AACE 28th Annual Scientific & Clinical Congress:

Reducing Risk of Chronic Kidney Disease Achievable in Patients with Diabetes

With Roberto Pecoits Filho, MD, PhD, Bruce Neal, PhD, and Ahmet Can, MD

In a late-breaking session, investigators from the George Institute for Global Health in Australia announced topline results of the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial to attendees,1 during the 2019 American Association of Clinical Endocrinologists (AACE) annual meeting.

Presenting very favorable outcomes, the researchers found that canagliflozin (Invokana) reduced the risk of end stage kidney disease (ESKD)—the primary outcome—by 30%, as well as achieving a 34% reduction in mortality and other secondary outcomes.1,2

CREDENCE trial results lessen concerns about risk of amputation with SGLT2 inhibitors

Surprising Reassurance Gained from Results of CREDENCE Trial

These and other high points of the results from the full report of the CREDENCE trial,2 which was published in the New England Journal of Medicine, were reported by two members of the investigative team—Roberto Pecoits Filho, MD, PhD, FASN, FACP, a visiting fellow and Bruce Neal, MB ChB, MRCP, PhD, FRCP, FAHA, professor of medicine at the University of New South Wales in Sydney, Australia, and deputy executive director of the cardiometabolic group at the George Institute for Global Health who presented some of the CREDENCE findings.

"If you take a patient with diabetes and early diabetic kidney disease and look at longevity, the kidney disease shortens the lifespan by about 16 years,"3 Dr. Pecoits Filho.

The study findings offer very welcome news for many patients with type 2 diabetes who also have advanced renal disease, he said.

In their hour-long presentation, the research duo summarized the study background, rationale and study design, discussed the effects on renal outcomes seen in patients receiving canagliflozin as well as any changes in cardiovascular and safety outcomes; they ended with a discussion about the implications for clinical practice.1

They reiterated that the good news from CREDENCE is that the outcomes—no imbalance was found between groups in rate of amputations, a major concern. The findings also indicated no differences seen between the treated and placebo groups for risk fracture.1,2 

Rationale Behind Renoprotective Effect of SGLT2 in Diabetes Patients

There has been a steady rise in the prevalence and number of new cases of end stage renal disease,4,5 Dr. Pecoits Filho said, with the need for kidney dialysis (renal replacement therapy) expected to nearly double by 2030—rising from 2.62 per million in 2010 to 5.44 in 2030.4 And, the leading cause, of course, is type 2 diabetes.5

How might the SGLT2 inhibitor, canagliflozin, be renal protective? Several mechanisms have been proposed for the favorable effect of this antidiabetes medication, such as a reduction in: intraglomerular pressure, blood glucose, blood pressure, arterial stiffness, blood volume, intra-renal inflammation, albuminuria, oxidative stress, and intrarenal angiotensin up-regulation.1

Tight control of blood glucose levels and good management of hypertension have been shown to slow the onset of diabetic nephropathy but these clinical strategies haven’t been enough to prevent it. The standard approach to delaying it and keeping renal function stable has been blockage of the renin-angiotensin-aldosterone system, especially with inhibitions of the angiotensin-converting enzyme.6

The speakers noted that the large cardiovascular outcomes trials with SGLT-2 inhibitors, specifically,  CANVAS,7 EMPA-REG Outcome, and DECLARE, offered indications of renal benefits.8

As such, the CREDENCE Trial was initiated to focus on kidney endpoints to provide a more definitive evaluation of the effect of canagliflozin on clinically important renal outcomes in those with T2D and established CKD,1,2 said the presenters.

