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SGLT2 Inhibitors and Renal Outcomes: Review of the CREDENCE Trial

Caitlin Dohoney, PharmD Candidate 2020
Lourdes Cross, PharmD, BCACP, CDE
Scott Hayes, PharmD, BCPS

Sullivan University College of Pharmacy and Health Sciences and University of Louisville Hospital, Louisville, KY

Diabetic Kidney Disease

Diabetic kidney disease occurs in 20-40% of patients diagnosed with diabetes which increases risk of cardiovascular (CV) complications.¹ Diabetes causes decreased filtration area in the glomeruli, increased glomerular blood flow, increased glomerular capillary pressure, glomerular injury, and ultimately, progression of renal disease.² Per the American Diabetes Association (ADA) guidelines, an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) is the preferred first-line agent for blood pressure treatment among hypertensive patients with diabetes, eGFR <60 mL/min/1.73m², and urine albumin-to-creatinine ratio (UACR) ≥30 mg/g Cr because of their proven benefits for prevention of chronic kidney disease (CKD).¹ Although there are currently no antidiabetic medications FDA-approved for the prevention of CKD, previously completed SGLT2 inhibitors trials have shown a trend towards decreased progression of albuminuria in patients with type 2 diabetes. The ADA guidelines now support the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists that have been shown to reduce the risk of CKD progression, cardiovascular events, or both in patients where CKD predominates.

CREDENCE Design

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Trial was a randomized, placebo-controlled study that evaluated the ability of canagliflozin to provide renal protection in patients with type 2 diabetes and CKD (eGFR 30 to <90 mL/min/1.73m²and albuminuria). The primary outcome was a composite of end-stage kidney disease, doubling of the serum creatinine level from baseline sustained for at least 30 days, or death from renal or cardiovascular disease.³

All patients in the trial were required to have diabetes-related kidney disease and be stable on an ACE inhibitor or ARB for at least 4 weeks prior to randomization. Exclusion criteria included treatment with immunosuppressive agents, dialysis, or kidney transplantation. After randomization and stratification, patients received either canagliflozin 100 mg by mouth once daily or placebo.³

CREDENCE Results

The mean age of trial participants was 63 years. The mean eGFR was 56.2 mL/min/1.73m², median UACR was 927 mg/g Cr, and the mean A1C was 8.3%. Within the study participant population, 14.5% were current smokers, 96.8% had a diagnosis of hypertension, 14.8% had a diagnosis of heart failure, and 50.4% had a diagnosis of CV disease. Due to overwhelming benefit, the trial was stopped early after a pre-specified interim analysis. The median follow-up was 2.62 years and the canagliflozin rate of adherence was 84%. The primary composite outcome for canagliflozin vs. placebo was 43.2 versus 61.2 per 1000 patient-years (hazard ratio 0.70 [95% CI 0.59-0.82], P=0.00001) and the number needed to treat was 22. The study also showed significantly lower relative risk in the canagliflozin group for other renal and CV components including: end-stage kidney disease; doubling of serum creatinine; composite of CV death, myocardial infarction, or stroke; and hospitalization for heart failure. There was no significant difference in rates of adverse events between the groups, including lower-limb amputation, although rates of diabetic ketoacidosis were higher with canagliflozin versus placebo (2.2 vs. 0.2 per 1000 patient-years).³

Conclusions

The results of this trial indicate that canagliflozin is superior to placebo in preventing adverse renal events among patients with type 2 diabetes and established CKD. The trial design was important because it focused on outcomes in a patient population specifically at risk for kidney failure. The median follow-up of this trial was 2.62 years, so it is important for future research to evaluate the long-term effects of SGLT2 inhibitors. Additional trials plan to investigate the role of other SGLT2 inhibitors, including empagliflozin and dapagliflozin, in renal protection.⁴ SGLT2 inhibitors have already demonstrated A1C lowering and CV disease benefit, but this study adds to the body of evidence of positive outcomes associated with this drug class beyond current indications.

References

1. American Diabetes Association. Standards of medical care in diabetes - 2019. Diabetes Care. 2019; 42(Suppl 1):S1-S193.
2. In: Lexi-Drugs [online database]. Hudson, OH. Accessed 2019 May 15.
3. Kennedy M, Masharani U. Pancreatic Hormones & Antidiabetic Drugs. In: Katzung BG. Basic & Clinical Pharmacology, 14 e. New York, NY: McGraw-Hill.
4. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. Apr 2019.
5. Gov[online database]. Bethesda, MD: U.S. National Library of Medicine. Available at https://clinicaltrials.gov. Accessed 2019 May 20.