LAS VEGAS – In the opinion of Dr. David Cherney, it’s not uncommon for physicians to feel grim about the limited efficacy of available agents to treat chronic kidney disease in patients with type 1 and type 2 diabetes.
Over a 10-year period, about 20% of patients with type I diabetes treated with angiotensin-converting enzyme (ACE) monotherapy still develop progression of their kidney disease, according to Dr. Cherney of the department of medicine at the University of Toronto.
"The diabetic nephroprotection area has been incredibly disappointing in the last 5-8 years," he said at a meeting sponsored by the National Kidney Foundation. "Patients tend to progress despite therapy or have side effects, no matter what we do. Endothelial antagonists cause edema. Protein kinase C beta-antagonists have little therapeutic effect, and antioxidants such as bardoxolone caused serious side effects. None of the drugs that we think will work, based on animal studies, seem to work very well when translated into humans."
Neurohormonal pathway blockade with an ACE inhibitor or an angiotensin II receptor blocker corrects early hemodynamic abnormalities in type 1 diabetes, he noted. "But the effects are partial. Dual, renin-angiotensin-aldosterone system blockade is associated with risk. When we use dual blockade in patients with type 1 diabetes, we’re not able to reduce hyperfiltration. The development of novel and safe renal protective therapies is critical."
Enter sodium-glucose cotransporter 2 (SGLT2) inhibitors such as empagliflozin and canagliflozin, which over the past decade have demonstrated positive endocrine effects in type 2 diabetes. According to Dr. Cherney, they lower hemoglobin A1c by about 1% and lead to 2-4 kg of weight loss.
"That’s fantastic, compared with other agents such as insulin that cause weight gain," he said. "That weight loss is sustained for up to 2 years. These agents also seem to have a very low risk of hypoglycemia, and they also lower blood pressure."
Animal models of diabetes have used SGLT2 inhibitors such as empagliflozin (developed by Boehringer Ingelheim and Eli Lilly) to demonstrate a decline in hyperfiltration, a decrease in proteinuria, and a decrease in the structural evidence of nephropathy on histology. An SGLT2 inhibitor might offer renal protection in humans with diabetes by blocking sodium reabsorption proximally, restoring distal delivery, and normalizing afferent tone and glomerular filtration rate (GFR), Dr. Cherney said.
He and his associates conducted an open-label, pilot trial of empagliflozin in patients with type 1 diabetes, known as the ATIRMA study. The objectives were to assess the impact of empagliflozin on GFR under controlled conditions of euglycemia and hyperglycemia in type 1 diabetes patients with and without hyperfiltration, as well as to examine its safety and efficacy as an add-on therapy to insulin (Circulation 2014;129:587-97).
"We hypothesized that we would reduce hyperfiltration and improve glycemic parameters in type 1 diabetes," Dr. Cherney said. In all, 40 patients with a mean age of 25 years were screened and underwent a 2-week run-in period, then took empagliflozin 25 mg once daily for 8 weeks. There were 13 patients in the normofiltration group and 27 patients in the hyperfiltration group.
At the end of 8 weeks, patients in the hyperfiltration group had a dramatic increase in 24-hour urinary glucose excretion, to 140 g/day, "which is about twice what you see in the type 2 studies," he said. "They had very dramatic tubular flow response."
Patients in the hyperfiltration group also had a 20% reduction in their hyperfiltration, a fall in hyperperfusion, an increase in renal vascular resistance, and a small reduction in blood pressure. The researchers also observed a 0.4% reduction in HbA1c, "which was highly statistically significant," Dr. Cherney said. "We also saw that weight and waist circumference decreased, fasting capillary glucose improved significantly, and their insulin doses decreased. As a consequence, they had less hypoglycemia."
How does this compare to currently used agents? ACE inhibitors reduce hyperfiltration by about 19.7%, Dr. Cheney said, while empagliflozin decreased hyperfiltration by 19.2% – almost an identical effect.
"But remember, ACE inhibitors are associated with hyperkalemia, acute kidney injury, and other potential side effects," he noted. SGLT2 inhibitors "don’t cause hyperkalemia. They don’t cause acute kidney injury, as far as we know. And as far as we know, they don’t have any important interactions with other RAAS inhibitors."
Dr. Cherney characterized the findings from ATIRMA as "promising first steps.
"We’ve been tricked many times before with other drugs," he noted. "We can’t by any means say that this is conclusive, but we need to have long-term renal protection studies to prove their relevance. I think we can clearly say that renal studies are warranted in type 1 and type 2 diabetes."