Efficacy and Safety of Dapagliflozin by Baseline Glycemic Status: A Prespecified Analysis From the DAPA-CKD Trial

Objective DAPA-CKD demonstrated risk reduction for kidney and cardiovascular outcomes with dapagliflozin versus placebo in participants with chronic kidney disease (CKD) with and without diabetes. We compared outcomes according to baseline glycemic status. Research Design and Methods We enrolled participants with CKD, estimated glomerular filtration rate (eGFR) 25–75ml/min/1.73m2 and urinary albumin-to-creatinine ratio 200–5000mg/g. The primary composite endpoint was sustained eGFR decline ≥50%, end-stage kidney disease, or kidney or cardiovascular death. Results Of 4304 participants, 738 had normoglycemia, 660 pre-diabetes, and 2906 type 2 diabetes. The effect of dapagliflozin on the primary outcome was consistent (p-interaction=0.19) in normoglycemia (HR [95%CI] 0.62 [0.39–1.01]), pre-diabetes (HR 0.37 [0.21–0.66]) and type 2 diabetes (HR 0.64 [0.52–0.79]). We found no evidence for effect modification on any outcome. Adverse events were similar, with no major hypoglycemia or ketoacidosis in participants with normoglycemia or pre-diabetes. Conclusions Dapagliflozin safely reduced kidney and cardiovascular events independent of baseline glycemic status.

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Effects of linagliptin on cardiovascular and kidney outcomes in people with normal and reduced kidney function: secondary analysis of the CARMELINA randomized trial

10.2337/figshare.12129993 ◽

2020 ◽

Author(s):

Vlado Perkovic ◽

Robert Toto ◽

Mark E Cooper ◽

Johannes FE Mann ◽

Julio Rosenstock ◽

...

Keyword(s):

Type 2 Diabetes ◽

Kidney Disease ◽

Secondary Analysis ◽

Cardiovascular Death ◽

Secondary Outcome ◽

First Occurrence ◽

Outcome Trial ◽

End Stage ◽

Reduced Kidney Function

Objective Type 2 diabetes is a leading cause of kidney failure, but few outcome trials proactively enrolled individuals with chronic kidney disease (CKD). We performed secondary analyses of cardiovascular and kidney outcomes across baseline eGFR categories (≥ 60, 45-<60, 30-<45 and < 30 ml/min/1.73 m2) in CARMELINA, a cardio-renal placebo-controlled outcome trial of the DPP-4 inhibitor linagliptin (NCT01897532). Research Design and Methods Participants with cardiovascular disease (CVD) and/or CKD were included. The primary outcome was time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (3P-MACE), with a secondary outcome renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline. Other endpoints included progression of albuminuria, change in HbA1c and adverse events (AEs) including hypoglycemia. Results 6979 subjects (mean age 65.9 years, eGFR 54.6 ml/min/1.73m2, 80.1% albuminuria) were followed for 2.2 years. Across eGFR categories, linagliptin as compared to placebo did not affect the risk for 3P-MACE (HR.1.02 [95% CI, 0.89, 1.17]), or the secondary kidney outcome (1.04 [0.89, 1.22]) (interaction p-values > 0.05). Regardless of eGFR, albuminuria-progression was reduced with linagliptin, as was HbA1c, without increasing risk for hypoglycemia. AEs were balanced between groups overall and across eGFR categories. Conclusions Across all GFR categories, in participants with type 2 diabetes and CKD and/or CVD, there was no difference in risk for linagliptin versus placebo on CV and kidney events. Significant reductions in risk for albuminuria progression and HbA1c, and no difference in AEs was observed.

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Effects of linagliptin on cardiovascular and kidney outcomes in people with normal and reduced kidney function: secondary analysis of the CARMELINA randomized trial

10.2337/figshare.12129993.v1 ◽

2020 ◽

Author(s):

Vlado Perkovic ◽

Robert Toto ◽

Mark E Cooper ◽

Johannes FE Mann ◽

Julio Rosenstock ◽

...

