SAN DIEGO – At a joint session of the American Society of Nephrology and the American Diabetes Association (ADA) as part of the ADA's 77th Scientific Sessions, nephrologists presented data on how diabetes drugs in the SGLT2, GLP-1 receptor agonists and DPP-4 inhibitors classes affected diabetes patients with diabetic kidney disease as well as how the drugs affect the kidneys of patients that might eventually develop the disease.

SGLT2 inhibitors produce improved glycemic control, increased insulin physiology levels, reduced uric acid levels, blood pressure and weight, which all likely contribute indirectly towards renal protection.

But SGLT2 inhibitors have a more direct effect since they act in the kidney. While their main benefit for diabetics is to target glucose re-absorption at the proximal tubule, resulting in more glucose excretion, it's likely the blocking of the sodium that's transported along with the glucose that contributes to renal protection and cardiovascular benefit.

The sodium reabsorption blocked by SGLT2 inhibitors may be hijacking the kidneys' natural auto-regulatory mechanism that reduces sodium filtration when people are sick, which results in dilatation and increased blood flow to avoid kidney damage. Researchers also hypothesize that SGLT2 inhibitors may be renal protective by reducing the hypoxia that leads to kidney damage in diabetics when sodium-glucose transport is blocked by SGLT2 inhibitors.

While there's evidence for SGLT2 inhibitors to be renal protective, most of the trials have tested continued kidney function decline and cardiovascular effects of SGLT2 inhibitor drugs in patients with renal and/or cardiovascular issues.

"The non-cardiovascular complication, non-renal complication, primary prevention cohort is still a huge unmet need," David Cherney, associate professor of medicine at the University of Toronto, told the audience.

GLP-1 receptor agonists reduce glucose levels by acting at the pancreas, enhancing glucose-induced insulin secretion, but GLP-1 receptors are located on other tissues including the kidney and macrophages that infiltrate the kidneys, offering a potential direct effect by GLP-1 receptor agonists.

The exact mechanism of renal benefit isn't known, but hypotheses include inhibiting PKC-beta, reducing oxidative stress, and reducing inflammation through reduction of macrophage infiltration. And like the SGLT2 inhibitors, GLP-1 receptor agonists also likely have an indirect effect on the kidneys by improving glycemic control.

Interim data from the AWARD-7 trial testing Trulicity (dulaglutide, Eli Lilly and Co.) in diabetics with stages 3-4 chronic kidney disease presented at ADA showed that Trulicity plus insulin improved albuminuria and estimated glomerular filtration rate (eGFR), two measurements of kidney function, compared to insulin alone.

"We're seeing a strong signal for renal protection," concluded Katherine Tuttle, clinical professor of medicine in the nephrology division at the University of Washington, School of Medicine.

While there's quite a bit of evidence for renal protection for SGLT2 inhibitors and GLP-1 receptor agonists, the data for DPP4 inhibitors are not as strong.

Mark Cooper, head of the diabetes department in the Central Clinical School at Monash University, presented data showing that the DPP4 inhibitors aren't causing kidney damage. Some of the DPP4 inhibitors need to be reduced as kidney function wanes in patients with chronic kidney disease resulting in less filtration and higher drug concentrations in the blood, but Cooper joked that even that isn't a major problem, "Although we should reduce the dose, the truth is that the emergency rooms are not filled with patients with DPP4 inhibitor overdoses."

But on the question of whether DPP4 inhibitors produce renal protection, he wasn't as convinced. One possible mechanism could be through DPP4 inhibition causing an increase of GLP-1, but the evidence is still out. "Unfortunately I cannot definitively answer that question today," Cooper told the audience.

Evidence of DPP4 inhibitors affect on kidney function could come from the CARMELINA trial testing Tradjenta (linagliptin, Boehringer Ingelheim Gmb and Eli Lilly and Co.) in patients with high vascular risk. While the trial isn't testing patients directly with kidney disease, the vascular risk criteria is enriched for that population, resulting in a two- to three-fold increase in the number of patients with evidence of kidney disease compared to previous clinical trials.

"If any clinical study is going to indentify a hard renal endpoint, this is the population; if these drugs are potentially renal protective, we may detect that when the results come out – probably in the next year," Cooper said of the CARMELINA study.