Meeting News

DECLARE-TIMI 58: Dapagliflozin shows ‘robust’ potential for kidney disease prevention in type 2 diabetes

SAN FRANCISCO —Beyond improved cardiovascular outcomes, the SGLT2 inhibitor dapagliflozin may also offer adults with type 2 diabetes the potential to prevent and treat kidney disease, according to findings presented at the American Diabetes Association Scientific Sessions and simultaneously published in The Lancet Diabetes & Endocrinology.

Ofri Mosenzon

“We have already shown in the first publication that dapagliflozin reduced the chance of what we call the cardiorenal and the renal-specific outcome. ... What we have shown this time is the fact that it’s actually reduced the risk of any of the components ... meaning reduction of [estimated glomerular filtration rate] by 40% or more to less than 60 [mL/min/1.73 m2], reduction of end-stage renal disease, reduction of combination of end-stage and renal death,” Ofri Mosenzon, MD, MSc, an attending physician in the department of internal medicine at Hadassah Hebrew University Hospital in Israel, told Endocrine Today. “These are very important outcomes.”

Mosenzon and colleagues conducted a renal analysis in 17,160 participants with type 2 diabetes from the DECLARE-TIMI 58 trial. Recruitment inclusion criteria for the trial included having an HbA1c of at least 6.5% but no more than 12% along with risk factors for atherosclerotic CVD or diagnosis of the condition itself and creatinine clearance of 60 mL/min or higher, according to the researchers.

A 10 mg daily regimen of dapagliflozin (Farxiga, AstraZeneca) or placebo was randomly assigned to participants, who were then followed for a median of 4.2 years. At baseline and then every 6 months during the first year, serum creatinine and urinary albumin and creatinine levels were assessed and eGFR was calculated. From there, these evaluations were conducted every 12 months until the trial’s conclusion. Among the participants, 5,057 had an eGFR of at least 90 mL/min/1.73 m2 (mean age, 61.2 years; 38% women) at baseline with 4,866 having a measure between 60 mL/min/1.73 m2 and 89 mL/min/1.73 m2 (mean age, 66.2 years; 37.1% women) and 814 having a measure of less than 60 mL/min/1.73 m2 (mean age, 67.3 years; 35.7% women).

According to Mosenzon, a 40% reduction in eGFR to below a 60 mL/min/1.73 m2 threshold along with ESRD or renal or CV death was the primary composite renal outcome. A secondary renal-specific outcome eliminated the CV death considerations.

Cardiorenal and renal-specific benefits

The event rate for the primary cardiorenal outcome was higher for those in the placebo group compared with the dapagliflozin group (5.3% vs. 4.2%), as was the event rate for the renal-specific outcome (2.6% vs. 1.5%; P < .0001 for both). The researchers further noted that dapagliflozin treatment reduced the incidence of the primary outcome by 24% (HR = 0.76; 95% CI, 0.67-0.87) and the incidence of the renal-only secondary outcome by 47% (HR = 0.53; 95% CI, 0.43-066).

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Beyond improved cardiovascular outcomes, the SGLT2 inhibitor dapagliflozin may also offer adults with type 2 diabetes the potential to prevent and treat kidney disease.
Adobe Stock

Those in the dapagliflozin group also had lower event rates for an eGFR decline of at least 40% below the 60 mL/min/1.73 m2 threshold (1.4% vs. 2.5%; P < .0001) and for ESRD (0.1% vs. 0.2%; P = .013) compared with the placebo group, which equated to risk reductions of 46% (HR = 0.54; 95% CI, 0.43-0.67 ) and 69% (HR = 0.31; 95% CI, 0.13-0.79), respectively. End-stage renal death was also less frequently reported in the dapagliflozin cohort compared with the placebo cohort (0.1% vs. 0.3% event rate; P = .012) with the risk decreased by 59% (HR = 0.41; 95% CI, 0.2-0.82).

Mosenzon noted that subgroup analysis did not reveal marked differences in these results based on demographics or pretreatment medical history, prior medication use or baseline HbA1c, eGFR or urinary albumin to creatinine ratio. Furthermore, the most noticeable differences between the two treatment groups were found after 2 years of treatment.