Keyword(s):

Type 2 Diabetes ◽

Kidney Disease ◽

Secondary Analysis ◽

Cardiovascular Death ◽

Secondary Outcome ◽

First Occurrence ◽

Outcome Trial ◽

End Stage ◽

Reduced Kidney Function

Objective Type 2 diabetes is a leading cause of kidney failure, but few outcome trials proactively enrolled individuals with chronic kidney disease (CKD). We performed secondary analyses of cardiovascular and kidney outcomes across baseline eGFR categories (≥ 60, 45-<60, 30-<45 and < 30 ml/min/1.73 m2) in CARMELINA, a cardio-renal placebo-controlled outcome trial of the DPP-4 inhibitor linagliptin (NCT01897532). Research Design and Methods Participants with cardiovascular disease (CVD) and/or CKD were included. The primary outcome was time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (3P-MACE), with a secondary outcome renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline. Other endpoints included progression of albuminuria, change in HbA1c and adverse events (AEs) including hypoglycemia. Results 6979 subjects (mean age 65.9 years, eGFR 54.6 ml/min/1.73m2, 80.1% albuminuria) were followed for 2.2 years. Across eGFR categories, linagliptin as compared to placebo did not affect the risk for 3P-MACE (HR.1.02 [95% CI, 0.89, 1.17]), or the secondary kidney outcome (1.04 [0.89, 1.22]) (interaction p-values > 0.05). Regardless of eGFR, albuminuria-progression was reduced with linagliptin, as was HbA1c, without increasing risk for hypoglycemia. AEs were balanced between groups overall and across eGFR categories. Conclusions Across all GFR categories, in participants with type 2 diabetes and CKD and/or CVD, there was no difference in risk for linagliptin versus placebo on CV and kidney events. Significant reductions in risk for albuminuria progression and HbA1c, and no difference in AEs was observed.

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Effect of dapagliflozin in DAPA-HF according to background glucose-lowering therapy

10.2337/figshare.12732806.v1 ◽

2020 ◽

Author(s):

Kieran F. Docherty ◽

Pardeep S. Jhund ◽

Olof Bengtsson ◽

David L. DeMets ◽

Silvio E. Inzucchi ◽

...

Keyword(s):

Type 2 Diabetes ◽

Primary Outcome ◽

Cardiovascular Death ◽

Glucose Lowering ◽

Reduced Ejection Fraction ◽

Lowering Therapy ◽

Improved Outcomes ◽

Glucose Lowering Therapy ◽

Design And Methods

Objective: To determine whether the benefits of dapagliflozin in patients with heart failure and reduced ejection fraction (HFrEF) and type 2 diabetes in DAPA-HF varied by background glucose-lowering therapy (GLT). Research design and methods: We examined the effect of study treatment by the use or not of GLT, and by GLT classes and combinations. The primary outcome was a composite of worsening HF (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death. Results: In the 2139 type 2 diabetes patients, the effect of dapagliflozin on the primary outcome was consistent by GLT use/no use (hazard ratio 0.72 [95%CI 0.58-0.88] versus 0.86 [0.60-1.23]; P-interaction=0.39) and across GLT classes. Conclusions: In DAPA-HF, dapagliflozin improved outcomes irrespective of use/no use of GLT or by GLT type used in patients with type 2 diabetes and HFrEF.

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Effects of linagliptin on cardiovascular and kidney outcomes in people with normal and reduced kidney function: secondary analysis of the CARMELINA randomized trial

10.2337/figshare.12129993.v2 ◽

2020 ◽

Author(s):

Vlado Perkovic ◽

Robert Toto ◽

Mark E Cooper ◽

Johannes FE Mann ◽

Julio Rosenstock ◽

...

Keyword(s):

Type 2 Diabetes ◽

Kidney Disease ◽

Secondary Analysis ◽

Cardiovascular Death ◽

Secondary Outcome ◽

First Occurrence ◽

Outcome Trial ◽

End Stage ◽

Reduced Kidney Function

Objective Type 2 diabetes is a leading cause of kidney failure, but few outcome trials proactively enrolled individuals with chronic kidney disease (CKD). We performed secondary analyses of cardiovascular and kidney outcomes across baseline eGFR categories (≥ 60, 45-<60, 30-<45 and < 30 ml/min/1.73 m2) in CARMELINA, a cardio-renal placebo-controlled outcome trial of the DPP-4 inhibitor linagliptin (NCT01897532). Research Design and Methods Participants with cardiovascular disease (CVD) and/or CKD were included. The primary outcome was time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (3P-MACE), with a secondary outcome renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline. Other endpoints included progression of albuminuria, change in HbA1c and adverse events (AEs) including hypoglycemia. Results 6979 subjects (mean age 65.9 years, eGFR 54.6 ml/min/1.73m2, 80.1% albuminuria) were followed for 2.2 years. Across eGFR categories, linagliptin as compared to placebo did not affect the risk for 3P-MACE (HR.1.02 [95% CI, 0.89, 1.17]), or the secondary kidney outcome (1.04 [0.89, 1.22]) (interaction p-values > 0.05). Regardless of eGFR, albuminuria-progression was reduced with linagliptin, as was HbA1c, without increasing risk for hypoglycemia. AEs were balanced between groups overall and across eGFR categories. Conclusions Across all GFR categories, in participants with type 2 diabetes and CKD and/or CVD, there was no difference in risk for linagliptin versus placebo on CV and kidney events. Significant reductions in risk for albuminuria progression and HbA1c, and no difference in AEs was observed.

