CREDENCE: Canagliflozin Cuts Risk of Renal Failure, Death 30% in Patients With Type 2 Diabetes, CKD

Canagliflozin, sold as Invokana by Janssen, cut the risk of renal failure or death by 30% in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) in a landmark trial. It is the first of several renal outcomes studies in a therapeutic class that has already changed diabetes care—and may continue to do so.

Results from the phase 3 CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), are being presented today in Melbourne, Australia, at the International Society of Nephrology 2019 World Congress of Nephrology. They show that canagliflozin, currently approved for T2D, easily achieved its primary endpoint; compared with placebo, canagliflozin reduced a composite of (1) the progression to end-stage renal disease (ESRD), defined as the need for chronic dialysis or renal transplant; (2) doubling of serum creatinine; and (3) renal or cardiovascular (CV) death. This was not unexpected, given the July 2018 announcement that the trial was ending early after independent evaluators determined the primary endpoint had been met.

Amputation Risk Not Seen in CREDENCE

What’s new is that CREDENCE did not show the elevated amputation risk seen in CANVAS, the cardiovascular outcomes trial for canagliflozin that caused FDA to issue a boxed warning, even though the same trial found benefits that led to an indication for lower risk of CV events. Asked if these results would prompt the drug maker to seek removal of the warning, Janssen officials said in an email that the new data are “reassuring” because they “show no imbalance” in either fractures or amputations between the canagliflozin or placebo arms; the company will be working with FDA, “to reflect these safety findings in the Invokana label.”

Janssen is seeking an additional indication for canagliflozin, based on the CREDENCE findings.

CREDENCE marks the first of a second wave of outcomes trials that promises to find additional benefits from sodium glucose co-transporter 2 (SGLT2) inhibitors, a group of glucose-lowering therapies with an entirely different mechanism from prior treatments for T2D. SGLT2 inhibitors work by targeting a protein that affects reuptake of glucose by the kidneys back into the bloodstream. Patients who take the drug excrete glucose out of the body through the urine. Makers of the other 2 top-selling SGLT2 inhibitors, dapagliflozin (Farxiga), and empagliflozin (Jardiance), have renal outcomes trials under way. AstraZeneca’s DAPA-CKD for dapagliflozin is due to report in November 2020, and EMPA-KIDNEY for empagliflozin, from Eli Lilly and Boehringer Ingelheim, is due in June 2022.

The study¹ and an accompanying editorial² were simultaneously published in the New England Journal of Medicine. CREDENCE was a double-blind trial that randomized 4401 patients with an average follow-up of 2.62 years. Patients had a mean age of 63 years (± 9.2 years) and had lived with T2D for an average of 15.8 years (± 8.6 years). All patients had an estimated glomerular filtration rate (eGFR) of 30 to <90 ml per minute per 1.73 m² of body surface area and albuminuria. All were being treated with standard of care, renin-angiotensin system blockade.

Findings included:

• The relative risk (RR) of the primary outcome was 30% lower for those taking 100 mg of canagliflozin compared with placebo; events rates were 43.2 and 61.2 per 1000 patient-years (hazard ratio [HR] 0.70; 95% CI, 0.59- 0.82; P = .00001).
• The RR for the renal-specific elements of the primary endpoint—excluding CV death&mdash;was 34% lower for those taking canagliflozin (HR, 0.66; 95% CI, 0.53-0.81; P<.001).
• The RR of ESRD was 32% lower for those taking canagliflozin (HR 0.68; 95% CI, 0.54-0.86; P = .002).
• Among secondary endpoints, those taking canagliflozin also had lower risk of CV death, myocardial infarction, or stroke (HR, 0.80; 95% CI, 0.67-0.95; P = .01), and for hospitalization for heart failure (HR, 0.61; 95% CI, 0.47 to 0.80; P <.001). While the authors wrote these measures may have been limited when the trial ended early, they were consistent with other randomized controlled trials and real-world studies in SGLT2 inhibitors.
• No significant differences were seen in rates of amputations or fractures. In amputation, the HR was 1.11 (95% CI: 0.79 to 1.56) and in adjudicated fractures, the HR was 0.98 (95% CI: 0.70 to 1.37). Lower limb amputation rates were 12.3 for canagliflozin versus 11.2 for placebo per 1000 patient-years.

