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

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

10.2337/figshare.14465844.v1 ◽

2021 ◽

Author(s):

Frederik Persson ◽

Peter Rossing ◽

Priya Vart ◽

Glenn M. Chertow ◽

Fan Fan Hou ◽

...

Keyword(s):

Type 2 Diabetes ◽

Kidney Disease ◽

Primary Outcome ◽

Composite Endpoint ◽

Cardiovascular Death ◽

Glycemic Status ◽

End Stage ◽

Design And Methods ◽

Egfr Decline

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

10.2337/figshare.14465844 ◽

2021 ◽

Author(s):

Frederik Persson ◽

Peter Rossing ◽

Priya Vart ◽

Glenn M. Chertow ◽

Fan Fan Hou ◽

...

Keyword(s):

Type 2 Diabetes ◽

Kidney Disease ◽

Primary Outcome ◽

Composite Endpoint ◽

Cardiovascular Death ◽

Glycemic Status ◽

End Stage ◽

Design And Methods ◽

Egfr Decline

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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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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Type 2 diabetes in patients with end‐stage kidney disease: influence on cardiovascular disease‐related mortality risk

The Medical Journal of Australia ◽

10.5694/mja18.00195 ◽

2018 ◽

Vol 209 (10) ◽

pp. 440-446 ◽

Cited By ~ 10

Author(s):

Wai H Lim ◽

David W Johnson ◽

Carmel Hawley ◽

Charmaine Lok ◽

Kevan R Polkinghorne ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Kidney Disease ◽

Mortality Risk ◽

End Stage Kidney Disease ◽

End Stage ◽

Related Mortality

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The Association Between Age of Onset of Type 2 Diabetes with Long-term Risk of End Stage Kidney Disease: A National Registry Study

10.2337/figshare.12273110.v1 ◽

2020 ◽

Author(s):

Jedidiah I Morton ◽

Danny Liew ◽

Stephen P McDonald ◽

Jonathan E Shaw ◽

Dianna J Magliano

Keyword(s):

Type 2 Diabetes ◽

Kidney Disease ◽

Cumulative Incidence ◽

Age Of Onset ◽

End Stage Kidney Disease ◽

Onset Of Diabetes ◽

End Stage ◽

Effect Of Age

Objective: The long-term risk of end-stage kidney disease (ESKD) in type 2 diabetes is poorly described, as is the effect that younger age of diabetes onset has on this risk. Therefore, we aimed to estimate the effect of age of onset on the cumulative incidence of ESKD from onset of type 2 diabetes. Research Design and Methods: This study included 1,113,201 people with type 2 diabetes registered on the Australian National Diabetes Services Scheme (NDSS) followed from 2002 until 2013. The NDSS was linked to the Australia and New Zealand Dialysis and Transplant Registry and the Australian National Death Index. Results: Between 2002 and 2013, there were 7,592 incident cases of ESKD during 7,839,075 person-years of follow up. In the first 10-15 years following onset of diabetes, the incidence of ESKD was highest in those with an older age of onset of diabetes, whereas over longer durations of diabetes the incidence of ESKD became higher in those with younger-onset diabetes. After 40 years of diabetes, the cumulative incidence of ESKD was 11.8% and 9.3% in those diagnosed with diabetes aged 10-29 and 30-39 years, respectively. When death from ESKD without renal replacement therapy was included, incidence of ESKD remained higher in older onset diabetes for the initial 20 years, with no clear effect of age thereafter. Conclusions: The long-term risk of ESKD in type 2 diabetes is high, which disproportionately affects those with younger-onset of diabetes as they are more likely to survive to longer diabetes durations.

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Pros and cons of gastric bypass surgery in individuals with obesity and type 2 diabetes: nationwide, matched, observational cohort study

BMJ Open ◽

10.1136/bmjopen-2018-023882 ◽

2019 ◽

Vol 9 (1) ◽

pp. e023882 ◽

Cited By ~ 10

Author(s):

Vasileios Liakopoulos ◽

Stefan Franzén ◽

Ann-Marie Svensson ◽

Mervete Miftaraj ◽

Johan Ottosson ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Gastric Bypass ◽