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Effect of dapagliflozin in DAPA-HF according to background glucose-lowering therapy

10.2337/figshare.12732806 ◽

2020 ◽

Author(s):

Kieran F. Docherty ◽

Pardeep S. Jhund ◽

Olof Bengtsson ◽

David L. DeMets ◽

Silvio E. Inzucchi ◽

...

Keyword(s):

Type 2 Diabetes ◽

Primary Outcome ◽

Cardiovascular Death ◽

Glucose Lowering ◽

Reduced Ejection Fraction ◽

Lowering Therapy ◽

Improved Outcomes ◽

Glucose Lowering Therapy ◽

Design And Methods

Objective: To determine whether the benefits of dapagliflozin in patients with heart failure and reduced ejection fraction (HFrEF) and type 2 diabetes in DAPA-HF varied by background glucose-lowering therapy (GLT). Research design and methods: We examined the effect of study treatment by the use or not of GLT, and by GLT classes and combinations. The primary outcome was a composite of worsening HF (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death. Results: In the 2139 type 2 diabetes patients, the effect of dapagliflozin on the primary outcome was consistent by GLT use/no use (hazard ratio 0.72 [95%CI 0.58-0.88] versus 0.86 [0.60-1.23]; P-interaction=0.39) and across GLT classes. Conclusions: In DAPA-HF, dapagliflozin improved outcomes irrespective of use/no use of GLT or by GLT type used in patients with type 2 diabetes and HFrEF.

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The dapagliflozin and prevention of adverse outcomes in chronic kidney disease: results of the DAPA-CKD study

Terapevticheskii arkhiv ◽

10.26442/00403660.2021.6.200891 ◽

2021 ◽

Vol 93 (6) ◽

pp. 713-723

Author(s):

Mikhail M. Batyushin

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Controlled Trial ◽

Composite Endpoint ◽

Cardiovascular Death ◽

Adverse Outcomes ◽

Double Blind ◽

Stage Renal Disease ◽

End Stage

Aim. The article presents the main results of a randomized, double-blind, parallel, placebo controlled trial of DAPA-CKD. Materials and methods. The study included patients with chronic kidney disease (CKD) and the possibility of using dapagliflozin at a dose of 10 mg once a day compared with placebo. The study involved 386 centers from 21 countries. A total of 4304 patients were included in the study, the average age was 61.8 years, men predominated, 2906 (67.5%) patients had an initial diagnosis of type 2 diabetes. Patients with diabetic and non-diabetic CKD were included with an estimated glomerular filtration rate (eGFR) of 25 to 75 ml/min/1.73 m2 and a urinary albumin/creatinine ratio of 200 to 5000 mg/g. Results. The primary composite endpoint (time to eGFR reduction of 50% or more compared to baseline, time to end-stage renal disease defined as eGFR15 ml/min/1.73 m2, need for chronic dialysis or kidney transplantation, time to renal or cardiovascular death) was shown to occur in 9.2% of patients treated with dapagliflozin and in 14.5% of patients treated with placebo. Also, dapagliflozin therapy was less likely to have a secondary endpoint, such as a combination of a decrease in eGFR by 50% or more, end-stage kidney disease, or renal death. Less frequently, the dapagliflozin group experienced cardiovascular death or hospitalization for heart failure, as well as death from any cause. Conclusion. Thus, dapagliflozin demonstrated the ability, in comparison with placebo, to reduce the primary composite point and a number of secondary composite points in patients with both diabetic and non-diabetic CKD.

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Lesser eGFR Decline with Dulaglutide Regardless of Weight Changes in People with Type 2 Diabetes and Moderate to Severe Chronic Kidney Disease (AWARD-7)

Diabetes ◽

10.2337/db18-1066-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 1066-P ◽

Cited By ~ 2

Author(s):

KATHERINE R. TUTTLE ◽

MARK LAKSHMANAN ◽

BRIAN L. RAYNER ◽

ROBERT S. BUSCH ◽

ALAN G. ZIMMERMANN ◽

...

