Conference Coverage

DECLARE-TIMI58 shows improved kidney function with dapagliflozin



The sodium-glucose transporter 2 inhibitor (SGLT2) dapagliflozin (Farxiga) was better than placebo at slowing down kidney disease in patients with type 2 diabetes, and it showed reductions in the relative risk of renal-specific and cardiorenal outcomes of 47% and 24%, respectively, over 4 years, according to an analysis of the DECLARE-TIMI58 trial presented at the annual scientific sessions of the American Diabetes Association.

Dr. Itamar Raz of the Hebrew University of Jerusalem, M. Alexander Otto

Dr. Itamar Raz

The findings add to a message physicians are hearing more and more frequently – that SGLT2 inhibitors, which also include empagliflozin (Jardiance) and canagliflozin (Invokana), could be useful for the early prevention of chronic kidney disease in patients who have type 2 diabetes. The main difference between the DECLARE-TIMI58 and previous study data was that most of its population did not have chronic kidney disease.

The drug should be given “at a very early stage of disease – it can reverse the disease and its complications [and] change the outcomes of patients,” said investigator Itamar Raz, MD, of Hebrew University, Jerusalem, in presenting the findings, which were published simultaneously in the Lancet Diabetes & Endocrinology (2019 Jun 10. doi: 10.1016/S2213-8587[19]30180-9).

What’s new in this renal analysis of DECLARE-TIMI58 is that patients were relatively healthy – 60% of them were without established cardiovascular disease and had much better renal function at baseline, compared with patients in other studies. About half of the patients started out with an estimated glomerular filtration rate (eGFR) more than 90 mL/min per 1.73 m2, which means that they had normal kidney function, and most of the rest of the patients had normal to near-normal renal function or mild renal failure. Findings from previous trials with SGLT2 inhibitors that showed renal protection generally included patients with established cardiovascular disease who started out with greater kidney impairment.

Previous findings have also demonstrated cardioprotective effects with SGLT2 inhibitors in patients with type 2 diabetes. For instance, in earlier results from the DECLARE-TIMI58 trial, dapagliflozin reduced the frequency of cardiovascular death or hospitalization for heart failure, compared with placebo (4.9% vs. 5.8%, respectively; New Engl J Med. 2019;380:347-57), although it did not significantly reduce the frequency of stroke, heart attack, or all-cause death, unlike the results from glucagonlike peptide–1 receptor agonists in much sicker patients (Circulation. 2019;139[17]:2022-31).

Taken as a whole, Dr. Raz said that findings for SGLT2 inhibitors, which, like the glucagonlike peptide–1 receptor agonists, are indicated as second-line therapy in type 2 diabetes after metformin, suggest that they should be used sooner in type 2 disease, perhaps in patients with a hemoglobin A1c level as low at 6.5%.

The absolute benefits of dapagliflozin, compared with placebo, notwithstanding, there are safety concerns with SGLT2s, including genitourinary infections, acute kidney injury, Fournier gangrene, diabetic ketoacidosis, bone fractures, and leg amputations (the latter two only with canagliflozin), many of which have been subject to warnings from the Food and Drug Administration.

Safety outcomes for dapagliflozin, compared with placebo, were not tabulated in the new renal report, but the authors noted a previously reported decrease of 30% in risk for acute kidney injury and major hypoglycemia with dapagliflozin over placebo. There was 1 case of Fournier gangrene with the drug versus 5 with placebo; 27 cases of diabetic ketoacidosis versus 12, respectively; 123 amputations versus 113; and 76 genital infections versus 9.

Dr. Matthew Riddle of Oregon Health and Science University, Portland M. Alexander Otto

Dr. Matthew Riddle

Matthew Riddle, MD, of Oregon Health and Science University, Portland, said SGLT2 studies “have shown important short-term benefit, but we have no information on long-term safety. These drugs are not physiologic; they do something powerful, but it’s nothing you see in nature. We don’t really know what they do yet; the physiology is still being worked out.”

DECLARE-TIMI58 randomized 8,582 patients with type 2 diabetes to receive dapagliflozin 10 mg orally daily and 8,578 patients to receive placebo. The patients remained on routine diabetes and cardiovascular care. Inclusion criteria included either established atherosclerotic cardiovascular disease (41% of patients) or cardiovascular risk factors (almost 60%), and creatinine clearance of at least 60 mL/min. Median follow-up was 4.2 years.

Overall, 4.2% of patients receiving dapagliflozin and 5.3% of those receiving placebo, met a prespecified secondary cardiorenal composite outcome of end-stage renal disease; death from renal or cardiovascular causes; or a decline of at least 40% in eGFR to less than 60 mL/min per 1.73 m2 according to two tests at least 4 weeks apart (hazard ratio, 0.76; P less than .0001).

Similarly, 1.5% of dapagliflozin patients and 2.6% of those on placebo met a prespecified renal-specific composite of those factors minus death from cardiovascular causes (HR, 0.53; P less than .0001).

Among placebo-treated patients, 2.5% had a sustained decline in eGFR of at least 40% to less than 60 mL/min per 1.73 m2, compared with 1.4% in the dapagliflozin group (HR, 0.54; P less than .0001). There were 11 cases of end-stage renal disease or renal death with dapagliflozin (0.1%), compared with 27 (0.3%) with placebo (HR, 0.41; P = .012).

Among patients who entered the trial with significant renal impairment – an eGFR of less than 60 mL/min per 1.73 m2 – the difference in further renal decline with dapagliflozin was not statistically significant against placebo because of the small number of patients, but Dr. Raz said the drug should still be used earlier in type 2 disease.

Dapagliflozin patients fared worse on renal measurements at 6 months, but caught up by year 2, and surpassed placebo at years 3 and 4, the authors wrote in the latest report.

Just more than 60% of participants were men; patients were in their 60s, on average, and overweight. About 80% of the patients were white.

AstraZeneca, which makes dapagliflozin, was involved with study design, data collection, data analysis, interpretation, and writing of the report. Four authors were employees of the company, and all but two of the 17 others, including Dr. Raz, disclosed personal payments from the company and/or research funding. Dr. Riddle disclosed receiving research funding from AstraZeneca.

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