Browsing by Subject "Diabetic Nephropathies"

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    Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis.
    (Stroke, 2021-05) Zhou, Zien; Jardine, Meg J; Li, Qiang; Neuen, Brendon L; Cannon, Christopher P; de Zeeuw, Dick; Edwards, Robert; Levin, Adeera; Mahaffey, Kenneth W; Perkovic, Vlado; Neal, Bruce; Lindley, Richard I; CREDENCE Trial Investigators*

    Background and purpose

    Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.

    Methods

    CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis.

    Results

    In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (<45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]).

    Conclusions

    Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791.
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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.
    (Diabetes care, 2020-08) Perkovic, Vlado; Toto, Robert; Cooper, Mark E; Mann, Johannes FE; Rosenstock, Julio; McGuire, Darren K; Kahn, Steven E; Marx, Nikolaus; Alexander, John H; Zinman, Bernard; Pfarr, Egon; Schnaidt, Sven; Meinicke, Thomas; von Eynatten, Maximillian; George, Jyothis T; Johansen, Odd Erik; Wanner, Christoph; CARMELINA investigators

    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 (CV) and kidney outcomes across baseline estimated glomerular filtration rate (eGFR) categories (≥60, 45 to <60, 30 to <45, and <30 mL/min/1.73 m2) in Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA), a cardiorenal placebo-controlled outcome trial of the dipeptidyl peptidase 4 inhibitor linagliptin (NCT01897532).

    Research design and methods

    Participants with CV disease and/or CKD were included. The primary outcome was time to first occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke (three-point major adverse CV event [3P-MACE]), with a secondary outcome of renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline. Other end points included progression of albuminuria, change in HbA1c, and adverse events (AEs) including hypoglycemia.

    Results

    A total of 6,979 subjects (mean age 65.9 years; eGFR 54.6 mL/min/1.73 m2; 80.1% albuminuria) were followed for 2.2 years. Across eGFR categories, linagliptin as compared with placebo did not affect the risk for 3P-MACE (hazard ratio 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 among groups overall and across eGFR categories.

    Conclusions

    Across all GFR categories, in participants with type 2 diabetes and CKD and/or CV disease, 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 were observed.
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    Primary Care Providers' Acceptance of Pharmacists' Recommendations to Support Optimal Medication Management for Patients with Diabetic Kidney Disease.
    (Journal of general internal medicine, 2020-01) Zullig, Leah L; Jazowski, Shelley A; Davenport, Clemontina A; Diamantidis, Clarissa J; Oakes, Megan M; Patel, Sejal; Moaddeb, Jivan; Bosworth, Hayden B

    Background

    Patients with diabetic kidney disease (DKD) often struggle with blood pressure control. In team-based models of care, pharmacists and primary care providers (PCPs) play important roles in supporting patients' blood pressure management.

    Objective

    To describe whether PCPs' acceptance of pharmacists' recommendations impacts systolic blood pressure (SBP) at 36 months.

    Design

    An observational analysis of a subset of participants randomized to the intervention arm of the Simultaneous risk factor control using Telehealth to slOw Progression of Diabetic Kidney Disease (STOP-DKD) study.

    Participants

    STOP-DKD participants for whom (1) the pharmacist made at least one recommendation to the PCP; (2) there were available data regarding the PCP's corresponding action; and (3) there were SBP measurements at baseline and 36 months.

    Intervention

    Participants received monthly telephone calls with a pharmacist addressing health behaviors and medication management. Pharmacists made medication-related recommendations to PCPs.

    Main measures

    We fit an unadjusted generalized linear mixed model to assess the association between the number of pharmacists' recommendations for DKD and blood pressure management and PCPs' acceptance of such recommendations. We used a linear regression model to evaluate the association between PCP acceptance and SBP at 36 months, adjusted for baseline SBP.

    Key results

    Pharmacists made 176 treatment recommendations (among 59 participants), of which 107 (61%) were accepted by PCPs. SBP significantly declined by an average of 10.5 mmHg (p < 0.01) among 47 of 59 participants who had valid measurements at baseline and 36 months. There was a significant association between the number of pharmacist recommendations and the odds of PCP acceptance (OR 1.19; 95%CI 1.00, 1.42; p < 0.05), but no association between the number of accepted recommendations and SBP.

    Conclusions

    Pharmacists provided actionable medication-related recommendations. We identified a significant decline in SBP at 36 months, but this reduction was not associated with recommendation acceptance.

