Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes.

BACKGROUND: Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease. METHODS: In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m2 of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed. RESULTS: A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m2 in the allopurinol group and 67.3 ml per minute per 1.73 m2 in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m2 (95% confidence interval [CI], -1.9 to 1.9; P = 0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m2 per year with allopurinol and -2.5 ml per minute per 1.73 m2 per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m2 per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups. CONCLUSIONS: We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).

Preventing Early Renal Loss in Diabetes (PERL) Study: A Randomized Double-Blinded Trial of Allopurinol-Rationale, Design, and Baseline Data.

OBJECTIVE: Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early Renal Loss in Diabetes (PERL) evaluates whether lowering SUA with allopurinol slows glomerular filtration rate (GFR) loss in people with type 1 diabetes (T1D) and mild to moderate DKD. We present the PERL rationale, design, and baseline characteristics. RESEARCH DESIGN AND METHODS: This double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40-99.9 mL/min/1.73 m2, SUA ≥4.5 m/dL, and micro- to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ≥3 mL/min/1.73 m2/year) to allopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period. RESULTS: Participants are 66% male and 84% white. At baseline, median age was 52 years and diabetes duration was 35 years, 93% of participants had hypertension, and 90% were treated with renin-angiotensin system inhibitors (median blood pressure 127/71 mmHg). Median HbA1c was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m2, and historical eGFR slope -3.5 mL/min/1.73 m2/year. Compared with participants with albuminuria (n = 419), those with NDKF (n = 94) were significantly older (56 vs. 52 years), had lower HbA1c (7.7 vs. 8.1%) and SUA (5.4 vs. 6.0 mg/dL), and had higher eGFR (82 vs. 74 mL/min/1.73 m2) and historical eGFR loss (-4.7 vs. -2.5 mL/min/1.73 m2/year). These differences persisted when comparing groups with similar rates of historical eGFR loss. CONCLUSIONS: PERL will determine the effect of allopurinol on mild to moderate DKD in T1D, with or without albuminuria. Participants with normoalbuminuria and rapid GFR loss manifested many DKD risk factors of those with albuminuria, but with less severity.

Comparison of Glycated Hemoglobin Results Based on At-Home and In-Lab Dried Blood Spot Sampling to Routine Venous Blood Sampling In-Lab in Adult Patients With Type 1 or Type 2 Diabetes.

OBJECTIVES: Regular measurement of glycated hemoglobin (A1C) is logistically demanding. Home blotter-paper collection offers an alternative. This study tested the viability of at-home blotter-paper A1C measurement. METHODS: Objective: compare accuracy of A1C levels collected on blotter paper at home (home-blotter) and blotter-paper collection in laboratory (lab-blotter) with venous A1C (routine measurement). Agreement was assessed by Pearson correlation, Lin concordance correlation coefficient (CCC), positive and negative predictive values (PPVs, NPVs) and Bland-Altman plots and associated statistics. RESULTS: Home-blotter, lab-blotter and venous A1C correlated strongly (0.93, 0.93). Home- and lab-blotter results were upwardly biased (0.387%, 0.1%). Bias increased with time. Bias correction provided agreement for both blotters (CCC >0.9); blotters correctly identifying levels above 7% (53 mmol/mol) were 100% for corrected home-blotters and 87% (95% confidence interval) for corrected lab-blotters. NPVs (% blotters correctly identifying levels of 7% or lower [53 mmol/mol]) were 100% for corrected home-blotters and 83% for corrected lab-blotters. After correction, >92% of corrected blotters had errors of 8% or less. Of our subjects, 88.5% found home sampling preferable to routine laboratory sampling. CONCLUSIONS: Home-blotter collection is an alternative to routine collection.

Diabetes Distress, Depression and Glycemic Control in a Canadian-Based Specialty Care Setting.

OBJECTIVES: The objectives of this study were to determine rates of diabetes distress and depression in patients with type 2 diabetes in a tertiary care setting, to examine the relationship among glycemic control, diabetes distress and depression, and to identify predictors of diabetes distress and depression on the basis of demographic and clinical characteristics. METHODS: We recruited 148 adults with type 2 diabetes who were presenting to a specialty diabetes clinic in Vancouver, British Columbia, Canada. Participants completed a questionnaire measuring diabetes distress, depressive symptoms and demographic backgrounds. The Diabetes Distress Scale was used to assess overall distress as well as 4 distinct distress dimensions, including emotional burden, physician-related, regimen-related and interpersonal distress. The Personal Health Questionnaire-9 was used to assess depressive symptoms. Glycated hemoglobin (A1C) data were also collected. RESULTS: The prevalence of diabetes distress and depression was 39% and 12% in our population, respectively. A1C levels emerged as a significant predictor of emotional burden (p=0.03) and regimen-related distress (p=0.01); higher A1C levels were associated with increased distress regarding emotional functioning and regimen adherence. A1C levels (p=0.02) and education levels (p=0.03) emerged as predictors of physician-related distress, with higher A1C levels associated with decreased distress regarding confidence in physicians. CONCLUSIONS: Our findings reveal that the rate of diabetes distress for patients in a tertiary care setting is high. Furthermore, diabetes distress, particularly emotion- and self-care-related distress, plays a significant role in glycemic control, whereas depression does not. Routine screening for diabetes distress as part of an initial specialty clinic evaluation should be explored.

Progesterone therapy, endothelial function and cardiovascular risk factors: a 3-month randomized, placebo-controlled trial in healthy early postmenopausal women.

