DECLARE Shows Diabetes Drug Farxiga Prevented Renal Decline, Even for Those With Good Kidney Health

Data from the DECLARE-TIMI 58 study, the cardiovascular outcomes trial (CVOT) for dapagliflozin (Farxiga), show the type 2 diabetes (T2D) drug significantly reduced the risk of renal decline, kidney failure, and renal death, according to results presented Sunday.¹

Findings reported at the 79th Scientific Session of the American Diabetes Association (ADA) in San Francisco, California, and published simultaneously in Lancet Diabetes & Endocrinology, say treatment with the sodium glucose co-transporter 2 (SGLT2) inhibitor made a difference even for those in good renal health when the study began, a point that study authors noted, as a dedicated renal outcomes trial for dapagliflozin is forthcoming.

“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 study authors led by Ofri Mosenzon, MD, of Hadassah Hebrew University in Jerusalem. “However, these trials focus on populations with nephropathy at baseline, and therefore should be considered as complementary to our findings.”

The need for better solutions to prevent renal decline in diabetes—and the apparent ability of SGLT2 inhibitors to offer options—are a major focus of this year’s ADA Scientific Sessions. People with diabetes are twice as without people without diabetes likely to develop chronic kidney disease (CKD) and 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. 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 rising rate of obesity.

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 the SGLT2 inhibitor empagliflozin reduced cardiovascular death by 38% and hospitalization for heart failure by 35%.

Thus, DECLARE is the only trial for an SGLT2 inhibitor to report a reduction in hospitalization for heart failure and cardiovascular death as a primary end point.

DECLARE investigators previously presented findings at the American Heart Association meeting November 2018² and the American College of Cardiology Scientific Sessions in March, focusing on the drug’s ability to prevent complications from heart failure.

Taken together, the results mean “We’re almost at a turning point here in treating the diabetic patient and their comorbidities or complications,” Kiersten Combs, vice president for US Cardiovascular & Metabolic Disease for AstraZeneca, the maker of dapagliflozin, 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, AstraZeneca, said in the interview with AJMC^®.

“Now, the evidence has brought us to a point where we say, diabetes is a risk factor that affects other vital organs, and the organs are the heart and the kidney,” he said. The DECLARE data had already produced a primary endpoint showing the 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 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] improve these patients’ quality of life and slow 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.

Last November, investigators reported a 24% decline in a composite of cardiorenal measures for patients taking dapagliflozin.² On Sunday, they reported that patients taking dapagliflozin had a 47% reduction compared with placebo in the relative risk of a composite renal outcome, which included: (1) kidney function decline, defined as sustained ≥40% decrease in estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73m²; (2) ESRD; and (3) 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 in the dapagliflozin group (0.1%) compared with 27 (0.3%) in the placebo group. Authors noted the 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 had been eliminated after 2 years, and 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 utilize Farxiga in this patient population,” said Khan. “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 still 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,” Khan said. “And yet we saw these benefits.…This is stage 1 [CKD] and earlier.

“It’s very impactful to look at how healthy the kidney was when they were getting the treatment,” he said, which 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, the first such study, CREDENCE, for canagliflozin, reported a 30% reduction in renal failure or death for patients with T2D and CKD. The renal outcomes study for dapagliflozin, called DAPA-CKD, is under way and has an estimated completion of November 2020.

There has been speculation that as SGLT2 inhibitors gain new indications and find their way into guidelines outside of diabetes—the American College of Cardiology now recommends the class in primary prevention&mdash;there will be greater use earlier on after a diagnosis of diabetes.

Combs said that 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.” The results should also give specialists, such as cardiologists, confidence to treat comorbidities seen in patients with diabetes, she said.

References

1. Mosenzon O, Wiviott SD, Cahn A, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE—TIMI 58 randomised trial [published online June 9, 2019]. Lancet Diab Endocrinol. http://dx.doi.org/10.1016/S2213-8587(19)30180-9.
2. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in diabetes. N Engl J Med. 2019;380:347-357. doi: 10.1056/NEJMoa1812389.