Effects on albuminuria status

During a press conference, Itamar Raz, MD, a professor of internal medicine at the Hadassah Medical School at the Hebrew University of Jerusalem, provided additional results of the DELCARE-TIMI 58 trial, specifically addressing changes in albuminuria status. According to Raz, compared with placebo, dapagliflozin yielded a 46% reduction in the chances of going from normal urinary albumin to creatinine ratio to either microalbuminuria or macroalbuminuria (HR = 0.54; 95% CI, 0.45-0.65) and increases of 54% and 18% in the odds of reversing microalbuminuria to normal urinary albumin-to-creatinine ratio (HR = 1.46; 95% CI, 1.31-1.62) and reversing macroalbuminuria to either microalbuminuria or normal urinary albumin to creatinine ratio (HR = 1.82; 95% CI, 1.51-2.2), respectively.

“We have shown that the reduction in the cardiorenal-specific outcome was achieved across all subgroups analysis, and that is very important ... because it showed the robustness of this finding,” Mosenzon said. “It gives us a great external validity. By that, it shows us something that is a very important addition to on-going and completed previous trials with SGLT2 inhibitors because all other trials were mainly concentrated and continue to concentrate more and more on patients with renal disease already.” – by Phil Neuffer

References:

Mosenzon AB. 236-OR. Effects of dapagliflozin on progression of diabetic kidney disease: Analysis from DECLARE-TIMI 58 trial.

Raz I. Effects of dapagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes: A predefined analysis from the DECLARE-TIMI 58 randomised, placebo-controlled trial. Both presented at: American Diabetes Association 79th Scientific Sessions; June 7-11, 2019; San Francisco.

Mosenzon O, et al. Lancet Diabetes Endocrinol. 2019;doi:10.1016/S2213-8587(19)30180-9.

Disclosures: Mosenzon reports she has received grants and personal fees from AstraZeneca, Bristol-Myers Squibb and Novo Nordisk and personal fees from Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Merck Sharp & Dohme, Novartis and Sanofi. Raz reports he has served on the advisory board for AstraZeneca, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk and Sanofi; as a consultant for AstraZeneca, Bristol-Myers Squibb, BOL, CamerEyes, DarioHealth, Diabot, Exscopia, Glucome, Insuline Medical, Medial EarlySign and Oregenesis; and on the speakers bureau for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk and Sanofi. He also reports he is a stock shareholder in BOL, CamerEyes, DarioHealth, Diabot, Glucome and Oregenesis.

SAN FRANCISCO —Beyond improved cardiovascular outcomes, the SGLT2 inhibitor dapagliflozin may also offer adults with type 2 diabetes the potential to prevent and treat kidney disease, according to findings presented at the American Diabetes Association Scientific Sessions and simultaneously published in The Lancet Diabetes & Endocrinology.

Ofri Mosenzon

“We have already shown in the first publication that dapagliflozin reduced the chance of what we call the cardiorenal and the renal-specific outcome. ... What we have shown this time is the fact that it’s actually reduced the risk of any of the components ... meaning reduction of [estimated glomerular filtration rate] by 40% or more to less than 60 [mL/min/1.73 m2], reduction of end-stage renal disease, reduction of combination of end-stage and renal death,” Ofri Mosenzon, MD, MSc, an attending physician in the department of internal medicine at Hadassah Hebrew University Hospital in Israel, told Endocrine Today. “These are very important outcomes.”

Mosenzon and colleagues conducted a renal analysis in 17,160 participants with type 2 diabetes from the DECLARE-TIMI 58 trial. Recruitment inclusion criteria for the trial included having an HbA1c of at least 6.5% but no more than 12% along with risk factors for atherosclerotic CVD or diagnosis of the condition itself and creatinine clearance of 60 mL/min or higher, according to the researchers.

A 10 mg daily regimen of dapagliflozin (Farxiga, AstraZeneca) or placebo was randomly assigned to participants, who were then followed for a median of 4.2 years. At baseline and then every 6 months during the first year, serum creatinine and urinary albumin and creatinine levels were assessed and eGFR was calculated. From there, these evaluations were conducted every 12 months until the trial’s conclusion. Among the participants, 5,057 had an eGFR of at least 90 mL/min/1.73 m2 (mean age, 61.2 years; 38% women) at baseline with 4,866 having a measure between 60 mL/min/1.73 m2 and 89 mL/min/1.73 m2 (mean age, 66.2 years; 37.1% women) and 814 having a measure of less than 60 mL/min/1.73 m2 (mean age, 67.3 years; 35.7% women).