Renal Outcomes with Canagliflozin in Patients with Diabetes

The CREDENCE trial evaluated 4,401 patients diagnosed with T2D and stage 2 or 3 chronic kidney disease—defined as an eGFR greater than 30 and less than 90 mL/mn/1.73 m2—and microalbuminuria—defined as a urinary albumin-to-creatine ratio of greater than 300 and less than 5,000 mg/g—who were receiving daily doses of an ACE inhibitor or an ARB.2

The primary endpoint was established as ESKD, defined as chronic dialysis for 30 days or more, kidney transplantation, eGFR <15 mL/min/1.73 m2 sustained for 30 days or more by central laboratory assessment; renal death in patients who were on a waiting list for renal replacement; and cardiovascular mortality.2

The canagliflozin produced a substantial reduction, 30%, in the risk of end stage kidney disease, the primary outcome of the CREDENCE trial (P = 0.00001), and also achieved a reduction in the risk of the secondary outcome of ESKD, doubling of serum creatinine/reducing renal death, by 34% (P < 0.001).2

"At the end of the 42 months of treatment, about 340 patients in the intervention group achieved the primary endpoint," Dr. Pecoits Filho said. ''In comparison, 245 participants in the placebo arm did."

Other reported results:2

  • Hemoglobin A1c (HbA1c): Baseline HbA1c averaged 8.3% in both the treatment and placebo groups; the mean difference by the end of the study was -0.25%. (95% CI: -0.31, -0.20) 
  • Systolic Blood Pressure (BP): The canagliflozin group averaged 139.8 mmHg and the placebo group was: 140.2 mmHg. Over the course of the study, the mean difference in BP was -3.30 mmHg, favoring canagliflozin (95% CI: -3.87, -2.73). 
  • Body Weight:  At baseline, the measures of body weight were similar—87.3 kg for canagliflozin and 86.9 kg for patients in the placebo group. Over the treatment period, the mean difference in body weight was -0.80, favoring the treatment group (95% CI: -0.92, -0.69). 
  • Albuminuria: Baseline levels were similar for both groups—914 mg/g for patients taking canagliflozin and 918 mg/g for those receiving the placebo. At the end of the trial, there was a mean -32% difference between the two groups, favoring canagliflozin (95% CI: -36, -28). 

Secondary Endpoints: Cardiovascular Events, and Overall Safety

Dr. Neal discussed the results pertaining to secondary outcomes, pointing out that among patients receiving canagliflozin, there was a significant reduction in the risk of CV death or hospitalization for heart failure, myocardial infarction, stroke, as well as ESKD, doubling of serum creatinine or renal death.1 However, he did indicate that the secondary endpoint of CV death did not reach statistical significance.2

"All together," Dr. Neal said, ''these are pretty convincing results for the positive effect of [canagliflozin] on cardiovascular outcomes in this patient group with significant kidney disease, and really, just what we expected based on what has been seen with this drug in the past."

As for overall safety, an independent blinded adjudication committee analyzed the data for adverse events (AEs) and potential adverse effects.2 Overall, in evaluating AEs and serious AEs, 2,200 patients in the canagliflozin group reported experiencing one or more AEs, compared to 2,197 patients receiving the placebo.2

 "Fracture had been identified as a noted risk in the CANVAS trial," Dr. Neal said. Regarding this concern, 68 patients receiving the placebo and essentially the same number (n= 67) of people taking canagliflozin experienced a fracture (HR 0.98, 95% CI, 0.70-1.37).

Likewise, no imbalance between groups was found in rates of amputation, with 70 patients taking canagliflozin and 63 patients on placebo who required limb amputation (HR 1.11, 95% CI, 0.79-1.56).2  Dr. Neal suggested that the difference was a chance finding in earlier research.1

The safety profile was otherwise consistent with previous canagliflozin studies, the investigators said.

Addressing Implications of CREDENCE Findings in Patient Care

Dr. Pecoits Filho turned once again to statistics when talking about applying the results of the CREDENCE trial to clinical practice. He noted among adults living with diabetes, about 30 to 40% are expected to  develop chronic kidney disease,6 he said, reflecting an adverse effect of consideration concern.

He reminded attendees of the risk factor management criteria established upon patient enrollment in the CREDENCE trial: a mean HbA1c of 8.3%, 99.9% of patients taking an ACE or ARB for blood pressure control, lower LDL-C achieved with about 70% of patients taking statin therapy.2

As such, the critical takeaway message for clinicians is, he said: "Canagliflozin safely reduced the risk of kidney failure and prevented CV events in people with T2D and CKD."

