Influence of hepatic impairment on everolimus pharmacokinetics: implications for dose adjustment.

OBJECTIVE: We assessed the influence of hepatic impairment on the pharmacokinetics of the immunosuppressant everolimus to provide dose recommendations for clinical use. METHODS: In this open-label, single-dose, case-control study, 8 subjects with liver cirrhosis classed as moderate hepatic impairment (Child-Pugh score, 7-9) and 8 demographically matched healthy control subjects received a single oral 2-mg dose of everolimus. Routine safety assessments were made, and blood samples were taken for determination of everolimus concentrations and protein binding. RESULTS: The apparent clearance of everolimus was significantly reduced by 53% in subjects with moderate hepatic impairment compared with healthy subjects (9.1 +/- 3.1 versus 19.4 +/- 5.8 L/h). This was manifested by a 115% higher area under the blood concentration-time curve (AUC) (245 +/- 91 versus 114 +/- 45 ng. h/ml) and 84% prolonged half-life (79 +/- 42 versus 43 +/- 18 hours) in subjects with hepatic impairment. The rate of absorption of everolimus was not altered by hepatic impairment on the basis of the maximum blood concentration (C(max)) and time to reach C(max) (t(max)). Protein binding was similar in the two groups (73.8% +/- 3.6% versus 73.5% +/- 2.4%). A significant positive correlation of the everolimus AUC with bilirubin level (r = 0.86) and a significant negative correlation with albumin concentration (r = 0.72) was observed. CONCLUSIONS: The dose of everolimus should initially be reduced by half in patients with mild and moderate hepatic impairment on the basis of the Child-Pugh classification. Therapeutic monitoring would be a helpful adjunct to subsequent titration of everolimus exposure in this subpopulation. Everolimus has not been assessed in patients with severe hepatic impairment.     

Screening tests for renal impairment in patients with type 2 diabetes: the what, when, and how

The global course of obesity and diabetes presents an alarming forecast for the near future. As the prevalence rates continue to increase and the afflicted population grows younger in age, the associated complications of diabetes will come to pose a greater strain on patients, society, and national health care systems. In recent years, a number of studies have demonstrated the clinical benefits of strict diabetes control in the prevention of debilitating complications, including retinal, renal, and cardiovascular disease. These data highlight the need to maximize our efforts in diabetes prevention and early disease management. Renal dysfunction is a surrogate marker of diabetic microvascular disease, and thus early recognition of renal impairment in patients with diabetes provides an opportunity to modify treatment strategy and improve long-term disease outcomes. This review will summarize methods of assessing renal function and the most recent guidelines for the early screening and diagnosis of diabetic kidney disease.     

Ceftriaxone pharmacokinetics in patients with various degrees of renal impairment

The effects of renal impairment on the pharmacokinetics of ceftriaxone in humans were examined after intravenous infusion of a 1-g dose over 15 min to 30 renally impaired patients. The study included 12 dialysis patients and 18 patients with severe, moderate, or mild renal impairment. Plasma and, where appropriate, urine and dialysate samples were collected at predetermined times and analyzed for ceftriaxone by high-pressure liquid chromatography. The elimination half-life (group mean ranged from 11.7 to 17.3 h) and plasma clearance (group mean ranged from 529 to 705 ml/h) did not correlate linearly with creatinine clearance. The renal clearance and fraction of dose excreted unchanged in urine were related linearly, however weakly, with creatinine clearance. Ceftriaxone was not removed from plasma to a significant extent during hemodialysis. The half-life was prolonged twofold, the plasma clearance was lowered less than 50%, and the volume of distribution was relatively unchanged in renally impaired patients compared with young or elderly healthy subjects with normal renal function at an equivalent dose. Since these changes are moderate, adjustment in the dosage regimen of ceftriaxone for patients with impaired renal function should not be necessary when ceftriaxone dosage is 2 g or less per day (2 g every 24 h or 1 g every 12 h). It was reported that the elimination half-life of ceftriaxone is substantially prolonged in a small percentage of patients with end-stage renal disease maintained on hemodialysis. Therefore, plasma concentrations of ceftriaxone should be monitored in dialysis patients to determine whether dosage adjustments are necessary.     

