ADA Standards Updated With Renal Guidance Based on CREDENCE

The American Diabetes Association (ADA) has updated its "living" Standards of Medical Care in Diabetes to incorporate findings from the Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy (CREDENCE) trial, including revised renal management guidelines.

The updates, from the ADA's Professional Practice Committee, are published in sections 10 (Cardiovascular Disease and Risk Management) and 11 (Microvascular Complications and Foot Care) of the association's online Standards.

The specific changes are detailed on a separate page.

In CREDENCE, which enrolled 4401 patients with type 2 diabetes and chronic kidney disease (CKD), canagliflozin (Invokana, Janssen), a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, lowered the risk for progression to end-stage renal disease (ESRD) by 30%, and was also associated with significantly lower rates of major cardiovascular events, including death and hospitalization for heart failure. In addition, risk of the renal-specific composite outcome of ESRD, doubling of serum creatinine, and death from renal causes was lowered by 34% in the canagliflozin group compared with placebo.

The main CREDENCE results, hailed as ground-breaking, were reported in April at the International Society of Nephrology 2019 World Congress and simultaneously published in the New England Journal of Medicine.

The trial, which was launched in 2014, was stopped nearly a year earlier than planned because it met its prespecified efficacy endpoints.

Importantly, notes ADA, "the renal and cardiovascular risk reduction observed in CREDENCE was present in patients with an eGFR in the 30-45 mL/min/1.73m² range."

And "although the adverse event profiles of these agents must be considered, the risk-benefit balance of SGLT2 inhibitor treatment appears to be favorable for most patients with type 2 diabetes and CKD," it adds.

"No increased risk of lower-limb amputations, fractures, acute kidney injury, or hyperkalemia were noted for canagliflozin relative to placebo in CREDENCE. An increased risk for diabetic ketoacidosis was noted, however, with 2.2 and 0.2 events per 1000 patient-years noted in the canagliflozin and placebo groups, respectively."

Updated Renal Management Guidelines

Based on the CREDENCE results, ADA now recommends as part of section 11 (Microvascular Complications and Foot Care):

11.1 At least once a year, assess urinary albumin (eg, spot urinary albumin-to-creatine ratio) and estimated glomerular filtration (eGFR) rate in patients with type 1 diabetes with duration of ≥ 5 years; in all patients with type 2 diabetes, regardless of treatment; and in all patients with comorbid hypertension. Grade of evidence: B
11.3 For patients with type 2 diabetes and diabetic kidney disease, consider use of an SGLT2 inhibitor in patients with an eGFR ≥ 30 mL/min/1.73m² and particularly in those with > 300 mg/g albuminuria to reduce risk of CKD progression, cardiovascular events, or both. Grade of evidence: A
In patients with CKD who are at increased risk for cardiovascular events, use of a glucagon-like peptide 1 (GLP-1) receptor agonist may reduce risk of progression of albuminuria, cardiovascular events, or both. Grade of evidence: C

Section 11.8 (continued monitoring of urinary albumin-to-creatinine ratio in patients with albuminuria treated with an ACE inhibitor or an angiotensin receptor blocker is reasonable to assess the response to treatment and progression of CKD) has been removed.

CREDENCE Information Added to CVD Section

In section 10 (Cardiovascular Disease and Risk Management), information about CREDENCE has been added to the third paragraph of the subsection "Antihyperglycemic Therapies and Cardiovascular Outcomes."

The updated section also summarizes data from the Canagliflozin Cardiovascular Assessment Study (CANVAS) and CANVAS renal endpoints trial (CANVAS-R), which were presented together at the American Diabetes Association (ADA) 2017 Scientific Sessions and simultaneously published in the New England Journal of Medicine (2017;377:644-657).

In CANVAS, canagliflozin reduced cardiovascular events by 14% and cut the rate of renal function decline by 40% but also doubled the risk for lower-limb amputation (6.3 vs 3.4 cases/1000 patient-years; hazard ratio, 1.97).

Information about CREDENCE is now also incorporated into the fourth paragraph of the subsection "Antihyperglycemic Therapies and Heart Failure" in section 10, noting that the risks for heart failure hospitalizations were reduced by 39% and the composite of cardiovascular death or heart failure hospitalization by 31% with canagliflozin.

The changes to section 10 have also been endorsed by the American College of Cardiology.

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