Dataset Information

Associations of Fenofibrate Therapy With Incidence and Progression of CKD in Patients With Type 2 Diabetes.

ABSTRACT:

Introduction

Abnormalities in lipid metabolism may contribute to the development and progression of chronic kidney disease (CKD) in patients with type 2 diabetes. Fenofibrate induces early and reversible reduction in estimated glomerular filtration rate (eGFR), but it may have protective effects on microvascular complications of diabetes. We hypothesized that randomization to fenofibrate versus placebo would be associated with beneficial long-term effects on kidney outcomes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial participants.

Methods

We conducted a post hoc analysis in the ACCORD Lipid Trial to examine the association of randomization to fenofibrate versus placebo with change in eGFR and with time-to-development of microalbuminuria, macroalbuminuria, CKD, and kidney failure.

Results

We analyzed 2636 participants in the fenofibrate arm and 2632 in the placebo arm. During a median follow-up of 4 years, treatment with fenofibrate was associated with lower rate of eGFR decline (-0.28 ml/min per 1.73 m² per year in the fenofibrate group vs. -1.25 ml/min per 1.73 m² per year in the placebo group, P < 0.01) and with lower incidence of microalbuminuria (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.43-0.72, P < 0.001) and macroalbuminuria (HR 0.72, 95% CI 0.57-0.91, P < 0.001). There was no difference in incidence of CKD (HR 0.92, 95% CI 0.74-1.15, P = 0.46) and/or kidney failure (HR 0.95, 95% CI 0.68-1.33, P = 0.76).

Conclusion

Compared with placebo, randomization to fenofibrate was associated with lower rates of incident albuminuria and a slower eGFR decline, but no difference in incidence of CKD or kidney failure in ACCORD participants.

SUBMITTER: Frazier R

PROVIDER: S-EPMC6308372 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

Associations of Fenofibrate Therapy With Incidence and Progression of CKD in Patients With Type 2 Diabetes.

Frazier Rebecca R Mehta Rupal R Cai Xuan X Lee Jungwha J Napoli Sara S Craven Timothy T Tuazon Jennifer J Safdi Adam A Scialla Julia J Susztak Katalin K Isakova Tamara T

Kidney international reports 20180918 1

<h4>Introduction</h4>Abnormalities in lipid metabolism may contribute to the development and progression of chronic kidney disease (CKD) in patients with type 2 diabetes. Fenofibrate induces early and reversible reduction in estimated glomerular filtration rate (eGFR), but it may have protective effects on microvascular complications of diabetes. We hypothesized that randomization to fenofibrate versus placebo would be associated with beneficial long-term effects on kidney outcomes in the Action ...[more]