Single-dose pharmacokinetics of cefpirome in patients with renal impairment.

The pharmacokinetic parameters of cefpirome (HR 810) were examined in 22 patients with different degrees of renal impairment. HPLC was used to analyze samples of blood and urine for cefpirome; and enzymatic assay of creatinine in serum and urine was used to assess kidney function. Creatinine clearance correlated linearly with both total and renal clearance of cefpirome. The loss of kidney function resulted in a decreased renal clearance, whereas the volume of distribution remained the same. This result led to an increase in the terminal half-life of the drug, from 2 hours in healthy subjects to 14 1/2 hours in patients with uremia. This increase also resulted in a prolonged high serum concentration well above the minimum inhibitory concentration. The following dosages are thus recommended: (1) creatinine clearance greater than 50 ml/min: normal daily dose, (2) creatinine clearance from 20 to 50 ml/min: 50% of normal daily dose, and (3) creatinine clearance less than 20 ml/min: 25% of normal daily dose. An initial loading dose of 1 gm, independent of renal function, is advised. Cefpirome was safe and well tolerated.     

Clinical application of exenatide in Japanese patients with type 2 diabetes mellitus

Exenatide belongs to a class of antidiabetic agents called incretin mimetics. In 2005, exenatide was first applied clinical therapy of type 2 diabetes mellitus patients in US, and it has now began to be used in Japanese type 2 diabetes mellitus patients since 2010. Large phase 3 clinical trials in Japan revealed that HbA1c, fasting glucose and postprandial glucose levels were improved with exenatide treatment, which were maintained over 52 weeks. Body weight reduction could be achieved with 10 microg treatment. HDL-C was significantly reduced. Exenatide was generally well tolerated, however incidence of hypoglycemia and gastro-intestinal side effect were elevated. Antibodies to exenatide were observed among approximately half of patients, however had no clinical relevant effects on the efficacy or safety.     

Efficacy of low-dose metformin in Japanese patients with type 2 diabetes mellitus

The goal of this study was to examine the antihyperglycemic effect of low-dose metformin in nonobese and obese Japanese patients with type 2 diabetes mellitus. After 3 months of reeducation and stabilization of diet therapy (25 kcal/kg of ideal body weight), metformin treatment was initiated. We administered metformin (500 to 750 mg daily) as monotherapy (n = 11) or in combination with a sulfonylurea (n = 14). After 6 months of treatment, the fasting plasma glucose level (mean ± SD) decreased from 190 ± 42 mg/dL to 155 ± 37 mg/dL and the glycated hemoglobin A_1c level (mean ± SD) from 8.8 ± 1.2% to 7.4 ± 1.0% in the monotherapy group. These same variables decreased from 218 ± 60 mg/dL to 162 ± 30 mg/dL and from 9.5 ± 1.2% to 8.4 ± 1.2% in the combination therapy group. All of these changes were statistically significant. Our results demonstrate that even low doses of metformin can improve hyperglycemia in Japanese patients with type 2 diabetes mellitus.     

Biomarkers of renal function and cognitive impairment in patients with diabetes

OBJECTIVE

Kidney disease is associated with cognitive impairment in studies of nondiabetic adults. We examined the cross-sectional relation between three measures of renal function and performance on four measures of cognitive function in the Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes (ACCORD-MIND) study.

RESEARCH DESIGN AND METHODS

The relationships among estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² (n = 2,968), albumin/creatinine ratio (ACR) ≥30 μg/mg (n = 2,957), and cystatin C level >1.0 mg/L (n = 532) with tertile of performance on the Mini-Mental State Examination, Rey Auditory Verbal Learning Test (RAVLT), Digit Symbol Substitution Test (DSST), and Stroop Test of executive function were measured.