According to Mosenzon, a 40% reduction in eGFR to below a 60 mL/min/1.73 m2 threshold along with ESRD or renal or CV death was the primary composite renal outcome. A secondary renal-specific outcome eliminated the CV death considerations.

Cardiorenal and renal-specific benefits

The event rate for the primary cardiorenal outcome was higher for those in the placebo group compared with the dapagliflozin group (5.3% vs. 4.2%), as was the event rate for the renal-specific outcome (2.6% vs. 1.5%; P < .0001 for both). The researchers further noted that dapagliflozin treatment reduced the incidence of the primary outcome by 24% (HR = 0.76; 95% CI, 0.67-0.87) and the incidence of the renal-only secondary outcome by 47% (HR = 0.53; 95% CI, 0.43-066).

#
Beyond improved cardiovascular outcomes, the SGLT2 inhibitor dapagliflozin may also offer adults with type 2 diabetes the potential to prevent and treat kidney disease.
Adobe Stock

Those in the dapagliflozin group also had lower event rates for an eGFR decline of at least 40% below the 60 mL/min/1.73 m2 threshold (1.4% vs. 2.5%; P < .0001) and for ESRD (0.1% vs. 0.2%; P = .013) compared with the placebo group, which equated to risk reductions of 46% (HR = 0.54; 95% CI, 0.43-0.67 ) and 69% (HR = 0.31; 95% CI, 0.13-0.79), respectively. End-stage renal death was also less frequently reported in the dapagliflozin cohort compared with the placebo cohort (0.1% vs. 0.3% event rate; P = .012) with the risk decreased by 59% (HR = 0.41; 95% CI, 0.2-0.82).

Mosenzon noted that subgroup analysis did not reveal marked differences in these results based on demographics or pretreatment medical history, prior medication use or baseline HbA1c, eGFR or urinary albumin to creatinine ratio. Furthermore, the most noticeable differences between the two treatment groups were found after 2 years of treatment.

Effects on albuminuria status

During a press conference, Itamar Raz, MD, a professor of internal medicine at the Hadassah Medical School at the Hebrew University of Jerusalem, provided additional results of the DELCARE-TIMI 58 trial, specifically addressing changes in albuminuria status. According to Raz, compared with placebo, dapagliflozin yielded a 46% reduction in the chances of going from normal urinary albumin to creatinine ratio to either microalbuminuria or macroalbuminuria (HR = 0.54; 95% CI, 0.45-0.65) and increases of 54% and 18% in the odds of reversing microalbuminuria to normal urinary albumin-to-creatinine ratio (HR = 1.46; 95% CI, 1.31-1.62) and reversing macroalbuminuria to either microalbuminuria or normal urinary albumin to creatinine ratio (HR = 1.82; 95% CI, 1.51-2.2), respectively.

“We have shown that the reduction in the cardiorenal-specific outcome was achieved across all subgroups analysis, and that is very important ... because it showed the robustness of this finding,” Mosenzon said. “It gives us a great external validity. By that, it shows us something that is a very important addition to on-going and completed previous trials with SGLT2 inhibitors because all other trials were mainly concentrated and continue to concentrate more and more on patients with renal disease already.” – by Phil Neuffer

References:

Mosenzon AB. 236-OR. Effects of dapagliflozin on progression of diabetic kidney disease: Analysis from DECLARE-TIMI 58 trial.

Raz I. Effects of dapagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes: A predefined analysis from the DECLARE-TIMI 58 randomised, placebo-controlled trial. Both presented at: American Diabetes Association 79th Scientific Sessions; June 7-11, 2019; San Francisco.

Mosenzon O, et al. Lancet Diabetes Endocrinol. 2019;doi:10.1016/S2213-8587(19)30180-9.

Disclosures: Mosenzon reports she has received grants and personal fees from AstraZeneca, Bristol-Myers Squibb and Novo Nordisk and personal fees from Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Merck Sharp & Dohme, Novartis and Sanofi. Raz reports he has served on the advisory board for AstraZeneca, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk and Sanofi; as a consultant for AstraZeneca, Bristol-Myers Squibb, BOL, CamerEyes, DarioHealth, Diabot, Exscopia, Glucome, Insuline Medical, Medial EarlySign and Oregenesis; and on the speakers bureau for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk and Sanofi. He also reports he is a stock shareholder in BOL, CamerEyes, DarioHealth, Diabot, Glucome and Oregenesis.

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