CREDENCE 'Knocks Your Socks Off'; New Analysis Reported at ADA

Marlene Busko

June 17, 2019

SAN FRANCISCO — In patients with type 2 diabetes and chronic kidney disease (CKD), the SGLT2 inhibitor canagliflozin (Invokana, Janssen) reduces the risk of cardiac and renal events — even in patients without prior cardiovascular disease (CVD) (primary prevention group).  

Researchers presented these latest findings from a deeper dive into the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) renal outcomes trial of canagliflozin in a press briefing and during a symposium at the recent American Diabetes Association (ADA) 2019 Scientific Sessions.

As reported by Medscape Medical News, the primary results from the "landmark" global phase 3 CREDENCE study were first presented in April at the International Society of Nephrology (ISN) 2019 World Congress and simultaneously published in the New England Journal of Medicine.

After a median follow-up of 2.5 years, the trial was stopped early because there was a 30% lower rate of the primary composite outcome — a doubling of serum creatinine, end-stage kidney disease (ESKD) (requiring dialysis or a kidney transplant), renal death, or cardiovascular (CV) death — in patients who received canagliflozin versus placebo added to standard care.  

This new analysis shows that in these patients with type 2 diabetes and CKD, canagliflozin provided "consistent and robust reductions in the risk of renal and CV outcomes in both primary and secondary prevention populations," Meg Jardine, MBBS, PhD, University of New South Wales, Sydney, Australia, summarized to the press at the ADA meeting.

"We were focused on" a population of patients at high risk of kidney disease progression, she told Medscape Medical News, adding that "this is the first study to show a benefit in" major outcomes in people with diabetes and CKD who have never had a prior CV event.  

Reassuring: No Increase in Amputations in CREDENCE

Canagliflozin is now the first new treatment option in 18 years for patients with type 2 diabetes who are at risk of worsening CKD. "We needed this," Jardine emphasized.

"We always start" patients with diabetes and CKD on an angiotensin receptor blocker (ARB) or angiotensin-converting enzyme (ACE) inhibitor, she explained, "but once that's done, there hasn't been anything more [to offer patients]. Now we've got something more."

And this latest analysis shows the drug can reduce CV and renal outcomes in people with type 2 diabetes and CKD, regardless of their previous history of CVD, she reiterated.

After the press briefing, moderator Robert H. Eckel, MD, University of Colorado Anschutz Medical Campus, told Medscape Medical News what he thinks of the trial.

"The power of the study is the fact that the lower dose of canagliflozin [100 mg instead of 300 mg] really had a pretty major impact on outcomes in the people with [moderately] advanced kidney disease," at least in terms of the "really incredibly relevant" combined composite outcome of renal and CVD events, and in the progression of renal disease, he noted.

It is also reassuring, he added, that there was no increase in amputations or bone fractures with canagliflozin compared with placebo, as an increased risk of these adverse events has been seen with the medication in other studies.  

In summary, "CREDENCE knocks your socks off," according to Eckel.  

Indeed, these CREDENCE findings mean that, in future, there may be a reduction in the estimated glomerular filtration rate (eGFR) cutpoint for the use of SGLT2 inhibitors.

Currently, they're not recommended for use in patients with an eGFR < 45 mL/min/1.73m². However, in CREDENCE, patients with the lowest eGFRs experienced the most benefit, as one expert explains in a viewpoint on Medscape Medical News.

Cardiac, Renal Events in Primary and Secondary Prevention

When CREDENCE was stopped, 4401 patients had been randomized who had type 2 diabetes and CKD and were receiving standard care — including the maximum tolerated daily dose of a renin-angiotensin system (RAS) inhibitor (ACE inhibitor or ARB) — to canagliflozin (100 mg/day) or placebo.

Patients were a mean age of 63 years and had had diabetes for about 16 years.

All participants had albuminuria (urine albumin-to-creatinine ratio [UACR], 300-5000 mg/g) and mild to moderate CKD (estimated glomerular filtration rate [eGFR], 30-90 mL/min/1.73m²).

About half (n = 2181) of patients had no prior coronary, cerebrovascular, or peripheral vascular disease (primary prevention group), and the remainder were deemed to be in the secondary prevention group, Kenneth Mahaffey, MD, Stanford University, California, co-principal investigator of CREDENCE, noted during the symposium at ADA.

Overall, 60% of patients had moderate CKD: 29% had an eGFR of 45 to < 60 mL/min/1.73 m2 (stage 3a, moderate CKD) and 31% had an eGFR of 30 to < 45 mL/min/1.73 m2 (stage 3b, moderate CKD). The remaining 40% had an eGFR of 60-90 mL/min/1.73 m2 (stage 2, mild CKD).

The new analysis examined the composite CV and renal outcome, a composite CV outcome and a composite renal outcome, in the primary and secondary prevention groups, respectively.

Compared with patients who received placebo, those who received canagliflozin had a similarly lower risk of the main study outcome — a composite of renal and CV events — if they were in the primary prevention group (a 31% lower risk; HR, 0.69) or secondary prevention group (a 30% lower risk; HR, 0.70).

Likewise, patients who received canagliflozin were less likely to have a CV event during follow-up, whether or not they had prior CVD.