Keyword(s):

Type 2 Diabetes ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Weight Changes ◽

Severe Chronic Kidney Disease ◽

Egfr Decline

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Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial

Diabetologia ◽

10.1007/s00125-021-05407-5 ◽

2021 ◽

Author(s):

David Z. I. Cherney ◽

◽

Bernard Charbonnel ◽

Francesco Cosentino ◽

Samuel Dagogo-Jack ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Kidney Disease ◽

Serum Creatinine ◽

Renal Dialysis ◽

Composite Endpoint ◽

Composite Outcome ◽

The Impact

Abstract Aims/hypothesis In previous work, we reported the HR for the risk (95% CI) of the secondary kidney composite endpoint (time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death) with ertugliflozin compared with placebo as 0.81 (0.63, 1.04). The effect of ertugliflozin on exploratory kidney-related outcomes was evaluated using data from the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881). Methods Individuals with type 2 diabetes mellitus and established atherosclerotic CVD were randomised to receive ertugliflozin 5 mg or 15 mg (observations from both doses were pooled), or matching placebo, added on to existing treatment. The kidney composite outcome in VERTIS CV (reported previously) was time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death. The pre-specified exploratory composite outcome replaced doubling of serum creatinine with sustained 40% decrease from baseline in eGFR. In addition, the impact of ertugliflozin on urinary albumin/creatinine ratio (UACR) and eGFR over time was assessed. Results A total of 8246 individuals were randomised and followed for a mean of 3.5 years. The exploratory kidney composite outcome of sustained 40% reduction from baseline in eGFR, chronic kidney dialysis/transplant or renal death occurred at a lower event rate (events per 1000 person-years) in the ertugliflozin group than with the placebo group (6.0 vs 9.0); the HR (95% CI) was 0.66 (0.50, 0.88). At 60 months, in the ertugliflozin group, placebo-corrected changes from baseline (95% CIs) in UACR and eGFR were −16.2% (−23.9, −7.6) and 2.6 ml min−1 [1.73 m]−2 (1.5, 3.6), respectively. Ertugliflozin was associated with a consistent decrease in UACR and attenuation of eGFR decline across subgroups, with a suggested larger effect observed in the macroalbuminuria and Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease (KDIGO CKD) high/very high-risk subgroups. Conclusions/interpretation Among individuals with type 2 diabetes and atherosclerotic CVD, ertugliflozin reduced the risk for the pre-specified exploratory composite renal endpoint and was associated with preservation of eGFR and reduced UACR. Trial registration ClinicalTrials.gov NCT01986881 Graphical abstract

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The Severity of Diabetic Retinopathy Is an Independent Factor for the Progression of Diabetic Nephropathy

Journal of Clinical Medicine ◽

10.3390/jcm10010003 ◽

2020 ◽

Vol 10 (1) ◽

pp. 3

Author(s):

Shi-Chue Hsing ◽

Chia-Cheng Lee ◽

Chin Lin ◽

Jiann-Torng Chen ◽

Yi-Hao Chen ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Kidney Disease ◽

Renal Disease ◽

Disease Progression ◽

Renal Disease Progression ◽

Hazard Ratios ◽

Stage Renal Disease ◽

End Stage

(1) Background: It has rarely been studied whether the severity of diabetic retinopathy (DR) could influence renal disease progression in end-stage renal disease (ESRD) and chronic kidney disease (CKD) in patients with type 2 diabetes. The aim of this study was to evaluate renal disease progression in ESRD and CKD according to DR severity in patients with type 2 diabetes. (2) Methods: We included 1329 patients and divided the cohort into two end-points. The first was to trace the incidence of ESRD in all enrolled participants and the other was to follow their progression to CKD. (3) Results: Significantly higher crude hazard ratios (HRs) of ESRD incidence in all enrolled participants were noted, and this ratio increased in a stepwise fashion. However, after adjustment, DR severity was not associated with ESRD events. Therefore, a subgroup of 841 patients without CKD was enrolled to track their progression to CKD. Compared with no diabetic retinopathy, the progression of CKD increased in a stepwise fashion, from mild nonproliferative diabetic retinopathy (NPDR) to moderate NPDR, to severe NPDR and to proliferative diabetic retinopathy (PDR), both in the crude and adjusted models. (4) Conclusions: The severity of retinopathy appeared to be associated with renal lesions and the development of CKD. Our findings suggest that the severity of DR is a risk factor for progression to CKD. Therefore, diabetic retinopathy is useful for prognosticating the clinical course of diabetic kidney disease.

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