PMID: 30596172

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Project description:Importance:Patients with type 2 diabetes are at high risk of cardiovascular disease (CVD) in part owing to hypertriglyceridemia and low high-density lipoprotein cholesterol. It is unknown whether adding triglyceride-lowering treatment to statin reduces this risk. Objective:To determine whether fenofibrate reduces CVD risk in statin-treated patients with type 2 diabetes. Design, Setting, and Participants:Posttrial follow-up of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Study between July 2009 and October 2014; 5 years of follow-up were completed for a total of 9.7 years at general community and academic outpatient research clinics in the United States and Canada. Of the original 5518 ACCORD Lipid Trial participants, 4644 surviving participants were selected based on the presence of type 2 diabetes and either prevalent CVD or CVD risk factors and high-density lipoprotein levels less than 50 mg/dL (<55 mg/dL for women and African American individuals). Interventions:Passive follow-up of study participants previously treated with fenofibrate or masked placebo. Main Outcomes and Measures:Occurrence of cardiovascular outcomes including primary composite outcome of fatal and nonfatal myocardial infarction and stroke in all participants and in prespecified subgroups. Results:The 4644 follow-on study participants were broadly representative of the original ACCORD study population and included significant numbers of women (n?=?1445; 31%), nonwhite individuals (n?=?1094; 21%), and those with preexisting cardiovascular events (n?=?1620; 35%). Only 4.3% of study participants continued treatment with fenofibrate following completion of ACCORD. High-density lipoprotein and triglyceride values rapidly equalized among participants originally randomized to fenofibrate or placebo. Over a median total postrandomization follow-up of 9.7 years, the hazard ratio (HR) for the primary study outcome among participants originally randomized to fenofibrate vs placebo (HR, 0.93; 95% CI, 0.83-1.05; P?=?.25) was comparable with that originally observed in ACCORD (HR, 0.92; 95% CI, 0.79-1,08; P?=?.32). Despite these overall neutral results, we continued to find evidence that fenofibrate therapy effectively reduced CVD in study participants with dyslipidemia, defined as triglyceride levels greater than 204 mg/dL and high-density lipoprotein cholesterol levels less than 34 mg/dL (HR, 0.73; 95% CI, 0.56-0.95). Conclusions and Relevance:Extended follow-up of ACCORD-lipid trial participants confirms the original neutral effect of fenofibrate in the overall study cohort. The continued observation of heterogeneity of treatment response by baseline lipids suggests that fenofibrate therapy may reduce CVD in patients with diabetes with hypertriglyceridemia and low high-density lipoprotein cholesterol. A definitive trial of fibrate therapy in this patient population is needed to confirm these findings. Trial Registration:clinicaltrials.gov Identifier: NCT00000620.

Project description:OBJECTIVE: Diabetic patients with moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-59 mL/min/1.73 m(2)) are at particular cardiovascular risk. Fenofibrate's safety in these patients is an issue because it may elevate plasma creatinine. Furthermore, guidelines regarding fenofibrate dosing in renal impairment vary internationally. We investigated fenofibrate's effects on cardiovascular and end-stage renal disease (ESRD) events, according to eGFR, in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. RESEARCH DESIGN AND METHODS: Type 2 diabetic patients (aged 50-75 years) with eGFR ?30 mL/min/1.73 m(2) were randomly allocated to a fixed dose of fenofibrate (200 mg daily) (n = 4,895) or placebo (n = 4,900) for 5 years. Baseline renal function (Modification of Diet in Renal Disease equation) was grouped by eGFR (30-59, 60-89, and ?90 mL/min/1.73 m(2)). The prespecified outcome was total cardiovascular events (composite of cardiovascular death, myocardial infarction, stroke, and coronary/carotid revascularization). Serious adverse events and instances of ESRD (plasma creatinine >400 ?mol/L, dialysis, renal transplant, or renal death) were recorded. Analysis was by intention to treat. RESULTS: Overall, fenofibrate reduced total cardiovascular events, compared with placebo (hazard ratio 0.89 [95% CI 0.80-0.99]; P = 0.035). This benefit was not statistically different across eGFR groupings (P = 0.2 for interaction) (eGFR 30-59 mL/min/1.73 m(2): 0.68 [0.47-0.97], P = 0.035; eGFR ?90 mL/min/1.73 m(2): 0.85 [0.70-1.02], P = 0.08). ESRD rates were similar between treatment arms, without adverse safety signals of fenofibrate use in renal impairment. CONCLUSIONS: Patients with type 2 diabetes and moderate renal impairment benefit from long-term fenofibrate, without excess drug-related safety concerns compared with those with no or mild renal impairment. Fenofibrate treatment should not be contraindicated in moderate renal impairment, suggesting that current guidelines may be too restrictive.

