Highlighting Links Between Kidney, CV Disease in Diabetes

From sessions on treatment choices for cardiorenal protection, to multiple clinical trials on cardiovascular and renal outcomes, to the choice of a leading researcher in diabetes and renal care to deliver the annual Bierman Lecture—it’s been hard to miss a theme of cardiorenal care at the 79th Scientific Sessions of the American Diabetes Association (ADA) in San Francisco, California.

Researchers have known for years that people with diabetes face higher cardiovascular risk—they are up to 4 times more likely to die from heart disease. It is also well-known that diabetes is linked to kidney failure; about 30% of those with type 1 diabetes (T1D) and 10% to 40% of those with type 2 diabetes (T2D) will progress to this stage.

But, as Peter Rossing, MD, DMSc, of the Steno Diabetes Center in Copenhagen, Denmark, said Monday after accepting the Edwin Bierman Award, more work is being done to understand the functional links between chronic kidney disease (CKD) and cardiovascular disease, and how to treat them.

“Diabetes, cardiovascular disease, and renal disease—that’s an unfortunate triad,” he said. CKD, in particular, “is a disease multiplier,” because of its effect on life expectancy. A 30-year-old with diabetes and CKD can expect to lose 15 to 16 years of life due to the complications, Rossing said.

This work is informing guidelines for clinical care, he said, and in 2019 the ADA has issued 2 guidelines updates based on the DECLARE and CREDENCE trials, with the most recent one coming June 3, 2019.

The wave of cardiovascular outcomes trials (CVOTs) for sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists produced secondary outcomes that show these classes have cardiorenal benefits; drugs in the SGLT2 class, in particular, are now being studied in dedicated renal outcomes trials.

Mechanisms for these findings were not understood at first, Rossing said. “How can it be that that these glucose-lowering agents protect the kidney and the heart? It must not be about glucose—it must be about something else.”

And it is likely that lowering uric acid and volume contribute to these results, he added.

Whatever the reason, having new options is important, Rossing said, because data show relying on lifestyle changes alone for people with diabetes to reach targets in glycated hemoglobin, blood pressure, and cholesterol won’t work.

Both in the Bierman Lecture and at length the day prior, during a session between ADA and the American Society of Nephrology (ASN), Rossing discussed work on blocking the hormone aldosterone, given the increased understanding of its role as an independent facilitator of kidney damage. He called attention to 2 ongoing trials, FIDELIO and FIGARO, that are investigating, respectively, whether the compound finerenone can (1) reduce the progression of kidney disease and (2) cardiovascular mortality and morbidity in patients with T2D and diabetic kidney disease.

Rossing also discussed the importance of biomarkers. “Many of the markers in kidney disease are also good markers in cardiovascular disease,” he said.

He discussed the role of inflammation, oxidative stress, uric acid, as well as new work that could signal gut microbiota as a potential treatment target. Studies of adipose tissue are revealing inflammatory markers, but said, “I think we need a lot more data in this area to know how to use adipose tissue as a marker or target.”

On the horizon, Rossing is working on the PROMINENT trial, which is looking at pemafibrate to treat triglycerides and reduce cardiovascular events.

Precision Medicine in Diabetes and Kidney Disease

At the ADA/ASN joint session, Alice Cheng, MD, FRCPC, of the University of Toronto, said that diabetes medicine for many years took a “one-size-fits-all” approach. As recently as 2009, the guidelines had minimal options: metformin, basal insulin, sulfonylureas, and intensive insulin.

Now, there are multiple options and physicians can be more precise, she said. Diabetes is not where oncology is in the use of biomarkers to match treatments with patients based on individual characteristics, but it’s moving in that direction.

More work on the genetics of diabetes is allowing researchers to hone in on variables such as insulin deficiency, insulin resistance, or whether diabetes is obesity related or age related.

“In diabetic kidney disease, this is clearly an area of interest,” Cheng said. Use of biomarkers and data integration will eventually allow better risk stratification—and when drugs are tested, researchers will be able to “identify those who will respond the best.”

She outlined how work by the Berthier research group has led to findings about the role of JAK1/JAK2 inflammation in the progression of kidney disease, and in turn this led to phase 2 findings that JAK1/JAK2 inhibition with baricitinib decreased albuminuria in patients with T2D and diabetic kidney disease.

This kind of work involves the “omics,” as in the proteomics, genomics, and more—and there may be more than one pathway toward a target, depending on the patient. It all starts with tissue, and Cheng said this is a key issue, because while studies show patients are willing to share samples of blood and tissue to create data banks, they have some concerns and many want results back.

In the future, clinical trial designs may look very different based on this type of work, she said. “There will be many therapeutic options in the future,” and when considering the needs of an individual, “We want to capture the diagnostics and patient preferences of course, and ultimately fit the right drug for the right stage.”

“We really require early engagement of stakeholders for this to be successful,” she said.

Inflammation in Kidney Disease

Also at the ADA/ASN session, Aruna Pradham, MD, MPH, MSc, of Harvard and Brigham and Women’s Hospital, discussed the CANTOS trial for canakinumab in atherosclerotic cardiovascular disease and asked, “What does the CANTOS trial tell us about inflammation and diabetes risk—and these 2 connected pathways?”

Pradham talked about the role of C-reactive protein (CRP), which is a blood test marker for inflammation in the body. “Inflammation is a consistent predictor a year before one develops a myocardial infarction,” she said, so the thinking was that treating patients with a history of high CRP would prevent events.

Inflammation as a marker, especially for patients with CKD, turned out to be extremely important. Among patients in CANTOS with CKD (estimated glomerular filtration rate <60 cc/min/1.73 m²), those taking canakinumab saw an 18% reduction in major adverse vascular events, and the benefits were greatest among those whose CRP was greatly reduced.

“Independent of other risk factors, these data suggest the signal is real,” she said.

Those with high CRP and high levels of low-density lipoprotein cholesterol had the worst outcomes, so Pradman suggests a dual therapy to treat both conditions is needed.

Understanding the Role of Uric Acid

Diana Jalal, MD, a nephrologist at the University of Iowa concluded the ADA/ASN session by discussing conflicting results from trials involving uric acid. High levels of uric acid are seen in kidney disease, and hyperuricemia is linked to both cardiovascular and kidney disease, with strong associations with heart failure and obesity.

“The data do suggest a link between hyperuricemia and outcomes in patients with diabetes and chronic kidney disease,” she said, and thus, lowering uric acid may improve outcomes.

However, Jalal reviewed trials and found that studies that showed lowering uric acid led to better outcomes were not adequately powered and could not be replicated, and “None were designed to evaluate hard outcomes in patients with DKC and type 2 diabetes.”

More work is needed to understand whether the elevation of uric acid “is a manifestation of disease,” she said.