In the primary prevention group, compared with patients who received placebo, those who received canagliflozin had a 32% lower risk of the composite three-point major adverse CV event (MACE) outcome of CV death, myocardial infarction, or stroke (HR, 0.68).

And in the secondary prevention group, compared with those who received placebo, those who received canagliflozin had a 15% lower risk of 3-point MACE (HR, 0.85).

In addition, canagliflozin was associated with a 26% relative risk reduction in the composite outcome of CV death or hospitalization for heart failure (HR, 0.74) in the primary prevention group and a 34% relative risk reduction of this outcome in the secondary prevention group (HR, 0.66).

Similarly, two key primarily renal outcomes — ESKD, renal death, or CV death; and dialysis, kidney transplant, or renal death — favored canagliflozin over placebo among both primary and secondary prevention patients.

"We are excited for our patients about the magnitude of the improvement in kidney and heart outcomes," said Mahaffey in an ADA press release. "The benefits were consistent in many different subgroups of patients, and this is the first treatment advance for patients with type 2 diabetes and chronic kidney disease in nearly two decades," he restated.

Canagliflozin Generally Well Tolerated in CREDENCE

"Despite the high risk of adverse events in this population, canagliflozin was generally well tolerated with no difference in the risk of acute kidney injury, hyperkalemia, fracture, or amputation observed with canagliflozin versus placebo," Jardine reported.

"What was really reassuring was we didn't see any excess in amputation or in fracture" with canagliflozin versus placebo, Jardine told Medscape Medical News.

"The amputation result was just about the same as [that seen with another SGLT2 inhibitor, dapagliflozin (Farxiga/Forxiga, AstraZeneca) in] DECLARE-TIMI. That's probably where the true effect is."

"The CANVAS program was an odd result [with regard to the signal for amputation] that I don't think anyone has been able to explain," she added.  

Clinical Implications: NNT Ranges From 16 to 40

Bernard Zinman, MD, Mount Sinai Hospital, Toronto, Ontario, Canada, who is also an investigator for the CREDENCE trial, presented what he believes are some clinical implications from the study.

He pointed out that patients in this trial were at higher risk of progressing to ESKD than those in other [CV outcomes] trials of SGLT2 inhibitors, with worse mean eGFRs [mean eGFR of 56 mL/min/1.73 m2 in CREDENCE], understandably so, because CREDENCE was a study specifically of patients with diabetes and CKD. They also had a worse mean UACR than patients in the other trials.

In EMPA-REG, CANVAS, and DECLARE, mean eGFRs ranged from 74 to 85 mL/min/1.73 m2.

During the first 6 months, there was a greater decline in eGFR in the canagliflozin group than with placebo — which clinicians should expect — but overall, during the 2.5 years, the rate of decline in eGFR was 60% less with canagliflozin than placebo (–1.85 vs –4.59 mL/min/1.73 mper year).

In these patients with type 2 diabetes and CKD, the number needed to treat was 40 to prevent one CV death or MI or stroke over 2.5 years.

The number needed to treat was 22 to prevent one primary composite outcome event (doubling of serum creatinine, ESKD, renal death, or CV death) over 2.5 years.

And among patients with stage 3b moderate CKD at baseline, the number needed to treat was just 16 to prevent one primary composite outcome event over 2.5 years.

"Canagliflozin safely reduced the risk of kidney failure and prevented CV events in people with type 2 diabetes and CKD," across a broad spectrum of subgroups, with a safety profile that was consistent with this drug and with no increased risk of amputation, Zinman summarized.

This suggests, he concluded, that it can be used for primary and secondary prevention of major CV events in patients with type 2 diabetes and CKD.

CREDENCE is the first of several ongoing renal outcomes trials of SGLT2 inhibitors in patients with type 2 diabetes and CKD. Others include Dapa-CKD with dapagliflozin in 4000 patients with baseline eGFR of 25-75 mL/min/1.73m2. Results are due in November 2020. Boehringer Ingelheim and Lilly's ongoing study of empagliflozin (EMPA-KIDNEY) has a similar patient population and will enroll 5000 patients with moderate to severe CKD (down to eGFR 20 mL/min/1.73m2). Results are expected in June 2022. 

CREDENCE was funded by Janssen. Jardine has received research support from Gambro, Baxter, CSL, Amgen, Eli Lilly, and MSD; and has served on advisory boards for Akebia, Baxter, Boehringer Ingelheim, CSL, and Vifor Pharma; serves on a steering committee for a trial sponsored by Janssen; and has spoken at scientific meetings sponsored by Janssen, Amgen, and Roche. Mahaffey has received research support from Afferent, Amgen, Apple, AstraZeneca, Cardiva Medical, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St Jude, and Tenax; and has received speaker fees from Abbott, Ablynx, AstraZeneca, Baim Institute, Boehringer Ingelheim, Bristol-Myers Squibb, Elsevier, GlaxoSmithKline, Johnson & Johnson, MedErgy, Medscape, Mitsubishi, MyoKardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, Springer Publishing, and UCSF. Zinman has received grant support from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk, and consulting fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi Aventis.

ADA 2019 Scientific Sessions. Presented on June 11, 2019.

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