Project description:Background and objectivesAmong people with diabetes mellitus, CKD may promote hypoglycemia through altered clearance of glucose-lowering medications, decreased kidney gluconeogenesis, and blunted counter-regulatory response. We conducted a prospective observational study of hypoglycemia among 105 individuals with type 2 diabetes treated with insulin or a sulfonylurea using continuous glucose monitors.Design, setting, participants & measurementsWe enrolled 81 participants with CKD, defined as eGFR<60 ml/min per 1.73 m2, and 24 control participants with eGFR?60 ml/min per 1.73 m2 frequency-matched on age, duration of diabetes, hemoglobin A1c, and glucose-lowering medications. Each participant wore a continuous glucose monitor for two 6-day periods. We examined rates of sustained level 1 hypoglycemia (<70 mg/dl) and level 2 hypoglycemia (<54 mg/dl) among participants with CKD. We then tested differences compared with control participants as well as a second control population (n=73) using Poisson and linear regression, adjusting for age, sex, and race.ResultsOver 890 total days of continuous glucose monitoring, participants with CKD were observed to have 255 episodes of level 1 hypoglycemia, of which 68 episodes reached level 2 hypoglycemia. Median rate of hypoglycemic episodes was 5.3 (interquartile range, 0.0-11.7) per 30 days and mean time spent in hypoglycemia was 28 (SD 37) minutes per day. Hemoglobin A1c and the glucose management indicator were the main clinical correlates of time in hypoglycemia (adjusted differences 6 [95% confidence interval, 2 to 10] and 13 [95% confidence interval, 7 to 20] fewer minutes per day per 1% higher hemoglobin A1c or glucose management indicator, respectively). Compared with control populations, participants with CKD were not observed to have significant differences in time in hypoglycemia (adjusted differences 4 [95% confidence interval, -12 to 20] and -12 [95% confidence interval, -29 to 5] minutes per day).ConclusionsAmong people with type 2 diabetes and moderate to severe CKD, hypoglycemia was common, particularly with tighter glycemic control, but not significantly different from groups with similar clinical characteristics and preserved eGFR.

Project description:Background and objectivesQuantitative data for prediction of incidence and progression of early CKD are scarce in individuals with type 2 diabetes. Therefore, two risk prediction models were developed for incidence and progression of CKD after 5.5 years and the relative effect of predictors were ascertained.Design, setting, participants, & measurementsBaseline and prospective follow-up data of two randomized clinical trials, ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and Outcome Reduction with Initial Glargine Intervention (ORIGIN), were used as development and independent validation cohorts, respectively. Individuals aged ≥55 years with type 2 diabetes and normo- or microalbuminuria at baseline were included. Incidence or progression of CKD after 5.5 years was defined as new micro- or macroalbuminuria, doubling of creatinine, or ESRD. The competing risk of death was considered as an additional outcome state in the multinomial logistic models.ResultsOf the 6766 ONTARGET participants with diabetes, 1079 (15.9%) experienced incidence or progression of CKD, and 1032 (15.3%) died. The well calibrated, parsimonious laboratory prediction model incorporating only baseline albuminuria, eGFR, sex, and age exhibited an externally validated c-statistic of 0.68 and an R(2) value of 10.6%. Albuminuria, modeled to depict the difference between baseline urinary albumin/creatinine ratio and the threshold for micro- or macroalbuminuria, was mostly responsible for the predictive performance. Inclusion of clinical predictors, such as glucose control, diabetes duration, number of prescribed antihypertensive drugs, previous vascular events, or vascular comorbidities, increased the externally validated c-statistic and R(2) value only to 0.69 and 12.1%, respectively. Explained variation was largely driven by renal and not clinical predictors.ConclusionsAlbuminuria and eGFR were the most important factors to predict onset and progression of early CKD in individuals with type 2 diabetes. However, their predictive ability is modest. Inclusion of demographic, clinical, and other laboratory predictors barely improved predictive performance.

Dataset Information

Associations of Fenofibrate Therapy With Incidence and Progression of CKD in Patients With Type 2 Diabetes.

Introduction

Methods

Results

Conclusion

Publications

Associations of Fenofibrate Therapy With Incidence and Progression of CKD in Patients With Type 2 Diabetes.

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