RESULTS

In adjusted logistic regression models, ACR ≥30 μg/mg was associated with performance in the lowest tertile, compared with the highest two tertiles, on the RAVLT (odds ratio 1.30, 95% CI 1.09–1.56, P = 0.006), equivalent to 3.6 years of aging, and on the DSST (1.47, 1.20–1.80, P = 0.001), equivalent to 3.7 years of aging. Cystatin C >1.0 mg/L was borderline associated with the lowest tertile on the DSST (1.81, 0.93–3.55, P = 0.08) and Stroop (1.78, 0.97–3.23, P = 0.06) in adjusted models. eGFR was not associated with any measure of cognitive performance.

CONCLUSIONS

In diabetic people with HbA_1c >7.5% at high risk for cardiovascular disease, decreased cognitive function was associated with kidney disease as measured by ACR, a measure of microvascular endothelial pathology, and cystatin C, a marker of eGFR.A parallel decline in renal function and cognitive function has been described in people without diabetes (1,2). For example, there is a graded association between estimated glomerular filtration rate (eGFR) and cognitive function, especially at eGFR <45 mL/min/1.73 m² (2,3). Albuminuria (urine albumin/creatinine ratio [ACR] ≥30 μg/mg) is also associated with cognitive impairment (4). The protein kinase inhibitor cystatin C, which colocalizes with brain β-amyloid and can be used as a measure of GFR, was recently found to be significantly associated with both baseline cognitive impairment and incident cognitive decline (5).eGFR diminishes and albuminuria increases with age, particularly in people with diabetes, in whom these conditions are highly prevalent. At age ≥60 years, ∼15% of the general population and 25% of the diabetic population have eGFR <60 mL/min/1.73 m², and ∼15 and 35%, respectively, have albuminuria (6). Diabetes is the leading cause of chronic kidney disease (CKD) in North America (7). Up to 25% of adults aged ≥65 years have type 2 diabetes, and another 25% have impaired fasting or elevated postprandial glucose levels (8).Diabetes is also a recognized risk factor for cognitive impairment (9,10). Previously, we reported that HbA_1c was significantly associated with performance on cognitive tests in the Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes (ACCORD-MIND) study (10). Given the high prevalence of diabetes, CKD, and cognitive impairment in older adults, a better understanding of the association between different measures of declining renal function and cognitive impairment in people with diabetes is important. Such an understanding may lead to better means to detect and possibly prevent cognitive decline.We examined the cross-sectional relation between three measures of renal function and four measures of cognitive function, using data from the ACCORD-MIND study (11). We postulated that at baseline, cognitive function would be lower for 1) participants with eGFR <60 mL/min/1.73 m² than for participants with eGFR ≥60 mL/min/1.73 m²; 2) participants with albuminuria than for participants without albuminuria; and 3) participants with elevated cystatin C levels than for participants with lower cystatin C levels.     

Carbohydrate-induced memory impairment in adults with type 2 diabetes

OBJECTIVE: Memory impairment is observed in adults with type 2 diabetes. The focus of this study was to determine whether acute carbohydrate consumption contributes to or exacerbates memory dysfunction. RESEARCH DESIGN AND METHODS: The impact of consuming 50 g of rapidly absorbed carbohydrate (one half bagel and white grape juice) at breakfast was examined in 19 adults with type 2 diabetes. Subjects (mean age 63 +/- 9 years, mean BMI 26.1 +/- 4.5 kg/m(2)) were tested, under fed and fasted conditions, on verbal declarative memory using both word list and paragraph recall tests (immediate and delayed [7-min] recall), Trails Test Part B as a measure of general brain function, and mood (subjectively monitoring global vigor and affect). RESULTS: Under baseline (fasting) conditions, elevated blood HbA(1c) was negatively associated with immediate and delayed paragraph recall performance (R(2) = 0.30; P = 0.024) and higher fasting blood glucose trended toward poorer word list recall (R(2) = 0.09; P = 0.102). Carbohydrate ingestion influenced measures of delayed, but not immediate, recall in a time-dependent fashion (time x food) (word list, P = 0.046; paragraph, P = 0.044) such that delayed recall was improved at 15 min postingestion but was impaired at 30 min. Neither Trails Test scores (P = 0.17) nor mood (affect, P = 0.68 and vigor, P = 0.45) were influenced by food ingestion. CONCLUSIONS: In adults with type 2 diabetes, poorer glycemic control is associated with lower performance on tests of declarative memory. Acute ingestion of high glycemic index carbohydrate foods further contributes to the underlying memory impairment.     

