Adriana M. Hung

Comparative Effectiveness of Sulfonylurea and Metformin Monotherapy on Cardiovascular Events in Type 2 Diabetes Mellitus: A Cohort Study

BACKGROUND The effects of sulfonylureas and metformin on outcomes of cardiovascular disease (CVD) in type 2 diabetes are not well-characterized. OBJECTIVE To compare the effects of sulfonylureas and metformin on CVD outcomes (acute myocardial infarction and stroke) or death. DESIGN Retrospective cohort study. SETTING National Veterans Health Administration databases linked to Medicare files. PATIENTS Veterans who initiated metformin or sulfonylurea therapy for diabetes. Patients with chronic kidney disease or serious medical illness were excluded. MEASUREMENTS Composite outcome of hospitalization for acute myocardial infarction or stroke, or death, adjusted for baseline demographic characteristics; medications; cholesterol, hemoglobin A1c, and serum creatinine levels; blood pressure; body mass index; health care utilization; and comorbid conditions. RESULTS Among 253 690 patients initiating treatment (98 665 with sulfonylurea therapy and 155 025 with metformin therapy), crude rates of the composite outcome were 18.2 per 1000 person-years in sulfonylurea users and 10.4 per 1000 person-years in metformin users (adjusted incidence rate difference, 2.2 [95% CI, 1.4 to 3.0] more CVD events with sulfonylureas per 1000 person-years; adjusted hazard ratio [aHR], 1.21 [CI, 1.13 to 1.30]). Results were consistent for both glyburide (aHR, 1.26 [CI, 1.16 to 1.37]) and glipizide (aHR, 1.15 [CI, 1.06 to 1.26]) in subgroups by CVD history, age, body mass index, and albuminuria; in a propensity score-matched cohort analysis; and in sensitivity analyses. LIMITATION Most of the veterans in the study population were white men; data on women and minority groups were limited but reflective of the Veterans Health Administration population. CONCLUSION Use of sulfonylureas compared with metformin for initial treatment of diabetes was associated with an increased hazard of CVD events or death. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality and the U.S. Department of Health and Human Services.

Outpatient Nephrology Referral Rates after Acute Kidney Injury

AKI associates with an increased risk for the development and progression of CKD and mortality. Processes of care after an episode of AKI are not well described. Here, we examined the likelihood of nephrology referral among survivors of AKI at risk for subsequent decline in kidney function in a US Department of Veterans Affairs database. We identified 3929 survivors of AKI hospitalized between January 2003 and December 2008 who had an estimated GFR (eGFR) <60 ml/min per 1.73 m(2) 30 days after peak injury. We analyzed time to referral considering improvement in kidney function (eGFR ≥60 ml/min per 1.73 m(2)), dialysis initiation, and death as competing risks over a 12-month surveillance period. Median age was 73 years (interquartile range, 62-79 years) and the prevalence of preadmission kidney dysfunction (baseline eGFR <60 ml/min per 1.73 m(2)) was 60%. Overall mortality during the surveillance period was 22%. The cumulative incidence of nephrology referral before dying, initiating dialysis, or experiencing an improvement in kidney function was 8.5% (95% confidence interval, 7.6-9.4). Severity of AKI did not affect referral rates. These data demonstrate that a minority of at-risk survivors are referred for nephrology care after an episode of AKI. Determining how to best identify survivors of AKI who are at highest risk for complications and progression of CKD could facilitate early nephrology-based interventions.

Association Between Intensification of Metformin Treatment With Insulin vs Sulfonylureas and Cardiovascular Events and All-Cause Mortality Among Patients With Diabetes

