Kidney disease management in patients with type 2 diabetes may be entering a new era, according to researchers.
Recently reported findings from phase 3 randomized clinical trials provide strong evidence of the renal benefits of medications belonging to 2 classes of diabetes drugs: sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists. The medications include the SGLT2 inhibitors canagliflozin, dapagliflozin, and empagliflozin and the GLP-1 receptor agonist dulaglutide.
Key trials setting the stage for this possible evolution in care include:
• CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation), which showed that treatment with canagliflozin was associated with a significant 30% decreased risk of the trial’s primary composite outcome of end-stage renal disease (ESRD), a doubling of serum creatinine level, or death from renal or cardiovascular (CV) causes compared with placebo among patients with type 2 diabetes and kidney disease. Investigators presented the findings at the 2019 World Congress of Nephrology in Melbourne, Australia, on April 15. The presentation coincided with online publication of the findings in The New England Journal of Medicine.
• DECLARE (Dapagliflozin Effects on Cardiovascular Events)-TIMI 58, which demonstrated that patients with type 2 diabetes treated with dapagliflozin experienced a significant 24% decreased risk of the study’s primary composite renal outcome of a sustained 40% decline in estimated glomerular filtration rate (eGFR, in mL/min/1.73 m2) to below 60, ESRD, or death from renal or CV causes compared with placebo recipients. Investigators reported the findings at the American Diabetes Association’s 79th Scientific Sessions in San Francisco in June.
• EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), which in a post-hoc analysis demonstrated that empagliflozin improves kidney outcomes compared with placebo in patients with type 2 diabetes regardless of whether or not they have heart failure (HF), according to findings published in June in Circulation: Heart Failure. A previous post-hoc analysis showed that the drug significantly decreased the risk of renal function decline in the overall study population.
• REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes), which showed that treating type 2 diabetes in patients at least 50 years old with dulaglutide was associated with a significant 15% decreased risk of a composite outcome of new macroalbuminuria, a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. A separate analysis showed that dulaglutide treatment was associated with a significant 12% decreased risk of the study’s primary CV outcome of the first occurrence of the composite end point of non-fatal myocardial infarction, non-fatal stroke, or death from CV causes. Results of both analyses were published online ahead of print on June 7 in The Lancet.
• AWARD-7, which showed that the GLP-1 receptor agonist dulaglutide significantly slowed eGFR decline compared with insulin glargine therapy in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (CKD). The investigators published their findings last year in The Lancet Diabetes & Endocrinology.
“This is an exciting time for patients with, or at risk for, chronic kidney disease in diabetes. SGLT2 inhibitors and GLP-1 receptor agonists will be drugs of choice for glycemic control and organ protection—kidney and heart—in patients with or at risk of CKD,” said Katherine R. Tuttle, MD, Professor of Medicine at the University of Washington in Seattle and principal investigator on the AWARD-7 trial.
“Overall, I’m genuinely excited about these drug classes. I think they represent a breakthrough for people living with type 2 diabetes,” said Joseph Vassalotti, MD, Chief Medical Officer for the New York-based National Kidney Foundation. “After the seminal ACE inhibitor and angiotensin receptor blocker studies, an avalanche of negative diabetic kidney disease randomized trials intervened. These new therapies should re-invigorate nephrologists and inspire careers in kidney disease care and investigation.”
“These agents should be used early in the armamentarium of diabetes management for sure, and perhaps prediabetes,” said CREDENCE investigator George L. Bakris, MD, Professor of Medicine and Director of the Comprehensive Hypertension Center at University of Chicago Medicine.
Dr Bakris said he predicts that SGLT2 inhibitors in particular, because they reduce oxidative stress and inflammation, would have renal and CV benefits in patients without diabetes, although the effects would not be as robust as in patients with diabetes.
“SGTL2 inhibitors should not be thought of as diabetes drugs only, but rather cardiorenal risk reducing drugs that have glucose lowering as a side effect,” Dr Bakris said.
“Based on the CREDENCE results, we now have a single therapy—canagliflozin—that improves the metabolic profile, reduces renal failure, and improves cardiovascular outcomes in patients with type 2 diabetes and albuminuric chronic kidney disease,” said CREDENCE investigator Kenneth W. Mahaffey, MD, Professor of Medicine at Stanford University School of Medicine in Stanford, California, where he is Vice Chair of Clinical Research in the Department of Medicine.
“Canagliflozin is the first drug in 18 years to show a benefit on renal and CV outcomes in this patient population,” Dr Mahaffey said.
As a result of the CREDENCE findings, the American Diabetes Association, in an update to its 2019 Standards of Care, said clinicians should consider use of a SGLT2 inhibitor in type 2 diabetes patients with diabetic nephropathy who have an eGFR of 30 mL/min/1.73 m2 or higher and have albuminuria exceeding 300 mg/g to decrease the risk of kidney disease progression and CV events.
Javed Butler, MD, MPH, a cardiovascular researcher who led the EMPA-REG OUTCOME post hoc analysis comparing renal outcomes associated with empagliflozin use by HF status in diabetics, said it is “quite likely” SGLT2 inhibitors and GLP-1 receptor agonists will lead to a major shift in diabetic kidney disease management. In terms of the drugs’ CV benefits, “we might use these agents in high-risk patients irrespective of any other consideration,” said Dr Butler, the Patrick Lehan Chair of Cardiovascular Research at the University of Mississippi Medical Center in Jackson. “They may become first-line therapies, but we have to wait and see.” Importantly, he said, these are not competitive, but complementary, and the CV benefit may necessitate use of both SGLT2 inhibitors and GLP-1 receptor agonists, regardless of glycemic control.
SGLT2 inhibitors have a wide range of pharmacodynamic effects on the kidney, heart, and vasculature, as well as on metabolism, adiposity, and other physiologic processes, he noted. “This raises the possibility that the benefit may extend to non-diabetic patients as well,” he said.
Coordination of care needed
Although SGLT2 inhibitors and GLP-1 receptor agonists may represent a significant advance in the treatment of type 2 diabetes and its complications, maximally tolerated doses of ACE inhibitors and angiotensin receptor blockers remain an important component of type 2 diabetes management, Dr Vassalotti pointed out. In addition, assimilation of SGLT2 inhibitors and GLP-1 receptor agonists into the management of type 2 diabetes will make coordination of care imperative among various subspecialists (such as nephrologists, endocrinologists, and cardiologists) and primary care physicians, he said. “Clear communication among caregivers is necessary to avoid situations such as one clinician placing a patient on an SGLT2 inhibitor and another doctor taking the patient off the drug because of lack of familiarity with the drug class,” he said.
Dr Mahaffey also acknowledged the importance of inter-specialist communication. “We need to consolidate our care pathways for these patients by coordinating treatment plans across clinicians who care for these patients,” he said.