More DECLARE-TIMI: Robust Renal Effects of Dapagliflozin

Marlene Busko

June 11, 2019

SAN FRANCISCO — An in-depth analysis of renal and safety data from the landmark Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) study of the sodium-glucose cotransporter type 2 (SGLT2) inhibitor dapagliflozin (Farxiga/Forxiga, AstraZeneca) to treat type 2 diabetes shows the drug is safe and improves kidney function in a broader patient population with normal kidney function and no atherosclerotic disease.

The new trial data were presented during a 2-hour symposium here at the American Diabetes Association (ADA) 2019 Scientific Sessions and simultaneously published in the Lancet Diabetes & Endocrinology.

"Dapagliflozin seemed to prevent and reduce progression of kidney disease compared with placebo in this large and diverse population of patients with type 2 diabetes with and without established atherosclerotic cardiovascular disease (CVD), most of whom had preserved renal function," Ofri Mosenzon, MD, Hebrew University of Jerusalem, Israel, and colleagues write.

In the overall DECLARE-TIMI trial, first reported last November, there was a 24% reduction with dapagliflozin in a composite renal outcome of a ≥ 40% decrease in estimated glomerular filtration rate (eGFR) (to < 60 mL/min/1.73 m2), end-stage renal disease (ESRD), or death from renal or CV causes compared with placebo.  

The new report provides data on the individual components of these outcomes, a subgroup analyses of renal outcomes, and changes in eGFR over time.

"I think the most important finding is the fact that, even in a population of patients with mainly normal renal function...and [normal urinary albumin-creatinine ratio (UACR < 30 mg/g)], dapagliflozin was able to prove prevention of renal function deterioration and clinically important renal endpoints," Mosenzon told Medscape Medical News.

"These results emphasize the value of SGLT2 inhibitors as an important component of both prevention and treatment of chronic kidney disease (CKD) among patients with type 2 diabetes," she told the audience at the conference.

Renal Outcomes With SGLT2 Inhibitors in CVOTs Support CREDENCE

"Importantly, DECLARE-TIMI 58 included a substantial number of participants without diagnosed atherosclerotic CVD at baseline and with mild or no CKD, all of whom seemed to derive benefit from dapagliflozin," agreed Ian H. de Boer, MD, University of Washington, Seattle, in an editorial accompanying the article.

"These are large robust effects on important renal outcomes," he stressed.

And these new renal data from DECLARE-TIMI 58 "are fundamentally consistent with secondary analyses of the EMPA-REG OUTCOME and CANVAS program trials of empagliflozin and canagliflozin, respectively."

"Furthermore, in many ways, these three CV outcomes trials [with SGLT2 inhibitors] provide data that are synergistic with those from the [dedicated renal] CREDENCE trial," he added.

In the recently reported breakthrough global CREDENCE trial, the SGLT2 inhibitor canagliflozin lowered the risk for progression to ESRD by 30% in patients with type 2 diabetes and CKD.

Canagliflozin is the first new therapy in nearly 20 years to reduce the risk for kidney failure when added to current standard of care in patients with CKD and type 2 diabetes, the leading cause of ESRD around the world.

CREDENCE "is a crucial trial," explains de Boer, because it showed renal efficacy of an SGLT2 inhibitor in a population selected for the presence of CKD, with renal effects as the main focus.

"In DECLARE-TIMI 58 and the other CV outcomes trials, renal outcomes were secondary outcomes, and therefore considered hypothesis generating. However, their internal validity is now supported by CREDENCE."

Overall Accumulated Data Support Leading Role for SGLT2 Inhibitors

So now, the "overall, accumulated data support a leading role for SGLT2 inhibitors in the management of type 2 diabetes," de Boer continues.

"Cost permitting, and pending the emergence of data for the issues that remain to be addressed (additional trials are underway), there is a strong argument in favor of expanding the population in which use of this drug class could be recommended," he concludes.

Itamar Raz, MD, Hadassah University Medical Center, Jerusalem, Israel, who is a DECLARE-TIMI investigator and senior author of the new analysis on renal outcomes, was even more forthright.

"Medications like dapagliflozin should also be considered as first-line therapy in [type 2 diabetes] patients without established CVD," he states in a press release by the ADA. "The drugs have a high safety margin and should be used regularly by primary care physicians."

According to Raz, the approach of treating patients with newly diagnosed type 2 diabetes by first recommending lifestyle (dietary) changes, then moving on, in turn, to oral antidiabetic monotherapy, up titration, combination therapy, adding basal insulin, and lastly adding multiple daily insulin injections is a "treatment to failure approach."

"Before DECLARE-TIMI 58, physicians knew SGLT2 inhibitors reduced major adverse cardiovascular events (MACE) and heart failure in patients with type 2 diabetes and atherosclerotic CVD, and prevented renal deterioration in patients with cardiorenal disease," he said during a press briefing at ADA.

But it remained unknown how this drug class affects a broader population of patients with type 2 diabetes without atherosclerotic CVD and patients with multiple risk factors and relatively preserved renal function.

In DECLARE-TIMI 58, individuals were eligible if they had just one cardiometabolic risk factor — hypertension, dyslipidemia, or smoking — which 70% of patients with type 2 diabetes have.

What Does This Mean for Diabetes Treatment?

It's now known that dapagliflozin prevents hospitalization for heart failure in a broad population of people with type 2 diabetes, with or without established atherosclerotic CVD and mostly with preserved renal function.

Compared with placebo, those treated with dapagliflozin had higher rates of improvements in UACR and lower rates of deterioration in UACR. And dapagliflozin appears to be especially effective in reducing CV events in high-risk patients with prior heart failure, reduced ejection fraction, or myocardial infarction.

