Mark E. Cooper
PHILADELPHIA — Large cardiovascular outcome trials for antidiabetes agents in two drug classes have yielded potentially promising data with respect to their secondary renal outcomes, offering new options for patients with diabetic kidney disease, according to a speaker here.
“As cardiovascular disease has actually decreased significantly, unfortunately, we’ve unmasked another problem — that of chronic kidney disease,” Mark E. Cooper, MD, PhD, professor of diabetes and head of the department of diabetes, Central Clinical School at Monash University in Melbourne, Australia, said during a presentation at the second annual Heart in Diabetes Clinical Education Conference. “Essentially, we have these two competing endpoints that are both manifestations of organ injury in diabetes.”
Despite advances in modern treatments, diabetic kidney disease remains refractory to many available therapies, Cooper said. However, both SGLT2 inhibitors, such as empagliflozin (Jardiance, Boehringer Ingelheim), and GLP-1 receptor agonists, such as liraglutide (Victoza, Novo Nordisk), have shown promise as therapies that not only improve glycemic control and reduce CV risk in patients with established CVD, but also slow the progression of renal disease, Cooper said.
Glucose lowering, renal benefit
There are good data suggesting that optimal glycemic control can lead to slower decline in kidney function, including a 20% to 30% reduction in the progression of either normo- to microalbuminuria or micro- to macroalbuminuria, Cooper said. However, albuminuria is not always progressive, and many patients with diabetes do experience remission, he said.
Newer antidiabetes agents have also been associated with reduced risk for new-onset microalbuminuria and slowed progression of micro- to macroalbuminuria, likely, in part, through their glucose-lowering properties, Cooper said. Yet, studies have not demonstrated that glucose lowering is a mechanism behind any observed renal benefits.
In both the ADVANCE and ACCORD studies, for example, there was no evidence that glucose lowering affected estimated glomerular filtration rate, Cooper said. He also cautioned that it can take time for glucose lowering to lead to any observed renal benefit.
“Even if glucose lowering does something, we probably have not had trials long enough to answer that question,” Cooper said. “I still believe the kidney is likely the most glucose-sensitive organ in the body.”
New tools for treatment
GKP-1 receptor agonists have shown potential antialbuminuric benefits in several large CV outcomes trials, Cooper said.
The LEADER study, designed to assess the CV safety of liraglutide in more than 9,300 patients with poorly controlled type 2 diabetes and established CVD or chronic renal failure, showed that risk for kidney disease progression fell by 22% (HR = 0.78; 95% CI, 0.67-0.92) over a mean of 3.8 years in patients assigned liraglutide vs. placebo. The key renal outcome was a composite endpoint of development of macroalbuminuria, doubling of serum creatinine, end stage renal disease (ESRD) or renal death.
Similar results were observed in SUSTAIN-6 with semaglutide (Ozempic, Novo Nordisk) and with dulaglutide (Trulicity, Eli Lilly), with results mostly driven by a reduction in albuminuria, Cooper said
“This has been a fascinating area, because we have no mechanism of action to explain why these drugs would be renoprotective,” Cooper said.
SGLT2 inhibitors have shown the most promise with respect to renal benefits, Cooper said — the most interesting finding being an observed stabilization of eGFR in patients with diabetic kidney disease.
In an analysis of the EMPA-REG CV outcome trial, the composite endpoint of incident or worsening nephropathy or CV death was lower in patients with type 2 diabetes and established CVD assigned empagliflozin vs. patients assigned placebo, Cooper said. Those assigned empagliflozin were also less likely to progress to macroalbuminuria, experience a doubling of serum creatinine level or initiate renal replacement therapy vs. those assigned placebo.
“Even in the fast progressing group, there is a benefit with empagliflozin,” Cooper said. “In the patients with normoalbuminuria, microalbuminuria and macroalbuminuria, you see dramatic improvements in renal function in all three groups. Spectacular seeing these patients with macroalbuminuria, where we see not total prevention, but a marked slowing down in rate of decline in renal function. Which would mean that for many of these people who are rapidly on their way to end stage renal failure and dialysis, this has been delayed by two- to three-fold.”
Additionally, in the CANVAS study, patients with type 2 diabetes at high risk for CVD assigned canagliflozin (Invokana, Janssen) saw a 33% reduction in risk for hospitalization for heart failure and were 40% less likely to experience renal decline vs. those assigned placebo, Cooper said.
“I think the data are very robust that sglt2 inhibitors are clearly renoprotective, and I think this will turn out to be a class effect,” Cooper said.
Thiazolidinediones, or TZDs, are “clearly associated” with decreases in albuminuria, Cooper said. In patients with type 2 diabetes and normo- to microalbuminuria, use of TZDs have been associated with decreases of up to 65% in urinary albumin excretion rate and decreases of up to 25% urinary albumin to creatinine ratio, Cooper said, with a greater reduction in urinary albumin to creatinine ratio in patients with macroalbuminuria. Additionally, in the ProACTIVE study, use of pioglitazone was associated with a 50% reduction in the rate of decline in eGFR, Cooper said.
The data for DPP-IV inhibitors, however, have been “rather confusing,” Cooper said, though he characterized any observed renal benefit as “weakly positive.” In the SAVOR-TIMI 53 CV outcomes trial, use of saxagliptin (Onglyza, Astra Zeneca) was associated with a very modest reduction in albuminuria, with no effect on hard renal endpoints, Cooper said. Similarly, in the TECOS trial, there was no clear-cut benefit observed in the reduction of microalbuminuria with sitagliptin (Januvia, Merck).
The ongoing CAROLINA study, a CV outcome study of linagliptin (Tradjenta, Boehringer Ingelheim) vs. glimepiride in adults with type 2 diabetes, may provide more renal data, Cooper said.
“I think we’ll finally confirm or refute the anti-albuminuria effect of this class of drugs,” Cooper said. – by Regina Schaffer
Cooper ME. Renal effects of antihyperglycemic agents. Presented at: Presented at: Heart in Diabetes Clinical Education Conference; July 14-16, 2018; Philadelphia.
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