    Trial registration

    NCT01829256.
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    Racial differences in nocturnal dipping status in diabetic kidney disease: Results from the STOP-DKD (Simultaneous Risk Factor Control Using Telehealth to Slow Progression of Diabetic Kidney Disease) study.
    (Journal of clinical hypertension (Greenwich, Conn.), 2017-12) Zullig, Leah L; Diamantidis, Clarissa J; Bosworth, Hayden B; Bhapkar, Manjushri V; Barnhart, Huiman; Oakes, Megan M; Pendergast, Jane F; Miller, Julie J; Patel, Uptal D
    While racial variation in ambulatory blood pressure (BP) is known, patterns of diurnal dipping in the context of diabetic kidney disease have not been well defined. The authors sought to determine the association of race with nocturnal dipping status among participants with diabetic kidney disease enrolled in the STOP-DKD (Simultaneous Risk Factor Control Using Telehealth to Slow Progression of Diabetic Kidney Disease) trial. The primary outcome was nocturnal dipping-percent decrease in average systolic BP from wake to sleep-with categories defined as reverse dippers (decrease <0%), nondippers (0%-<10%), and dippers (≥10%). Twenty-four-hour ambulatory BP monitoring was completed by 108 participants (54% were nondippers, 24% were dippers, and 22% were reverse dippers). In adjusted models, the common odds of reverse dippers vs nondippers/dippers and reverse dippers/nondippers vs dippers was 2.6 (95% confidence interval, 1.2-5.8) times higher in blacks than in whites. Without ambulatory BP monitoring data, interventions that target BP in black patients may be unable to improve outcomes in this high-risk group.
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    Racial Differences in the Effectiveness of a Multifactorial Telehealth Intervention to Slow Diabetic Kidney Disease.
    (Medical care, 2020-11) Kobe, Elizabeth A; Diamantidis, Clarissa J; Bosworth, Hayden B; Davenport, Clemontina A; Oakes, Megan; Alexopoulos, Anastasia-Stefania; Pendergast, Jane; Patel, Uptal D; Crowley, Matthew J

    Background

    African Americans are significantly more likely than non-African Americans to have diabetes, chronic kidney disease, and uncontrolled hypertension, increasing their risk for kidney function decline.

    Objective

    The objective of this study was to compare how African Americans and non-African Americans with diabetes responded to a multifactorial telehealth intervention designed to slow kidney function decline.

    Research design

    Secondary analysis of a randomized trial. Primary care patients (N=281, 56% African American) were allocated to either: (1) a multifactorial, pharmacist-delivered phone-based telehealth intervention focused on behavioral and medication management of diabetic kidney disease; or (2) an education control.

    Measures

    The primary study outcome was change in estimated glomerular filtration rate (eGFR). Linear mixed models were used to explore the moderating effect of race on the relationship between study arm and eGFR decline over time; the mean annual rate of eGFR decline was estimated by race and study arm.

    Results

    Findings demonstrated a differential intervention effect on kidney function over time by race (Pinteraction=0.005). Among African Americans, the intervention arm had significantly greater preservation of eGFR over time than the control arm (difference in the annual rate of eGFR decline=1.5 mL/min/1.73 m; 95% confidence interval: 0.04, 3.02). For non-African Americans, the intervention arm had a faster decline in eGFR over time than the control arm (difference in the annual rate of eGFR decline=-1.7 mL/min/1.73 m; 95% confidence interval: -3.3, -0.02).