IMPORTANCE Preferred second-line medication for diabetes treatment after metformin failure remains uncertain. OBJECTIVE To compare time to acute myocardial infarction (AMI), stroke, or death in a cohort of metformin initiators who added insulin or a sulfonylurea. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort constructed with national Veterans Health Administration, Medicare, and National Death Index databases. The study population comprised veterans initially treated with metformin from 2001 through 2008 who subsequently added either insulin or sulfonylurea. Propensity score matching on characteristics was performed, matching each participant who added insulin to 5 who added a sulfonylurea. Patients were followed through September 2011 for primary analyses or September 2009 for cause-of-death analyses. MAIN OUTCOMES AND MEASURES Risk of a composite outcome of AMI, stroke hospitalization, or all-cause death was compared between therapies with marginal structural Cox proportional hazard models adjusting for baseline and time-varying demographics, medications, cholesterol level, hemoglobin A1c level, creatinine level, blood pressure, body mass index, and comorbidities. RESULTS Among 178,341 metformin monotherapy patients, 2948 added insulin and 39,990 added a sulfonylurea. Propensity score matching yielded 2436 metformin + insulin and 12,180 metformin + sulfonylurea patients. At intensification, patients had received metformin for a median of 14 months (IQR, 5-30), and hemoglobin A1c level was 8.1% (IQR, 7.2%-9.9%). Median follow-up after intensification was 14 months (IQR, 6-29 months). There were 172 vs 634 events for the primary outcome among patients who added insulin vs sulfonylureas, respectively (42.7 vs 32.8 events per 1000 person-years; adjusted hazard ratio [aHR], 1.30; 95% CI, 1.07-1.58; P = .009). Acute myocardial infarction and stroke rates were statistically similar, 41 vs 229 events (10.2 and 11.9 events per 1000 person-years; aHR, 0.88; 95% CI, 0.59-1.30; P = .52), whereas all-cause death rates were 137 vs 444 events, respectively (33.7 and 22.7 events per 1000 person-years; aHR, 1.44; 95% CI, 1.15-1.79; P = .001). There were 54 vs 258 secondary outcomes: AMI, stroke hospitalizations, or cardiovascular deaths (22.8 vs 22.5 events per 1000 person-years; aHR, 0.98; 95% CI, 0.71-1.34; P = .87). CONCLUSIONS AND RELEVANCE Among patients with diabetes who were receiving metformin, the addition of insulin vs a sulfonylurea was associated with an increased risk of a composite of nonfatal cardiovascular outcomes and all-cause mortality. These findings require further investigation to understand risks associated with insulin use in these patients.

Estimating Baseline Kidney Function in Hospitalized Patients with Impaired Kidney Function

BACKGROUND AND OBJECTIVES Inaccurate determination of baseline kidney function can misclassify acute kidney injury (AKI) and affect the study of AKI-related outcomes. No consensus exists on how to optimally determine baseline kidney function when multiple preadmission creatinine measurements are available. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The accuracy of commonly used methods for estimating baseline serum creatinine was compared with that of a reference standard adjudicated by a panel of board-certified nephrologists in 379 patients with AKI or CKD admitted to a tertiary referral center. RESULTS Agreement between estimating methods and the reference standard was highest when using creatinine values measured 7-365 days before admission. During this interval, the intraclass correlation coefficient (ICC) for the mean outpatient serum creatinine level (0.91 [95% confidence interval (CI), 0.88-0.92]) was higher than the most recent outpatient (ICC, 0.84 [95% CI, 0.80-0.88]; P<0.001) and the nadir outpatient (ICC, 0.83 [95% CI, 0.76-0.87; P<0.001) serum creatinine. Using the final creatinine value from a prior inpatient admission increased the ICC of the most recent outpatient creatinine method (0.88 [95% CI, 0.85-0.91]). Performance of all methods declined or was unchanged when the time interval was broadened to 2 years or included serum creatinine measured within a week of admission. CONCLUSIONS The mean outpatient serum creatinine measured within a year of hospitalization most closely approximates nephrologist-adjudicated serum creatinine values.

Comparative effectiveness of incident oral antidiabetic drugs on kidney function.

