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Evidence-Based Diabetes Management June 2019
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CREDENCE: First Renal Outcomes Trial Finds Canagliflozin Cuts Risk of Renal Failure, Death; Prompts ADA Updates
Mary Caffrey
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CREDENCE: First Renal Outcomes Trial Finds Canagliflozin Cuts Risk of Renal Failure, Death; Prompts ADA Updates

Mary Caffrey
Presentations at 2 major scientific conferences showed that the SGLT2 inhibitor cut the risk of renal failure or death by 30% and had renal benefits for patients with and without previous cardiovascular disease.
CREDENCE, the first of a coming wave of dedicated renal outcomes trials for sodium glucose cotransporter 2 (SGLT2) inhibitors, has reported 2 sets of results that

suggest there is more news to come for the drug class that has already changed diabetes care since reaching the market in 2013.1

Investigators for CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), reported on April 14, 2019, that canagliflozin cut the risk of renal failure or death by 30% in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD).2 These results, unveiled at the International Society of Nephrology 2019 World Congress of Nephrology in Melbourne, Australia, were simultaneously reported in the New England Journal of Medicine.2

Canagliflozin is sold as Invokana by Janssen Pharmaceutical Companies of Johnson and Johnson.

The findings prompted the American Diabetes Association (ADA) to update its Standards of Medical Care in Diabetes on June 3, 2019,3 in 2 chapters that deal with cardiovascular (CV) disease and risk management4 and microvascular complications and foot care.5

Then, on June 11, 2019, during the Scientific Sessions in San Francisco, California, CREDENCE coprincipal investigator Kenneth Mahaffey, MD, of Stanford University Medical Center, shared additional data on what the results mean for primary and secondary prevention—namely, how well canagliflozin prevented renal decline in individuals with T2D who had been diagnosed with CV disease or had experienced an event (secondary prevention) as well as those who had neither (primary prevention).6

After a series of CV outcomes trials (CVOTS) showed a class effect for CV benefits for SGLT2 inhibitors,7-9 there was plenty of interest at the 79th Scientific Sessions not only for CREDENCE, but also for secondary findings on renal outcomes from the CVOTS for rival drugs. Other manufacturers have their own dedicated renal outcomes trials in process: AstraZeneca has Dapa-CKD for dapagliflozin (Farxiga),10 due to report in November 2020, and Boehringer Ingelheim and Eli Lilly have sponsored EMPA-KIDNEY for empagliflozin (Jardiance), due to report in June 2022.11 Various dedicated trials exploring the therapeutic value of SGLT2 inhibitors

in heart failure for patients with and without diabetes are also under way.12

SGLT2 inhibitors lower blood glucose by targeting a protein that affects reuptake of glucose by the kidneys back into the bloodstream. Patients who take these drugs excrete glucose out of the body through the urine, and this unique system for discharging extra blood glucose accounts for the drugs’ protective effects on the renal system. As described by Christoph Wanner, MD, in a 2017 article, “The potential mechanisms responsible are likely multifactorial, and direct renovascular and hemodynamic effects are postulated to play a central role.”13 

Although an early completion date of CREDENCE had suggested positive results,14 the magnitude of the benefit surprised some. While moderating a press briefing at the 79th Scientific Sessions, Robert H. Eckel, MD, of the University of Colorado, exclaimed, “CREDENCE—that just knocks your socks off, doesn’t it?”

Initial Findings Show No Amputation Risk 

Phase 3 results reported in Melbourne show that CREDENCE easily achieved its primary end point; 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 CV death.2 This was not unexpected, given the June 2018 announcement that the trial was ending early after independent evaluators determined the primary end point had been met.14

CREDENCE did not show the elevated risk of lower extremity amputation seen in CANVAS,8 the CVOT for canagliflozin that caused the FDA to issue a boxed warning, even though the same trial found benefits that led to an indication for lower risk of CV events.15 When 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 the FDA, “to reflect these safety findings in the Invokana label.”

Janssen is seeking an additional indication for canagliflozin, based on the CREDENCE findings.16

CREDENCE was a double-blind trial that randomized 4401 patients with a median 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 included2:

• The relative risk (RR) of the primary outcome was 30% lower for those taking 100 mg of canagliflozin compared with placebo; event 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 end point—excluding CV death—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 end points, the risks 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, 0.47-0.80; P <.001) was lower among those taking canagliflozin. The authors wrote that these measures may have been limited when the trial ended early, but 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, 0.79-1.56) and in adjudicated fractures, the HR was 0.98 (95% CI, 0.70-1.37). 

Lower limb amputation rates were 12.3 for canagliflozin versus 11.2 for placebo per 1000 patient-years. There has been much speculation about 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.”2

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.17

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 familar 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.18 With T2D being the top cause of kidney failure, a treatment to prevent patients with T2D from needing dialysis or transplant would potentially save millions of dollars for Medicare. A 2018 report from the US Renal Data System (USRDS) found that 1% of the patients in Medicare have ESRD, but they account for 7% of Medicare fee-for-service costs.19

When the first CVOT, 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 that accompanied publication of the study.20 EMPA-REG OUTCOME 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. 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.21 Ingelfinger and Rosen wrote that, although several T2D medications show benefits beyond lowering blood glucose, “the SGLT2 inhibitors appear to be the most promising.”20

CREDENCE shows that canagliflozin has the 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 individuals in the United States. The USRDS estimates the cost of a year of dialysis at $89,000 per patient19, and, as Ingelfinger and Rosen wrote, the ranks in need of dialysis and kidney transplants are growing due to rising levels of obesity.20 They noted that the investigators estimate that among

1000 patients treated over 2.5 years,21 would need to be treated with canagliflozin to avoid dialysis or transplant, doubling the serum creatinine level, or renal or CV death.2 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.22

However, the CREDENCE investigators 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.

Evidence in Both Primary, Secondary Prevention

 
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