It may also be effective for both preventing and treating CKD across a broad range of patients with type 2 diabetes, and it has a "reassuring overall safety across a broad array of subgroups," Raz emphasized

The trial implies that we need a "new approach to diabetes treatment in the newly diagnosed patient," he said.

Clinicians should make an "early diagnosis; consider combination therapy [with SGLT2 inhibitors/GLP-1 receptor agonists]; treat to 'cure'; ensure durability [of treatment response]; and [provide] personal therapy according to cardiorenal status," he urged.

"It's a matter of expenses. If you give two drugs which are safe, you can 'cure' diabetes, you can bring the sugar down to normal, and this can give you years of not having diabetes," Raz told Medscape Medical News.

SGLT2 inhibitors "in 90% to 95% of patients do not cause side effects. The patient loves the drug, they see fantastic effects. It reduces high blood pressure if they have it — and many have it. It reduces weight and it can prevent deterioration of kidney disease or even heart failure."

"So this is really a breakthrough in medicine. The time to give this drug is very early in the disease."

But he also acknowledges, "Cost is the limiting factor."

Remarkable Safety

The new analysis of DECLARE-TIMI 58 comprehensively collected and evaluated safety data, in particular, for known potential side effects of the drug class (such as amputations and genital infections), said Lawrence A. Leiter, MD, University of Toronto, Ontario, Canada, while presenting safety outcomes at the conference.

"The drug demonstrated remarkable overall safety across a broad array of subgroups," he summarized. "Acute kidney injury and major hypoglycemia were less frequent with dapagliflozin."

Diabetic ketoacidosis events and genital infections were rare but more common with dapagliflozin, consistent with the known safety profile of SGLT2 inhibitors.  

And there were no differences in other key safety outcomes, he noted.

"As a class," he said, "I think there were a lot of initial concerns about [SGLT2 inhibitors]."

This included a big worry about the effect of SGLT2 inhibitors on amputations. A higher rate of lower limb amputations (mainly toe) was observed in the CANVAS trials with canagliflozin but wasn't seen in cardiovascular outcome trials of the other SGLT2 inhibitors. But in the renal trial CREDENCE, no increase in amputations was seen with canagliflozin.

So these concerns have not been borne out "in any of the large trials that have been completed," Leiter told Medscape Medical News.

"One always has to balance potential benefit versus potential risks," he continued but, given the demonstrated benefits on heart disease and kidney disease, he too agrees "these drugs probably deserve to be moved up in our therapeutic regimen."

Details of Effects of Dapagliflozin on Kidney Disease

Drilling down the effects on renal outcomes, at the conference Mosenzon noted that patients with diabetes are twice as likely to develop CKD and between six and 12 times more likely to develop ESRD than individuals without diabetes.

In DECLARE-TIMI, 17,160 patients with type 2 diabetes were randomized, but as previously detailed, they were a much broader and healthier population than in previous CV outcomes trials with diabetes drugs. Participants received dapagliflozin (10 mg daily) or placebo in addition to usual therapy and were followed for a median of 4.2 years.

A total of 8162 patients (48%) had good renal function, an estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m2), 7732 patients (45%) had an eGFR of 60 to < 90 mL/min/1.73 m2, and the remaining 1265 patients (7.4%) had an eGFR < 60 mL/min/1.73 m2.

Overall, 120 patients who received dapagliflozin had a sustained decline in eGFR by at least 40% compared with 221 patients who received placebo, a 46% reduction with dapagliflozin (HR, 0.54; P < .0001).

And ESRD or renal death (an infrequent but highly clinically relevant outcome) occurred less frequently in the dapagliflozin than the placebo group (11 vs 27 events; HR, 0.41; P = .012).

Acute kidney injury occurred in 1.5% and 2.0% of patients in the dapagliflozin and placebo groups, respectively.

"On the basis of available evidence, SGLT2 inhibitors seem to reduce the risk of both progression and development of nephropathy in patients with type 2 diabetes, irrespective of the presence of atherosclerotic CVD or baseline renal function," say Mosenzon and colleagues.

"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,” they add.

“However, these trials focus on populations with nephropathy at baseline, and therefore should be considered as complementary to our findings."

Questions Remain About SGLT2 Inhibitors

"Important questions still remain about the use of SGLT2 inhibitors," said de Boer. DECLARE-TIMI 58 was only 4.2 years long, "and unknown adverse effects may develop later."

He also believes the effect of SGLT2 inhibitors on amputations should be closely monitored as these drugs become more commonly used.

He notes that optimal complimentary interventions need to be defined and it is not clear if other patients — such as those who have had a kidney transplant — would benefit from an SGLT2 inhibitor.

Furthermore, we need to investigate the appropriate lower limit of eGFR, and trials of patients at high risk of acute kidney injury may be warranted.   

An ongoing 4000-patient trial is evaluating the effects of dapagliflozin on renal outcomes and CV mortality in patients with CKD (Dapa-CKD). Results are due in November 2020.  

A similar trial with empagliflozin is also underway, EMPA-KIDNEY, which is enrolling 5000 patients with severe to moderate CKD (down to eGFR 20 mL/min/1.73 m2) and examining both kidney disease progression and CV death. Results are expected in June 2022. 

DECLARE-TIMI 58 was initially funded by AstraZeneca and Bristol-Myers Squibb, but by the time of publication, AstraZeneca was the sole funder. de Boer and Mosenzon have no financial relationships with these companies. Leiter and Raz have reported receiving grants and/or being on speakers bureaus and/or receiving honoraria from these companies.

Lancet Diabetes Endocrinol. Published online June 10, 2019. Abstract, Editorial

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