Diabetes is a major cause of chronic kidney disease, and oral antidiabetic drugs are the mainstay of therapy for most patients with Type 2 diabetes. Here we evaluated their role on renal outcomes by using a national Veterans Administration database to assemble a retrospective cohort of 93,577 diabetic patients who filled an incident oral antidiabetic drug prescription for metformin, sulfonylurea, or rosiglitazone, and had an estimated glomerular filtration rate (eGFR) of 60 ml/min or better. The primary composite outcome was a persistent decline in eGFR from baseline of 25% or more (eGFR event) or a diagnosis of end-stage renal disease (ESRD). The secondary outcome was an eGFR event, ESRD, or death. Sensitivity analyses included using a more stringent definition of the eGFR event requiring an eGFR <60 ml/min per 1.73 m2 in addition to the 25% or more decline; controlling for baseline proteinuria thereby restricting data to 15,065 patients; and not requiring persistent treatment with the initial oral antidiabetic drug. Compared to patients using metformin, sulfonylurea users had an increased risk for both the primary and the secondary outcome, each with an adjusted hazard ratio of 1.20. Results of sensitivity analyses were consistent with the main findings. The risk associated with rosiglitazone was similar to metformin for both outcomes. Thus, compared to metformin, oral antidiabetic drug treatment with sulfonylureas increased the risk of a decline in eGFR, ESRD, or death.

IL-1β Receptor Antagonist Reduces Inflammation in Hemodialysis Patients

Chronic inflammation is highly prevalent in maintenance hemodialysis (MHD) patients and associates with increased mortality. IL-1β, a pro-inflammatory cytokine, is elevated in MHD patients. A balance between IL-1β and its naturally occurring antagonist may determine the inflammatory response and its consequences in this population. We performed a pilot randomized placebo-controlled trial to evaluate the efficacy of the administration of recombinant human IL-1 receptor antagonist (IL-1ra) on biomarkers of inflammation and nutrition in MHD patients with three consecutive high sensitivity C-reactive protein (hsCRP) measurements >5 mg/L. We randomly assigned 22 patients to placebo or IL-1ra (1:1) for 4 weeks; 14 completed the trial. Patients in the IL-1ra arm had a 53% reduction in mean hsCRP compared with 1% in the placebo arm (P = 0.008), a 40% reduction in mean IL-6 levels compared with a 20% increase in the placebo arm (P = 0.03), and a 23% increase in mean prealbumin compared with 6% in the placebo arm (P = NS). In conclusion, the administration of IL-1ra in MHD patients can lower biomarkers of inflammation. Whether IL-1ra administration improves survival in this population requires additional long-term studies.

Considerations and Challenges in Defining Optimal Iron Utilization in Hemodialysis

Trials raising concerns about erythropoiesis-stimulating agents, revisions to their labeling, and changes to practice guidelines and dialysis payment systems have provided strong stimuli to decrease erythropoiesis-stimulating agent use and increase intravenous iron administration in recent years. These factors have been associated with a rise in iron utilization, particularly among hemodialysis patients, and an unprecedented increase in serum ferritin concentrations. The mean serum ferritin concentration among United States dialysis patients in 2013 exceeded 800 ng/ml, with 18% of patients exceeding 1200 ng/ml. Although these changes are broad based, the wisdom of these practices is uncertain. Herein, we examine influences on and trends in intravenous iron utilization and assess the clinical trial, epidemiologic, and experimental evidence relevant to its safety and efficacy in the setting of maintenance dialysis. These data suggest a potential for harm from increasing use of parenteral iron in dialysis-dependent patients. In the absence of well powered, randomized clinical trials, available evidence will remain inadequate for making reliable conclusions about the effect of a ubiquitous therapy on mortality or other outcomes of importance to dialysis patients. Nephrology stakeholders have an urgent obligation to initiate well designed investigations of intravenous iron in order to ensure the safety of the dialysis population.

Determinants of C‐reactive protein in chronic hemodialysis patients: Relevance of dialysis catheter utilization