Possible impairment of transcardiac utilization of adiponectin in patients with type 2 diabetes

OBJECTIVE: Adiponectin, an adipocyte-derived protein, has been suggested to enhance insulin sensitivity and prevent atherosclerosis. Circulating adiponecin levels are reduced in states of insulin resistance such as type 2 diabetes. We examined transcardiac utilization of adiponectin in patients with and without type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 17 male type 2 diabetic patients and 17 male nondiabetic patients were investigated. Venous blood samples were taken to measure glucose and lipid variables. Blood samples for the measurement of adiponectin were collected simultaneously from the aortic root and coronary sinus. Angiographic semiquantitative stenosis score of coronary artery was also evaluated. RESULTS: The adiponectin levels in both the aortic root and coronary sinus in the diabetic patients were significantly lower than those in the nondiabetic patients. The adiponectin level was significantly lower in the coronary sinus than in the aortic root in the nondiabetic patients, but there was no significant difference between adiponectin levels in the aortic root and coronary sinus in the diabetic patients. The total stenosis score, as an index of severity of coronary artery stenosis, was significantly higher in the diabetic patients than in the nondiabetic patients. The stenosis score was correlated with the degree of transcardiac utilization of adiponectin from the aortic root to coronary sinus in the nondiabetic patients but not in the diabetic patients. CONCLUSIONS: Diabetic patients not only have a decreased adiponectin level in the basal state compared with nondiabetic patients but also have impaired utilization of adiponectin in the coronary artery and/or the heart, which may promote the development of atherosclerosis.     

2型糖尿病患者早期认知功能障碍弥散峰度成像研究

目的:采用弥散峰度成像技术分析2型糖尿病(T2DM)患者早期认知功能障碍的全脑弥散结构改变,并分析其与认知行为学及临床实验室指标的相关性,为T2DM患者早期认知功能障碍的诊断与治疗提供有力的影像学依据.方法:对18例早期无其它并发症的T2DM患者组及19例种族、性别、年龄、受教育年限相匹配的正常对照组(HC)进行DKI...     

Lactate levels in Asian patients with type 2 diabetes mellitus on metformin and its association with dose of metformin and renal function

AIM: Our aims are to discover the average fasting plasma lactate level (FPL) in Asian patients with type 2 diabetes mellitus on metformin, with or without renal impairment and whether FPL is associated with the total daily dose of metformin (Tmet) and the degree of renal impairment in these patients. METHODS: We conducted an observational cross-sectional study of Asian patients with type 2 diabetes, using measurements of FPL levels and glomerular filtration rate (GFR) calculated, using the abbreviated modification of diet in renal disease (MDRD) formula. The association between FPL, Tmet, GFR and other potential predictors was analysed. RESULTS: A total of 97 subjects were recruited from our diabetes centre between July 2005 and February 2006. Sixty (61.9%) of the subjects were males; 69 (71.1%) Chinese, 21 (21.6%) Malays and 6 (6.2%) Indians. The mean (SD) age was 58.8 years (10.7) and the mean body mass index was 27.1 kg/m(2) (5.3). The mean FPL was 1.8 mmol/l (0.9) with 20 (20.6%) of subjects having an FPL beyond the upper limit of our reference range of 2.2 mmol/l. The mean FPL (two SE) of subjects with Tmet of < or = 1000, 1001-2000 and > 2000 mg were 1.7 mmol/l (0.2), 1.6 mmol/l (0.2) and 2.1 mmol/l (0.5) respectively, (p = 0.119). The mean FPL of subjects with GFR of < 60, 60-90 and > 90 ml/min/1.73 m(2) was 1.7 mmol/l (0.3), 1.8 mmol/l (0.3) and 1.8 mmol/l (0.4) respectively, p = 0.757. Among the potential predictors analysed, aspartate transaminase (p = 0.001) was found to be significantly associated with FPL. CONCLUSIONS: Our study shows no correlation between Tmet and GFR with FPL in Asian type 2 diabetic patients on metformin.     

