (HR 0.70, 95% CI 0.59-0.82; P=0.00001); Event-based NNT 22

Canagliflozin 100 mg/d (245/2202) 11% vs. placebo (340/2199) 15%: ARR 4%; Percent based NNT 25

Only the composite endpoint was considered the primary outcome. Components of the primary outcome are shown here for simplicity's sake.

Doubling of creatinine: 20.7 vs. 33.8 events/1000 P-Y (HR 0.60; 95% CI 0.48-0.76; P<0.001)

ESKD: 20.4 vs. 29.4 events/1000 P-Y (HR 0.68; 95% CI 0.54-0.86; P=0.002)

eGFR <15 ml/min/1.73 m²: 13.6 vs. 22.2 events/1000 P-Y (HR 0.60; 95% CI 0.45-0.80; P not given)

Dialysis or kidney transplant: 13.3 vs. 17.7 events/1000 P-Y (HR 0.74; 95% CI 0.55-1.00; P not given)

Renal mortality: 0.3 vs. 0.9 events/1000 P-Y (HR and P not given)

CVD mortality: 19.0 vs. 24.4 events/1000 P-Y (HR 0.78; 95% CI 0.61-1.00; P=0.05)

Secondary Outcomes

CV death or hospitalization for heart failure

31.5 vs. 45.4/1000 P-Y (HR 0.69; 95% CI 0.57–0.83; P<0.001)

CV death, MI or stroke

38.7 vs. 48.7/1000 P-Y (HR 0.80; 95% CI 0.67–0.95; P=0.01), NNT=40 (23-165)

HF hospitalization

15.7 vs. 25.3/1000 P-Y (HR 0.61; 95% CI 0.47–0.80; P<0.001)

ESRD, doubling baseline serum creatinine, or renal death

27.0 vs. 40.4/1000 P-Y (HR 0.66; 95% CI 0.53–0.81; P<0.001)

Death from any cause

29.0 vs. 35.0/1000 P-Y (HR 0.83; 95% CI 0.68–1.02; P not given)

CV death, MI, stroke, HF hospitalization, or unstable angina hospitalization

49.4 vs. 66.9/1000 P-Y (HR 0.74; 95% CI 0.63–0.86; P not given)

Exploratory Analysis

ESRD, renal death, or cardiovascular death

37.6 vs. 51.2/1000 P-Y (HR 0.73; 95% CI 0.61–0.87; P not given)

Dialysis, kidney transplantation, or renal death

13.6 vs. 18.6/1000 P-Y (HR 0.72; 95% CI 0.54–0.97; P not given)

Adverse Events

Any adverse event

351.4 vs. 379.3/1000 P-Y (HR 0.87; 95% CI 0.82–0.93; P not given)

Any serious adverse event

145.2 vs. 164.4/1000 P-Y (HR 0.87; 95% CI 0.79–0.97; P not given)

Serious adverse event related to trial drug

12.2 vs. 8.6/1000 P-Y (HR 1.45; 95% CI 0.98–2.14; P not given)

Amputation

12.3 vs. 11.2/1000 P-Y (HR 1.11; 95% CI 0.79–1.56; P not given)

Fracture

11.8 vs. 12.1/1000 P-Y (HR 0.98; 95% CI 0.70–1.37; P not given)

Genital mycotic infection

Males: 8.4 vs. 0.9/1000 P-Y (HR 9.30; 95% CI 2.83–30.60; P not given)

Females: 12.6 vs. 6.1/1000 P-Y (HR 2.10; 95% CI 1.00–4.45; P not given)

DKA

2.2 vs. 0.2/1000 P-Y (HR 10.80; 95% CI 1.39-83.65; P not given)

Criticisms

• Stopped early at planned interim analysis: risk of overestimation of effects
• Decrease of eGFR (~6) seen with the first weeks after initial therapy, though stabilized afterwards
• Statin use was not universal in this trial (~70%). Statins prevent CVD and may reduce progression of CKD.

Funding

Janssen Research & Development