Coverage of DECLARE, CARMELINA, and other studies that highlight the connection between diabetes and renal outcomes
From sessions on treatment choices for cardiorenal protection, to 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 was hard to miss the 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 a higher cardiovascular risk. They are up to 4 times more likely to die from heart disease.1 It is also well known that diabetes is linked to kidney failure2; about 30% of those with type 1 diabetes and 10% to 40% 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 June 10, 2019, after accepting the Edwin Bierman Award,3 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 added. This year, the ADA issued guideline updates based on results from 2 trials—–DECLARE4 for dapagliflozin and CREDENCE5 for canagliflozin—–with the most recent revision coming June 3.6,7
The wave of cardiovascular outcomes trials for sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 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, with CREDENCE producing the first results in April 2019 (see Cover story).
Mechanisms for these findings were not understood at first, Rossing said. “How can it be 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 on June 9, 2019, during a session between the 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, FIDELIO8 and FIGARO,9 that are investigating, respectively, whether the compound finerenone can reduce (1) 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 roles of inflammation, oxidative stress, uric acid, and new work that could signal gut microbiota as a potential treatment target.10 Studies of adipose tissue are revealing inflammatory markers, Rossing said, but “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.11
Precision Medicine in Diabetes and Kidney Disease
Also at the ADA/ASN joint session, Alice Cheng, MD, FRCPC, of the University of Toronto, said that diabetes medicine took a one-size-fits-all approach for many years. As recently as 2009, the guidelines had minimal options: metformin, basal insulin, sulfonylureas, and intensive insulin.12
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, she said, but it’s moving in that direction.
More work on the genetics of diabetes is allowing researchers to home 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. The 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 led to findings about the role of JAK1/JAK2 inflammation in the progression of kidney disease and how that led to phase 2 findings that JAK1/JAK2 inhibition with baricitinib decreased albuminuria in patients with T2D and diabetic kidney disease.13
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, which Cheng said this is a key issue. Although study results show patients are willing to share blood and tissue samples 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 Pradhan, MD, MPH, MSc, of Harvard and Brigham and Women’s Hospital, discussed the CANTOS trial14 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?”
Pradhan talked about the role of C-reactive protein (CRP), 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), major adverse vascular events dropped 18% among those taking canakinumab; the benefits were greatest among those whose CRP was greatly reduced.15
“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 Pradhan 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. Thus, lowering uric acid may improve outcomes.
However, Jalal reviewed trials and found that studies with results that showed lowering uric acid led to better outcomes were not adequately powered and could not be replicated. “None were designed to evaluate hard outcomes in patients with CKD and type 2 diabetes.”
More work is needed to understand whether the elevation of uric acid “is a manifestation of disease,” she said.
A symposium on renal outcomes in type 2 diabetes (T2D) therapies held June 11, 2019, at the 79th Scientific Sessions of the American Diabetes Association (ADA) featured results from CARMELINA,1 a study that evaluated the effect of linagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, on cardiovascular and kidney safety. During a press briefing ahead of the program, investigators emphasized that patients with T2D and kidney disease have received less attention in trials of DPP-4 inhibitors.
Results showed, compared with placebo, there was no significant difference in the 3-part major adverse cardiovascular events (MACE) and neutral findings for renal outcomes in elderly patients.
Before results for CARMELINA were presented, Boehringer Ingelheim and Eli Lilly, which market linagliptin as Tradjenta, announced results for CAROLINA,2 which compared linagliptin with glimepiride, a second-generation sulfonylurea. Officials touted CAROLINA as “the only active comparator outcome trial” for a DPP-4 inhibitor, with the results showing that linagliptin was not inferior to glimepiride in the first occurrence of 3-part MACE and similar in a secondary end point of 3-part MACE plus hospitalization for unstable angina.
More patients taking linagliptin achieved a second composite outcome of reaching a glycated hemoglobin level of 7% without a rescue medication, moderate or severe hypoglycemia, or 2% weight gain.
When asked during a press briefing where DPP-4 inhibitors generally and linagliptin specifically fit in among T2D therapies, investigator Julio Rosenstock, MD, director of the Dallas Diabetes Research Center, said the results from CARMELINA show that linagliptin is safe to use for older patients who need help with glycemic control. “We can state with a great deal of confidence that using a DPP-4, including linagliptin, is safe from a cardiovascular point of view and safe if they have kidney disease—and safe in older people,” he said. “That’s my take-home message.”
