The CREDENCE Trial: Less ESKD in Diabetes “Up Around the Bend”?

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In April of this year, the highly-anticipated CREDENCE Trial was presented (and live-streamed) at the International Society of Nephrology (ISN) World Congress of Nephrology in Australia and simultaneously published in NEJM. But before we start dusting off our vintage Creedence Clearwater Revival (CCR) records and making Big Lebowski jokes, let’s break down the results first, Dude. I know it’s not spelled with two e’s, but we were all thinking it.

The CRE(e)DENCE Trial investigated the effects of canagliflozin, an SGLT2 inhibitor, on the progression of kidney disease in patients with type 2 diabetes. As this is a blog run by aspiring nephrologists for nephrologists, the implications of that statement should be obvious. An estimated 3 million people in the world are currently receiving treatment for kidney failure and that number is expected to nearly double by 2030. To make matters worse, approximately 5 to 10 million people die each year from kidney disease worldwide, according to the WHO. That number doesn’t appear to be shrinking, either, with increasing incidences of diabetes, cardiovascular disease, and obesity. It should naturally go without saying that any new therapy that promises to stifle these trends should be readily welcomed with open arms. And I think that is exactly what’s about to happen with canagliflozin, if not all SGLT2 inhibitors.

4,401 patients in 36 different countries across the world with type 2 diabetes and diabetic nephropathy  were randomly assigned to receive either once daily canagliflozin or placebo. Diabetic nephropathy was defined as an eGFR between 30 and <90 and a urinary albumin-to-creatinine ratio of >300 to 5,000 in patients with a hemoglobin A1c between 6.5 and 12%. It was, of course, a double-blinded study (this is the NEJM). The primary outcome was a composite of:

  • End-stage kidney (ESKD) disease (be it dialysis, transplantation, or eGFR <15)
  • A doubling of the baseline serum creatinine level
  • Death from renal or cardiovascular events.

Of note, all patients included in the study were already receiving a stable dose of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker prior to randomization. The study was stopped early after the prespecified efficacy criteria for early cessation was met, the hallmark of a successful trial.

The primary outcome was 30% lower in the canagliflozin group than in the placebo group. Furthermore, patients in the canagliflozin group were shown to fare better in many secondary outcomes as well, such as lower risk of heart failure hospitalizations, a composite outcome of cardiovascular-related death, myocardial infarction, or stroke, and lower hemoglobin A1c levels, blood pressure, and body weight. All good things, right? To put it another way, the number needed to treat to prevent ESKD, a doubling of the baseline serum creatinine level, or renal or cardiovascular death was 22 over 2.5 years. To prevent cardiovascular-related death, MI, or stroke, it’s 25. To make things even more interesting, the rates of limb amputation and fracture were similar between both the canagliflozin group and the placebo group. This is inconsistent with the CANVAS Trial, which showed an increased rate of both limb amputations and fractures in patients receiving canagliflozin.

The mechanisms that underlie these results are starting to be elucidated and are likely both kidney and systemic. In patients with diabetes, hyperglycemia leads to enhanced glucose (and sodium) reabsorption along the proximal convoluted tubule the sodium/glucose co-transporter 2 (SGLT2) receptor. This leads to decreased sodium delivery to the macula densa, resulting in afferent arteriolar dilation and intraglomerular hypertension. Inhibition of the SGLT2 co-transporter restores balance by increasing delivery of glucose and sodium to the distal convoluted tubule, which is sensed by the juxtaglomerular apparatus as increased kidney perfusion, resulting in increased vasoconstriction of the afferent arteriole and, thus, decreasing the glomerular pressure. This effect was captured in the CREDENCE Trial as patients in the canagliflozin group were shown to have a decreased estimated GFR early on in the trial which then stabilized.

Overall, bother me tomorrow; today, I’ll buy no sorrows. Canagliflozin has shown itself to be a useful therapy in the progression of kidney disease in patients with type 2 diabetes and kidney disease. I’m sure that, overtime, the same will be shown of other SGLT2 inhibitors, as well. And the future will thank us. The Dude does indeed abide. Take a listen to the Freely Filtered Podcast for a deep discussion on CREDENCE.

Post by: Anthony Nicolaysen, MD
Internal Medicine Resident, PGY-1
Mount Sinai Beth Israel

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