The CREDENCE data offered sound reinforcement of the value of this SGLT-2 regimen for patients diagnosed with type 2 diabetes and evidence of progressing kidney disease.1,7

According to Ahmet Selcuk Can, MD, program director of the Arnot-Ogden Endocrinology Fellowship Program and adjunct assistant clinical professor at Arnot-Ogden Medical Center in Elmira, New York, who attended the presentation, he felt the “CREDENCE trial findings are well-established." Like others, he also was relieved to hear that "The results showed no [increased] risk of amputation."

He offered a practical assessment of these results for EndocrineWeb. "There was a potential concern with canagliflozin of increased risk of amputations," he said, citing the initial CANVAS trial findings,6 published in the New England Journal of Medicine.

"This issue was picked up by some lawyers and TV ads that scared our patients and caused reluctance on the part of physicians and patients with diabetes to utilize canagliflozin. The CREDENCE trial showed no statistically significant difference between patients taking placebo and those receiving canagliflozin for the rate of amputation," meaning this concern can be put aside.

"I use this drug for patients with type 2 diabetes and no evidence of renal insufficiency (eGFR more than 60 mL/min/1.73 m2). Canagliflozin (300 mg per day) should be given to patients with GFR above 60, while a dose of 100 mg is sufficient for individuals with an eGFR over 45 mL/min/1.73 m2,” said Dr. Can.

Since the trial showed positive outcomes in the progression of diabetic kidney disease, clinicians may consider treatment in patients even in the early phase of diabetic kidney disease, which begins as microalbuminuria, then progresses to microalbuminuria. The CREDENCE trial showed that canagliflozin also appears effective in patients with diabetes who present with macroalbuminuria. In this case, the investigators started low-dose canagliflozin treatment of 100 mg in patients who have an eGFR over 30 mL/min/1.73 m2.

He now plans to prescribe canagliflozin more often given the strength of the CREDENCE study results, Dr. Can said. One benefit of the trial is that the fear for increased risk of amputations has been resolved, and "The second issue (resolved with the trial findings) is that we can prescribe this SGLT-2 to more patients who have a lower eGFR with worse kidney function and elevated urine microalbumin levels in the range of macroalbuminuria," he said.

"Although long-term side effects are listed in the product information sheet, as a practicing endocrinologist, I most often see genital or urinary tract infections and dehydration with concomitant use of diuretics. These can be addressed with increased fluid intake and good general hydration but if the side effects persist or recur, then I would typically discontinue the medication."

In an editorial accompanying publication of the CREDENCE results,9 Julie R. Ingelfinger, MD, professor of pediatrics at Harvard Medical School and senior consultant in pediatric nephrology at MassGeneral Hospital in Boston, Massachusetts and Clifford J. Rosen, MD, professor of medicine at Tufts University School of Medicine in Boston, and director of the Center for Clinical and Translational Research Maine Medical Center in Scarborough, wrote: ''the importance of CREDENCE cannot be overstated." The recent results, ''are certain to be welcomed by patients with diabetes and chronic kidney disease and by the clinicians who treat them."

Background on the CREDENCE Trial

Launched in 2014, this phase 3 interventional, randomized, multicenter, double-blind, placebo-controlled parallel treatment trial, was initiated to assess the effects of canagliflozin on renal and cardiovascular outcomes in patients with type 2 diabetes (T2D).2

Ultimately, 4,401 patients receiving treatment for their diabetes were enrolled across 690 sites in 34 countries. After the planned interim analysis, the Independent Data Monitoring Committee made the recommendation to discontinue the trial in mid-2018 given the strength of the demonstrated efficacy.2   

Dr. Roberto Pecoits-Filho reported receiving consulting fees from AKEBIA, AstraZeneca, Novo Nordisk and Fresenius Medical Care, speaker honorarium from AstraZeneca, Novo Nordisk, and Janssen. Dr. Neal reported advisory board and/or consultancy fees from Janssen, and Merck Sharp and Dohme. Dr. Can, Dr. Ingelfinger, and Dr. Rosen had no related financial disclosures.  

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