Data from the DECLARE-TIMI 58 study, the cardiovascular outcomes trial (CVOT) for dapagliflozin (Farxiga), reveal that the type 2 diabetes (T2D) drug significantly reduced the risk of renal decline, kidney failure, and renal death, according to results presented June 9, 2019.1
Findings, reported at the 79th Scientific Sessions of the American Diabetes Association (ADA), held in San Francisco, California, and published simultaneously in Lancet Diabetes & Endocrinology show that treatment with the sodium glucose cotransporter 2 (SGLT2) inhibitor made a difference even for those in good renal health when the study began. The study authors noted this point, because a dedicated renal outcomes trial for dapagliflozin is forthcoming.2
“The effect of SGLT2 inhibitors on nephropathy is being examined in dedicated studies of renal outcomes, both in patients with and without type 2 diabetes,” wrote the study authors, led by Ofri Mosenzon, MD, of Hadassah Hebrew University Hospital in Jerusalem. “However, these trials focus on populations with nephropathy at baseline, and therefore should be considered as complementary to our findings.”1
The need for better solutions to prevent renal decline in diabetes—and the apparent ability of SGLT2 inhibitors to offer options—were a major focus of the Scientific Sessions. Diabetes, cardiovascular disease, and chronic kidney disease (CKD) often occur together, and having 1 condition increases the risk of developing the others, along with other comorbidities; for this reason, CKD is often called a “disease multiplier.”3 Those with CKD are at least 6 times more likely to develop end-stage renal disease (ESRD), one of the most debilitating conditions for patients and one of the costliest for the health system.4
The cost of dialysis per patient is estimated at $89,000 per year; patients who reach this point automatically qualify for Medicare. Estimates show that 750,000 people in the United States have ESRD, and this number has been projected to increase due to the rising rate of obesity.5
Like other CVOTs, DECLARE was required to demonstrate safety under a 2008 FDA guidance. Investigators expanded the trial to include hospitalization for heart failure as a second primary end point, after the 2015 EMPA-REG OUTCOME trial unexpectedly showed that the SGLT2 inhibitor empagliflozin reduced cardiovascular death by 38% and hospitalization for heart failure by 35%.6
Thus, DECLARE is the only trial for an SGLT2 inhibitor to report reduced hospitalization for heart failure and cardiovascular death as a primary end point.7 ​​​​​​​
DECLARE investigators previously presented findings at the American Heart Association meeting in November 20187 and the American College of Cardiology (ACC) Scientific Session in March, focusing on the drug’s ability to prevent complications from heart failure.8
Taken together, the results hold much promise, according to Kiersten Combs, vice president for US cardiovascular and metabolic disease for AstraZeneca, the maker of dapagliflozin. “We’re almost at a turning point here in treating the diabetic patient and their comorbidities or complications,” Combs said in an interview with The American Journal of Managed Care® (AJMC®).
In the past, the conversation with health systems has been about how well a T2D therapy controlled blood glucose levels, but the growing body of evidence for cardiorenal results generates a broader conversation, said Naeem Khan MD, vice president of medical for US Cardiovascular and Metabolic Diseases at AstraZeneca, in the interview with AJMC®. “Now the evidence has brought us to a point where we say [that] diabetes is a risk factor that affects other vital organs, and the organs are the heart and the kidney,” Khan said.
The DECLARE data had already produced a primary end point showing that dapagliflozin reduced hospitalization for heart failure and cardiovascular death, Khan said, and now the data show benefits for the renal system. Given the grim trajectory for patients with diabetes who develop cardiovascular disease and CKD, the results “change the whole paradigm,” he said.
“What you’re seeing, which is so exciting, with the SGLT2 class—and with Farxiga specifically, with DECLARE—is this body of evidence around how treating beyond the A1C [glycated hemoglobin] improves these patients’ quality of life and slows not only the diabetes [but also] the disease that the diabetes can exacerbate,” Combs said.
These latest results are from a prespecified exploratory analysis of renal-only outcomes, examining results from 17,160 patients with T2D and mostly preserved renal function, regardless of underlying atherosclerotic cardiovascular disease. Follow-up was 4.2 years.1
Last November, investigators reported a 24% decline in a composite of cardiorenal measures for patients taking dapagliflozin.7 At the 79th Scientific Sessions, they reported that patients taking dapagliflozin had a 47% reduction compared with placebo in the relative risk of a composite renal outcome, which included kidney function decline, defined as sustained ≥40% decrease in estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73m2; ESRD; and renal death. The difference was 1.5% versus 2.8%; (hazard ratio [HR], 0.53; 95% CI, 0.43-0.66; P = .0001).1 ​​​​​​​
This result was driven by a 46% reduction in kidney function decline, as there were relatively few incidents of ESRD or renal death: 11 (0.1%) in the dapagliflozin group compared with 27 (0.3%) in the placebo group. The authors noted that preservation of renal function with dapagliflozin was seen across subgroups. Although there was a decline in eGFR in the dapagliflozin group relative to placebo after 6 months, this difference was eliminated after 2 years; at years 3 and 4, the mean decrease in eGFR was less with dapagliflozin.
“In both aspects, when you look at the renal by itself or the cardiorenal, you see great benefit when you [use] Farxiga in this patient population,” Khan said. “That’s not only the people with established cardiovascular disease but also the people with multiple risk factors. And that’s the kind of patient population the physician actually sees in the office.”
Khan pointed out that most study participants had good renal health at baseline, yet taking dapagliflozin made a significant difference in their long-term outcomes. Of the group, 47.6% had a baseline eGFR of at least 90 mL/min/1.73m2, which is normal renal function, and another 45.1% had an eGFR of 60 to <90 mL/min/1.73m2.
“These are results we saw in a broad range of patient population that actually had a mean eGFR of 85 [mL/min/1.73m2]. That’s quite a healthy kidney, and yet we saw these benefits,” Khan said. “This is stage 1 [CKD] and earlier,” he added.
“It’s very impactful to look at how healthy the kidney was when they were getting the treatment,” Khan said. This points to how much damage diabetes can do to the renal system in a relatively short period.
As CVOTs for the SGLT2 inhibitor class demonstrated the drugs’ ability to slow renal decline, makers of these therapies launched dedicated renal outcomes studies. In March, investigators for the first such study, CREDENCE, for canagliflozin, reported a 30% reduction in renal failure or death for patients with T2D and CKD.9 The renal outcomes study for dapagliflozin, Dapa-CKD, is under way and has an estimated completion of November 2020.2
There has been speculation that as SGLT2 inhibitors gain new indications and find their way into guidelines outside of diabetes—the ACC now recommends the class in primary prevention—there will be greater use by patients newly diagnosed with diabetes.
Along with the results for Dapa-HF, a dedicated heart failure trial due to report later this year, this evidence “should give the primary care physician the confidence to treat more aggressively earlier in diabetes,” Combs said. The results should also give specialists such as cardiologists the confidence to treat comorbidities seen in patients with diabetes, she said.