Kidney Disease ◽

Secondary Outcome ◽

Control Group ◽

Positive Effects ◽

All Cause Mortality

ObjectivesLong-term effects of gastric bypass (GBP) surgery have been presented in observational and randomised studies, but there are only limited data for persons with obesity and type 2 diabetes mellitus (T2DM) regarding postoperative complications.DesignThis is a nationwide observational study based on two quality registers in Sweden (National Diabetes Register, NDR and Scandinavian Obesity Surgery Register, SOReg) and other national databases.SettingAfter merging the data, we matched individuals with T2DM who had undergone GBP with those not surgically treated for obesity on propensity score, based on sex, age, body mass index (BMI) and calendar time. The risks of postoperative outcomes (rehospitalisations) were assessed using Cox regression models.ParticipantsWe identified 5321 patients with T2DM in the SOReg and 5321 matched controls in the NDR, aged 18–65 years, with BMI >27.5 kg/m² and followed for up to 9 years.Primary and secondary outcome measuresWe assessed risks for all-cause mortality and hospitalisations for cardiovascular disease, severe kidney disease, along with surgical and other medical conditions.ResultsThe results agree with the previously suggested lower risks of all-cause mortality (49%) and cardiovascular disease (34%), and we also found positive effects for severe kidney disease but significantly increased risks (twofold to ninefold) of several short-term complications after GBP, such as abdominal pain and gastrointestinal conditions, frequently requiring surgical procedures, apart from reconstructive plastic surgery. Long-term, the risk of anaemia was 92% higher, malnutrition developed approximately three times as often, psychiatric diagnoses were 33% more frequent and alcohol abuse was three times as great as in the control group.ConclusionsThis nationwide study confirms the benefits and describes the panorama of adverse events after bariatric surgery in persons with obesity and T2DM. Long-term postoperative monitoring and support, as better selection of patients by appropriate specialists in interdisciplinary settings, should be provided to optimise the outcomes.

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Retinopathy progression and the risk of end-stage kidney disease: results from a longitudinal Japanese cohort of 232 patients with type 2 diabetes and biopsy-proven diabetic kidney disease

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000726 ◽

2019 ◽

Vol 7 (1) ◽

pp. e000726 ◽

Cited By ~ 6

Author(s):

Masayuki Yamanouchi ◽

Mikiro Mori ◽

Junichi Hoshino ◽

Keiichi Kinowaki ◽

Takeshi Fujii ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Kidney Disease ◽

Diabetic Kidney Disease ◽

End Stage Kidney Disease ◽

Diabetic Kidney ◽

Clinical Model ◽

Renal Lesions ◽

End Stage

ObjectiveThe predictive value of diabetic retinopathy on end-stage kidney disease (ESKD) has not been fully addressed in patients with type 2 diabetes and diabetic kidney disease.Research design and methodsWe studied 232 patients with type 2 diabetes and biopsy-proven diabetic kidney disease who were screened for diabetic retinopathy during the 1 month of kidney biopsy. We examined the association between retinopathy progression and renal lesions. We used Cox regression analyses to explore the risk of ESKD adjusting for known risk demographic and clinical variables. We assessed the incremental prognostic value of ESKD by adding diabetic retinopathy to the clinical variables.ResultsThe diabetic retinopathy progression positively correlated with all scores of renal lesions, especially with the glomerular-based classification (r=0.41), scores of interstitial fibrosis (r=0.41) and diffuse lesion (r=0.48). During a median follow-up of 5.7 years, 114 patients developed ESKD. Adjusting for known risk factors of ESKD, the HR for ESKD (patients with no apparent retinopathy as a reference) were 1.96 (95% CI 0.62 to 6.17) for patients with mild non-proliferative diabetic retinopathy (NPDR), 3.10 (95% CI 1.45 to 6.65) for patients with moderate NPDR, 3.03 (95% CI 1.44 to 6.37) for patients with severe NPDR, and 3.43 (95% CI 1.68 to 7.03) for patients with proliferative diabetic retinopathy, respectively. Addition of the retinopathy grading to the clinical model alone improved the prognostic value (the global χ2 statistic increased from 155.2 to 164.5; p<0.001), which is an improvement equivalent to the addition of the renal lesion grading to the clinical model.ConclusionsRetinopathy progression appeared to be associated with renal lesions and the development of ESKD. Our findings suggest that diabetic retinopathy and kidney disease share the same magnitude of disease progression, and therefore diabetic retinopathy may be useful for prognosticating the clinical course for diabetic kidney disease.

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