BACKGROUND: Progesterone is effective treatment for hot flushes/night sweats. The cardiovascular effects of progesterone therapy are unknown but evidence suggests that premenopausal normal estradiol with also normal progesterone levels may provide later cardiovascular protection. We compared the effects of progesterone to placebo on endothelial function, weight, blood pressure, metabolism, lipids, inflammation and coagulation. METHODS AND RESULTS: We conducted a randomized, double-blind, 3-month placebo-controlled trial of progesterone (300 mg daily) among 133 healthy postmenopausal women in Vancouver, Canada from 2003-2009. Endothelial function by venous occlusion plethysmography was a planned primary outcome. Enrolled women were 1-11 y since last menstruation, not using hormones (for >6 months), non-smoking, without diabetes, hypertension, heart disease or their medications. Randomized (1∶1) women (55 ± 4 years, body mass index 25 ± 3) initially had normal blood pressure, fasting lipid, glucose and electrocardiogram results. Endothelial function (% forearm blood flow above saline) was not changed with progesterone (487 ± 189%, n = 18) compared with placebo (408 ± 278%, n = 16) (95% CI diff [-74 to 232], P = 0.30). Progesterone (n = 65) and placebo (n = 47) groups had similar changes in systolic and diastolic blood pressure, resting heart rate, weight, body mass index, waist circumference, total cholesterol, low-density lipoprotein cholesterol and triglyceride levels. High-density lipoprotein was lower (-0.14 mmol/L, P = 0.001) on progesterone compared with placebo. Fasting glucose, hs-C-reactive protein, albumin and D-dimer changes were all comparable to placebo. Framingham General Cardiovascular Risk Profile scores were initially low and remained low with progesterone therapy and not statistically different from placebo. CONCLUSIONS: Results indicate that progesterone has short-term cardiovascular safety. Endothelial function, weight, blood pressure, waist circumference, inflammation and coagulation were unchanged as were lipids except for HDL-C. The statistically significant decrease in HDL-C levels was not clinically important (based on lack of Cardiovascular Risk Profile change). TRIAL REGISTRATION: ClinicalTrials.gov NCT00152438.

Hot flushes and night sweats differ in associations with cardiovascular markers in healthy early postmenopausal women.

OBJECTIVE: The aim of this study was to evaluate the associations between vasomotor symptoms ([VMS] hot flushes or flashes and night sweats) and markers of cardiovascular risk. METHODS: Healthy postmenopausal women in a randomized controlled trial of progesterone for VMS recorded VMS frequency in the Daily Menopause Diary for 28 days at baseline. Accepted risks for cardiovascular disease were measured: body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), blood pressure (BP), endothelial function by venous occlusion plethysmography, fasting lipids, glucose, high-sensitivity C-reactive protein, albumin, and D-dimer. Relationships between risk variables and VMS frequency (24 h, day and night) were assessed by univariate and multivariate robust regressions with adjustment for age and WHtR. RESULTS: Data were available for 145 healthy, nonsmoking women without heart disease, hypertension, or diabetes who were 1 to 11 years past their final menstruation and were aged 43 to 65 years, with a mean (SD) BMI of 25.0 (2.9) kg/m and WC of 79.1 (7.1) cm. Anthropometric variables (BMI, WC, and WHtR) were significantly negatively associated with total (24-h day) VMS frequency and with day VMS but not with night VMS frequency. Systolic BP decreased with greater 24-hour VMS frequency, and both systolic and diastolic BPs were inversely related to day but not night VMS frequency. Albumin was positively associated with night VMS frequency but not with day or 24-hour VMS frequency. Other variables showed little association with VMS frequency. CONCLUSIONS: Hot flushes, but not night sweats, were associated with lower cardiovascular risk factors in these healthy postmenopausal women. Future research should differentiate night sweats from hot flushes.

Post-liver transplantation diabetes mellitus: an association with hepatitis C.

A retrospective study was performed on all liver transplant recipients from British Columbia from 1989 to March 2000 to determine the prevalence and predictive factors of diabetes mellitus (DM) post-liver transplantation. DM was defined as hyperglycemia requiring treatment with insulin or oral hypoglycemic agents. Patient characteristics, cause of liver disease at transplantation, and immunosuppression regimen were considered. Both univariate and multiple logistic regression analyses were performed. Posttransplantation DM (PTDM) occurred in 43 of 177 transplant recipients (24%). Of these, 13 transplant recipients had DM pretransplantation, whereas 30 patients developed de novo PTDM. The majority of patients were treated with insulin (80%). In univariate analysis, transplantation for hepatitis C virus (HCV) liver disease was associated with a greater incidence of PTDM (odds ratio [OR], 3.01; 95% confidence interval [CI], 1.46 to 6.23) and de novo PTDM (OR, 5.20; 95% CI, 2.25 to 11.99). Patients administered tacrolimus had a greater incidence of PTDM (OR, 2.04; 95% CI, 1.01 to 4.13), and there was a trend toward increased PTDM in older patients (mean age, 49 years). Recipient sex, steroid dosage, and acute rejection were not predictive of PTDM. The incidence of graft loss and death rates were similar between the two groups. On logistic regression, HCV was the only independent predictor of PTDM (OR, 4.12; 95% CI, 1.91 to 8.90) and de novo PTDM (OR, 6.02; 95% CI, 2.55 to 14.20). In conclusion, DM post-liver transplantation is a common occurrence and is associated with HCV.