Hyperhomocysteinemia is a risk factor for coronary arteriosclerosis in Japanese patients with type 2 diabetes

OBJECTIVE: An increased plasma homocysteine level is an important risk factor for vascular disease, including coronary atherosclerosis, in the general population. However, the role of hyperhomocysteinemia in the development of coronary artery disease (CAD) in patients with type 2 diabetes is unknown. Therefore, we have endeavored to determine the relationship between plasma homocysteine levels and the presence of coronary arteriosclerosis in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The study group consisted of 145 Japanese patients (95 men and 50 women) who underwent routine coronary angiography to assess chest pain or suspected CAD. Plasma total homocysteine level, lipid level, and parameters of fibrinolytic activity were measured. All patients were identified as diabetic or nondiabetic by the new American Diabetes Association (ADA) criteria. The diagnoses of all patients studied were confirmed by coronary angiography. The severity of coronary artery stenosis was quantified using CAD scoring on the basis of prior reports, and subjects were graded as nonstenotic, stenotic single-vessel, stenotic two-vessel, or stenotic three-vessel based on the number of stenotic coronary arteries. Patients were classified into two groups: those with stenotic vessels and those without stenotic vessels. RESULTS: The plasma homocysteine level was significantly higher in patients with than in patients without stenotic vessels (13.8 +/- 3.9 vs. 11.7 +/- 3.9 mumol/l, respectively; P = 0.0009). The number of stenotic coronary arteries, which was used to grade each case as nonstenotic, stenotic single-vessel, stenotic two-vessel, or stenotic three-vessel, was related only to the total homocysteine level in the diabetic (diabetes mellitus [DM]) group, but it was associated with lipoprotein(a) in the nondiabetic (non-diabetes mellitus [non-DM]) group. Spearman's rank correlation test demonstrated that the plasma homocysteine level was strongly correlated with CAD score, both in the entire study group and in the DM group (P = 0.003 for the entire group and P = 0.011 for the DM group). Hyperhomocysteinemia, which was defined as total homocysteine level > 14.0 mumol/l, was seen in 57 (39.3%) of the patients. The CAD score was highest in diabetic patients with hyperhomocysteinemia (P < 0.05). CONCLUSIONS: There seems to be a clear relationship between hyperhomocysteinemia and an increased risk of coronary arteriosclerosis in Japanese patients with type 2 diabetes.     

老年2型糖尿病合并认知功能障碍患者血清骨钙素检测的意义

目的 探讨血清骨钙素在老年2型糖尿病(T2DM)合并认知功能障碍患者中的意义,为老年T2DM合并认知功能障碍患者早期干预提供依据。方法 选取上海交通大学附属第六人民医院临港院区就诊的150例患者作为研究对象,分为三组:(1)健康对照组(NC组);(2)2型糖尿病非认知障碍组(T2DM组);(3)2型糖尿病合并认知障碍组(CI-T2DM组),三组各50例,比较三组间患者血清骨钙素水平、一般生化指标和认知功能评分情况,并分析影响认知功能的相关因素,采用单因素和多元回归方法分析骨钙素与糖脂代谢及认知功能之间的关系。结果 与T2DM组比较,CI-T2DM组中腰围、糖化血红蛋白、内脏脂肪面积均升高,而骨钙素水平与简易精神状态检查量表(MMSE)评分下降; NC组、T2DM组、CI-T2DM组血清骨钙素水平逐渐下降,且组间差异有统计学意义;在老年T2DM人群中,MMSE评分与年龄、腰围、糖化血红蛋白及内脏脂肪面积呈负相关(P <0.05),而与骨钙素水平呈正相关(r=0.374,P <0.001);以骨钙素作为因变量,经多元线性回归分析发现,糖化血红蛋白、内脏脂肪面积、MMSE仍与骨钙...     