Biomarkers of inflammation, especially C‐reactive protein (CRP), have been consistently shown to predict poor outcomes in chronic hemodialysis (CHD) patients. However, the determinants of CRP and the value of its monitoring in CHD patients have not been well defined. We conducted a retrospective cohort study to evaluate possible determinants of the inflammatory response in CHD patients with a focus on dialysis catheter utilization. Monthly CRP were measured in 128 prevalent CHD patients (mean age 56.6 years [range 19–90], 68% African Americans, 39% diabetics [DM]) over a mean follow‐up of 12 months (range 2–26 months). There were a total of 2405 CRP measurements (median 5.7 mg/L; interquartile range [IQR] 2.4–16.6 mg/L). The presence of a dialysis catheter (p<0.002), cardiovascular disease (p=0.01), male gender (p=0.005), higher white blood cell count (p<0.0001), elevated phosphorus (p=0.03), and lower cholesterol (p=0.02) and albumin (p<0.0001) concentrations were independent predictors of elevated CRP in the multivariate analysis. Additionally, CRP levels were significantly associated with the presence of a catheter, when comparing the levels before and after catheter insertion (p=0.002) as well as before and after catheter removal (p=0.009). Our results indicate that the presence of a hemodialysis catheter is an independent determinant of an exaggerated inflammatory response in CHD patients representing a potentially modifiable risk factor.

A Comparison of Novel and Commonly-Used Indices of Insulin Sensitivity in African American Chronic Hemodialysis Patients

BACKGROUND Insulin resistance (IR) is highly prevalent in chronic hemodialysis (CHD) patients and is associated with poor cardiovascular outcomes. Hyperinsulinemic euglycemic glucose clamp (HEGC) is the gold standard for measuring IR. The comparison of commonly-used indirect indices of IR to HEGC has not been adequately performed in this population. Furthermore, the validity of newly proposed adipokine-based IR indices has not been explored. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This is an observational study performed in a single center, involving 12 prevalent CHD patients (50 ± 9 years old, 100% African American, 33% women, body mass index of 34.4 ± 7.6 kg/m(2)) who were studied three consecutive times. IR was assessed by HEGC (glucose-disposal rate [GDR]), homeostatic model assessment of IR (HOMA-IR), HOMA-IR corrected by adiponectin (HOMA-AD), leptin adiponectin ratio (LAR), QUICKI, and the McAuleys index at each time point. RESULTS Eighty-three percent of the subjects displayed either glucose intolerance or overt insulin resistance by HEGC (GDR median, 5.71; interquartile range [IQR], 4.16, 6.81). LAR and HOMA-AD were the best correlates of IR measured by HEGC (r=-0.72, P<0.001, and -0.67, P<0.001), respectively. Fat percentage, interleukin-6, and adipokines (leptin, adiponectin, and resistin) were strongly associated with GDR. HEGC, LAR, and HOMA-AD had the best intraclass correlation coefficients. CONCLUSION IR is common in CHD patients. Adipokine-based indices are the best correlates of IR measurements by HEGC. HOMA-IR and QUICKI are reasonable alternatives. Use of these indices may allow better detection of alterations in insulin sensitivity in CHD patients.

Predictors of Recurrent AKI

Recurrent AKI is common among patients after hospitalized AKI and is associated with progressive CKD. In this study, we identified clinical risk factors for recurrent AKI present during index AKI hospitalizations that occurred between 2003 and 2010 using a regional Veterans Administration database in the United States. AKI was defined as a 0.3 mg/dl or 50% increase from a baseline creatinine measure. The primary outcome was hospitalization with recurrent AKI within 12 months of discharge from the index hospitalization. Time to recurrent AKI was examined using Cox regression analysis, and sensitivity analyses were performed using a competing risk approach. Among 11,683 qualifying AKI hospitalizations, 2954 patients (25%) were hospitalized with recurrent AKI within 12 months of discharge. Median time to recurrent AKI within 12 months was 64 (interquartile range 19-167) days. In addition to known demographic and comorbid risk factors for AKI, patients with longer AKI duration and those whose discharge diagnosis at index AKI hospitalization included congestive heart failure (primary diagnosis), decompensated advanced liver disease, cancer with or without chemotherapy, acute coronary syndrome, or volume depletion, were at highest risk for being hospitalized with recurrent AKI. Risk factors identified were similar when a competing risk model for death was applied. In conclusion, several inpatient conditions associated with AKI may increase the risk for recurrent AKI. These findings should facilitate risk stratification, guide appropriate patient referral after AKI, and help generate potential risk reduction strategies. Efforts to identify modifiable factors to prevent recurrent AKI in these patients are warranted.