There has been much speculation whether the amputation findings in CANVAS were due to the makeup of the study population. Authors in CREDENCE wrote that the population in this trial was at high risk for CV events, and they discussed the disparity from the CANVAS findings.

“Whether the increased risk of lower limb amputation in the CANVAS Program was due to differing trial populations or protocols or to chance remains unclear,” they wrote. “The overall safety profile in our trial is otherwise consistent with the known adverse effects associated with canagliflozin.”

A Breakthrough With Potential Savings to the Health System

“Canagliflozin is the first medical breakthrough in nearly 20 years proven to slow the progression of chronic kidney disease in patients with diabetes at high risk of developing kidney failure,” the study’s lead author, Vlado Perkovic, MBBS, PhD, FASN, FRACP, said in a statement.

Perkovic, who is cochair of the CREDENCE Steering Committee and executive director of The George Institute for Global Health, Australia, said, “These impressive results from the CREDENCE study have significant clinical implications for preventing kidney failure and improving health for millions of people living with chronic kidney disease and type 2 diabetes.”

Researchers and physicians familiar with the CREDENCE trial have hinted as far back as the summer of 2017 that the renal outcomes suggested in CANVAS-R (the renal component of CANVAS) would be fully demonstrated in these results. With T2D being the top cause of kidney failure, a treatment to prevent T2D patients from needing dialysis or transplant would potentially save millions for Medicare. A 2018 report from the US Renal Data System (USRDS) finds that 1% of the patients in Medicare have ESRD, but they account for 7% of Medicare costs.

When the first CV outcomes trial, EMPA-REG OUTCOME, reported that empagliflozin reduced the risk of CV death in 2015, it “changed the landscape in diabetes management,” as Julie R. Ingelfinger, MD, and Clifford J. Rosen, MD, wrote in their editorial.² EMPA-REG and subsequent CVOTs showed that SGLT2 inhibitors reduced the risk of hospitalization for heart failure, suggesting that the drugs were not only beneficial to patients but could also reduce one of the high-cost items in healthcare, just as health systems were being graded on their ability to avoid repeat hospitalizations for this condition.

SGLT2 inhibitors have been shown to reduce hypertension and promote modest weight loss, and existing evidence showing prevention of renal decline last month prompted the American College of Cardiology and the American Heart Association to include the class, with glucagon-like peptide-1 receptor agonists, in an updated primary prevention guideline. Ingelfinger and Rosen wrote that while several T2D medications show benefits beyond lowering blood glucose, “the SGLT2 inhibitors appear to be the most promising.”

CREDENCE shows that canagliflozin has potential to achieve savings in an area of huge importance to policy makers. Few items tax the health system as much as ESRD, which affects 750,000 people in the United States. The USRDS estimates the cost of a year of dialysis at $89,000 per patient; as Ingelfinger and Rosen wrote, the ranks in need of dialysis and kidney transplants are growing due to rising levels of obesity. They noted that the investigators estimate that among 1000 people treated over 2.5 years, 21 would need be treated with canagliflozin to avoid dialysis or transplant, doubling the serum creatinine level, or renal or CV death.

Dialysis and kidney transplant care are so costly that patients with CKD who reach this stage automatically qualify for Medicare at any age; most Medicare Advantage plans do not accommodate these patients unless they have a special needs plan that handles ESRD.

However, researchers noted that they did not study patients who already had advanced CKD at baseline, or kidney disease believed to have been caused by conditions other than T2D.

References

1. Perkovic V, Jardine B, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy [published online April 14, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1811744.
2. Ingelfinger JR, Rosen CJ. Clinical credence—SGLT2 inhibitors, diabetes, and chronic kidney disease [published online April 14, 2019]. N Engl J Med.