2型糖尿病患者认知障碍的神经影像学研究进展

半数以上2型糖尿病(type 2 diabetes mellitus,T2DM)患者伴随轻、中度认知障碍,并以注意力及记忆力减退和信息处理速度及执行能力下降等为主要特征。近年除了在病理生理方面探究T2DM诱发认知功能障碍的机制外,各种MRI序列对于揭示糖尿病患者脑结构及脑功能改变方面有重要价值,如磁敏感加权成像、扩散张量成像、静息态功能磁共振成像及磁共振波谱成像等。作者结合病理生理改变及相关脑结构、功能变化对T2DM伴认知障碍患者的神经影像学研究进展进行综述。     

Factors affecting progression of renal failure in patients with type 2 diabetes

OBJECTIVE: Hyperglycemia and hypertension are known to be risk factors for the development of proteinuria in patients with diabetes. Little is known, however, about predictors of progression of renal failure in diabetic patients. RESEARCH DESIGN AND METHODS: We investigated factors affecting progression of renal failure by measuring the doubling of serum creatinine (s-Cr) as an end point in a cohort of 85 type 2 diabetic patients with chronic renal insufficiency/failure (s-Cr >1.5 and <3.7 mg/dl, 61 +/- 11 years old, 51 men and 34 women, mean s-Cr 2.3 +/- 0.6 mg/dl). RESULTS: The survey period (mean +/- SD) was 14.2 +/- 10.8 months. The cumulative incidence of the end point in patients with insulin therapy (n = 41) was significantly lower than that in patients without it (n = 44) (P = 0.0022, P values by log-rank test). Multivariate Cox analysis revealed insulin therapy (hazard ratio [HR] 0.435, 95% CI 0.252-0.750, P = 0.0027), serum albumin (0.484, 284-0.823, P = 0.0074), mean blood pressure (1.023, 1.004-1.043, P = 0.017), and hemoglobin (0.841, 0.728-0.972, P = 0.0194) to be independent and significant predictors of progression to renal failure, whereas HbA(1c) or serum cholesterol were not. CONCLUSION: In type 2 diabetic patients with renal failure, hypoalbuminemia, anemia, higher mean blood pressure, and lack of use of insulin predict rapid progression of renal failure, but HbA(1c) does not, and insulin therapy may be possibly an indicator of the delay in progression of renal failure.     

2型糖尿病患者发生认知功能障碍危险因素的Meta分析

目的系统评价2型糖尿病认知功能障碍危险因素。方法通过检索中英文数据库,筛选符合纳入标准的队列研究文献,应用Rev Man 5.3分析软件对资料进行分析。结果 1 910篇文献中21篇文献符合纳入标准,共纳入40个危险因素。经Meta分析,合并效应量具有统计学意义的RR值(95%CI)分别为女性1.21(1.16,1.25)、受教育程度0.81(0.77,0.85)、低血糖1.34(1.26,1.42)、脑血管疾病史1.46(1.08,1.99)、卒中史2.23(1.51,3.28)、肾病1.45(1.39,1.52)、视网膜病变1.35(1.21,1.51)、神经病变1.14(1.06,1.23)、降糖药物的使用1.10(1.04,1.16)、胰岛素的使用1.43(1.33,1.54)、抑郁1.38(1.32,1.45)。结论女性、低血糖、脑血管疾病史、卒中史、肾病、视网膜病变、神经病变、降糖药物使用、胰岛素使用、抑郁是认知功能障碍的危险因素,受教育程度是认知障碍的保护因素,而年龄、种族、糖尿病足、糖化血红蛋白、高血脂、高血压与认知功能障碍的关系在本研究中显示无统计学意义,有待开展大样本前瞻性队列研究予以验证。