    Conclusion

    A multifactorial, pharmacist-delivered telehealth intervention for diabetic kidney disease may be more effective for slowing eGFR decline among African Americans than non-African Americans.
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    Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk.
    (Cardiovascular diabetology, 2018-03-14) Rosenstock, Julio; Perkovic, Vlado; Alexander, John H; Cooper, Mark E; Marx, Nikolaus; Pencina, Michael J; Toto, Robert D; Wanner, Christoph; Zinman, Bernard; Baanstra, David; Pfarr, Egon; Mattheus, Michaela; Broedl, Uli C; Woerle, Hans-Juergen; George, Jyothis T; von Eynatten, Maximilian; McGuire, Darren K; CARMELINA® investigators
    BACKGROUND:Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINA® trial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk. METHODS:CARMELINA® is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events. Participants with evidence of CKD with or without CV disease and HbA1c 6.5-10.0% (48-86 mmol/mol) were randomized 1:1 to receive linagliptin once daily or matching placebo, added to standard of care adjusted according to local guidelines. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. The key secondary outcome is a composite of time to first sustained occurrence of end-stage kidney disease, ≥ 40% decrease in estimated glomerular filtration rate (eGFR) from baseline, or renal death. CV and kidney events are prospectively adjudicated by independent, blinded clinical event committees. CARMELINA® was designed to continue until at least 611 participants had confirmed primary outcome events. Assuming a hazard ratio of 1.0, this provides 90% power to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-sided α-level of 2.5%. If non-inferiority of linagliptin for the primary outcome is demonstrated, then its superiority for both the primary outcome and the key secondary outcome will be investigated with a sequentially rejective multiple test procedure. RESULTS:Between July 2013 and August 2016, 6980 patients were randomized and took ≥ 1 dose of study drug (40.6, 33.1, 16.9, and 9.4% from Europe, South America, North America, and Asia, respectively). At baseline, mean ± SD age was 65.8 ± 9.1 years, HbA1c 7.9 ± 1.0%, BMI 31.3 ± 5.3 kg/m2, and eGFR 55 ± 25 mL/min/1.73 m2. A total of 5148 patients (73.8%) had prevalent kidney disease (defined as eGFR < 60 mL/min/1.73 m2 or macroalbuminuria [albumin-to-creatinine ratio > 300 mg/g]) and 3990 patients (57.2%) had established CV disease with increased albuminuria; these characteristics were not mutually exclusive. Microalbuminuria (n = 2896 [41.5%]) and macroalbuminuria (n = 2691 [38.6%]) were common. CONCLUSIONS:CARMELINA® will add important information regarding the CV and kidney disease clinical profile of linagliptin by including an understudied, vulnerable cohort of patients with T2D at highest cardio-renal risk. Trial registration ClinicalTrials.gov identifier-NCT01897532; registered July 9, 2013.
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    Relation between BMI and diabetes mellitus and its complications among US older adults.
    (South Med J, 2015-01) Gray, Natallia; Picone, Gabriel; Sloan, Frank; Yashkin, Arseniy
    OBJECTIVES: This study examined relations between elevated body mass index (BMI) and time to diagnosis with type 2 diabetes mellitus and its complications among older adults in the United States. METHODS: Data came from the Medicare Current Beneficiary Survey, 1991-2010. A Cox proportional hazard model was used to assess relations between excess BMI at the first Medicare Current Beneficiary Survey interview and time to diabetes mellitus diagnosis, complications, and insulin dependence among Medicare beneficiaries, older than 65 years of age with no prior diabetes mellitus diagnosis, and who were not enrolled in Medicare Advantage (N = 14,657). RESULTS: Among individuals diagnosed as having diabetes mellitus, elevated BMIs were associated with a progressively higher risk of complications from diabetes mellitus. For women with a BMI ≥40, the risk of insulin dependence (hazard ratio [HR] 3.57; 95% confidence interval [CI] 2.36-5.39) was twice that for women with 25 ≤ BMI < 27.5 (HR 1.77; 95% CI 1.33-2.33). A similar pattern was observed in risk of cardiovascular (25 ≤ BMI < 27.5: HR 1.34; 95% CI 1.15-1.54; BMI ≥40: HR 2.45; 95% CI 1.92-3.11), cerebrovascular (25 ≤ BMI < 27.5: HR 1.30; 95% CI 1.06-1.57; BMI ≥40: HR 2.00; 95% CI 1.42-2.81), renal (25 ≤ BMI < 27.5: HR 1.31; 95% CI 1.04-1.63; BMI ≥40: HR 2.23; 95% CI 1.54-3.22), and lower extremity complications (25 ≤ BMI < 27.5: HR 1.41; 95% CI 1.22-1.61; BMI ≥40: HR 2.95; 95% CI 2.35-3.69). CONCLUSIONS: Any increase in BMI above normal weight levels is associated with an increased risk of being diagnosed as having complications of diabetes mellitus. For men, the increased risk of these complications occurred at higher BMI levels than in women. Ocular complications occurred at higher BMI levels than other complication types in both men and women.
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    Simultaneous Risk Factor Control Using Telehealth to slOw Progression of Diabetic Kidney Disease (STOP-DKD) study: Protocol and baseline characteristics of a randomized controlled trial.
    (Contemporary clinical trials, 2018-06) Diamantidis, Clarissa J; Bosworth, Hayden B; Oakes, Megan M; Davenport, Clemontina A; Pendergast, Jane F; Patel, Sejal; Moaddeb, Jivan; Barnhart, Huiman X; Merrill, Peter D; Baloch, Khaula; Crowley, Matthew J; Patel, Uptal D
    Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD) in the United States. Multiple risk factors contribute to DKD development, yet few interventions target more than a single DKD risk factor at a time. This manuscript describes the study protocol, recruitment, and baseline participant characteristics for the Simultaneous Risk Factor Control Using Telehealth to slOw Progression of Diabetic Kidney Disease (STOP-DKD) study. The STOP-DKD study is a randomized controlled trial designed to evaluate the effectiveness of a multifactorial behavioral and medication management intervention to mitigate kidney function decline at 3 years compared to usual care. The intervention consists of up to 36 monthly educational modules delivered via telephone by a study pharmacist, home blood pressure monitoring, and medication management recommendations delivered electronically to primary care physicians. Patients seen at seven primary care clinics in North Carolina, with diabetes and [1] uncontrolled hypertension and [2] evidence of kidney dysfunction (albuminuria or reduced estimated glomerular filtration rate [eGFR]) were eligible to participate. Study recruitment completed in December 2014. Of the 281 participants randomized, mean age at baseline was 61.9; 52% were male, 56% were Black, and most were high school graduates (89%). Baseline co-morbidity was high- mean blood pressure was 134/76 mmHg, mean body mass index was 35.7 kg/m2, mean eGFR was 80.7 ml/min/1.73 m2, and mean glycated hemoglobin was 8.0%. Experiences of recruiting and implementing a comprehensive DKD program to individuals at high risk seen in the primary care setting are provided.

    Trial registration

    NCT01829256.
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    Urine tricarboxylic acid cycle signatures of early-stage diabetic kidney disease.
    (Metabolomics : Official journal of the Metabolomic Society, 2021-12) Lunyera, Joseph; Diamantidis, Clarissa J; Bosworth, Hayden B; Patel, Uptal D; Bain, James; Muehlbauer, Michael J; Ilkayeva, Olga; Nguyen, Maggie; Sharma, Binu; Ma, Jennie Z; Shah, Svati H; Scialla, Julia J

    Introduction

    Urine tricarboxylic acid (TCA) cycle organic anions (OAs) are elevated in diabetes and may be biomarkers for diabetic kidney disease (DKD) progression.

    Objectives

    We assessed associations of 10 urine TCA cycle OAs with estimated glomerular filtration rate (eGFR) and eGFR slope.

    Methods

    This study is ancillary to the Simultaneous Risk Factor Control Using Telehealth to SlOw Progression of Diabetic Kidney Disease (STOP-DKD) Trial-a randomized trial of pharmacist-led medication and behavior management in 281 patients with early to moderate DKD at Duke from 2014 to 2015. We used linear mixed models to assess associations of urine TCA cycle OAs with outcomes and modelled TCA cycle OAs as: (1) the average of z-scores for each OA; and (2) principal component (PC) scores derived by principal component analysis (PCA). Untargeted urine metabolomics were added for additional discovery.

    Results

    Among 132 participants with 24 h urine samples (50% men; 58% Black; mean age 64 years [SD 9]; mean eGFR 74 ml/min/1.73m2 [SD 21] and median urine albumin-to-creatinine [UACR] 20 mg/g [IQR 8-95]), PCA identified 3 OA metabolite PCs. Malate, fumarate, pyruvate, α-ketoglutarate, lactate, succinate and citrate/isocitrate loaded positively on PC1; methylsuccinate, ethylmalonate and succinate loaded positively on PC2; and methylmalonate, ethylmalonate and citrate/isocitrate loaded negatively on PC3. Over a median follow-up of 1.8 years (IQR, 1.2 to 2.2), higher average OA z-score was strongly associated with higher eGFR after covariate adjustment (p = 0.01), but not with eGFR slope (p = 0.9). Higher PC3, but not other PCs, was associated with lower eGFR (p < 0.001). Conditional random forests and smooth clipped absolute deviation models confirmed methylmalonate, citrate/isocitrate, and ethylmalonate, and added lactate as top ranked metabolites in models of baseline eGFR (R-squared 0.32 and 0.33, respectively). Untargeted urine metabolites confirmed association of urine TCA cycle OAs with kidney function.

    Conclusion

    Thus, lower urine TCA cycle OAs, most notably lower methylmalonate, ethylmalonate and citrate/isocitrate, are potential indicators of kidney impairment in early stage DKD.