Adrienne A.M. Zandbergen

Physical training and fatigue, fitness, and quality of life in Guillain–Barré syndrome and CIDP

Many patients with Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) experience excessive fatigue, which may persist for years and reduce quality of life. The authors performed a 12-week study of bicycle exercise training in 20 patients with severe fatigue, 16 with relatively good recovery from GBS, and 4 with stable CIDP. Training seemed well tolerated, and self-reported fatigue scores decreased 20% (p = 0.001). Physical fitness, functional outcome, and quality of life were improved.

High antibody titer in an adult with Pompe disease affects treatment with alglucosidase alfa

Clinical trials have demonstrated beneficial effects of enzyme replacement therapy (ERT) with alglucosidase alfa in infants, children and adults with Pompe disease. Recent studies have shown that high antibody titers can occur in patients receiving ERT and counteract the effect of treatment. This particularly occurs in those patients with classic-infantile Pompe disease that do not produce any endogenous acid α-glucosidase (CRIM-negative). It is still unclear to what extent antibody formation affects the outcome of ERT in adults with residual enzyme activity. We present the case of a patient with adult-onset Pompe disease. He was diagnosed at the age of 39years by enzymatic testing (10.7% residual activity in fibroblasts) and DNA analysis (genotype: c.-32-13T>G/p.Trp516X). Infusion-associated reactions occurred during ERT and the patients disease progressed. Concurrently, the antibody titer rose to a similarly high level as reported for some CRIM-negative patients with classic-infantile Pompe disease. Using newly developed immunologic-assays we could calculate that approximately 40% of the administered alglucosidase alfa was captured by circulating antibodies. Further, we could demonstrate that uptake of alglucosidase alfa by cultured fibroblasts was inhibited by admixture of the patients serum. This case demonstrates that also patients with an appreciable amount of properly folded and catalytically active endogenous acid α-glucosidase can develop antibodies against alglucosidase alfa that affect the response to ERT.

Effect of losartan on microalbuminuria in normotensive patients with type 2 diabetes mellitus - A randomized clinical trial

Context Angiotensin-receptor antagonists reduce renal and cardiovascular complications in patients with type 2 diabetes and hypertension. The effect of these drugs on normotensive patients with type 2 diabetes is not known. Contribution This 10-week randomized, placebo-controlled trial showed that in normotensive diabetic patients receiving losartan, albumin excretion rate was significantly reduced and blood pressure slightly decreased. Cautions The study included patients with systolic blood pressure up to 150 mm Hg and was too brief to evaluate progression of clinical renal disease. Angiotensin-receptor antagonists hold promise in preserving renal function in patients with type 2 diabetes without marked hypertension, but they warrant further study. The Editors Diabetes mellitus is an important cause of nephropathy, end-stage renal disease, and cardiovascular events. Nephropathy occurs in about 40% of patients with type 2 diabetes, and 25% to 40% of diabetic patients in Europe and the United States develop end-stage renal disease. Increased urinary albumin excretion, the first marker of kidney damage, carries an increased risk for renal as well as cardiovascular disease (1-5). Because reduction in microalbuminuria is associated with marked renal protection, the delay or retardation of the disease process is important in the management of diabetes mellitus (1). Angiotensin-converting enzyme (ACE) inhibitors reduce albumin excretion in both normotensive and hypertensive patients with type 1 or type 2 diabetes. The antiproteinuric effects appear to be at least partly independent of the reduction in blood pressure caused by these agents (6-11), although some studies have not confirmed this finding (12). Angiotensin II is thought to play a prominent role in the pathogenesis of diabetic nephropathy. Therefore, both preventing the formation of angiotensin II by ACE inhibition and blockade of the angiotensin receptor might be renoprotective. The trials of angiotensin-receptor antagonists in hypertensive patients with type 1 or 2 diabetes mellitus and microalbuminuria showed a reduction in albumin excretion, regardless of pretreatment levels (13-20). Recently, the angiotensin-receptor antagonist irbesartan retarded progression from microalbuminuria to overt proteinuria in hypertensive patients with type 2 diabetes (21). In RENAAL (The Reduction of Endpoints in NIDDM [noninsulin-dependent diabetes mellitus] with the Angiotensin II Antagonist Losartan study) and IDNT (Irbesartan Diabetic Nephropathy Trial), losartan and irbesartan, respectively, reduced proteinuria and slowed the progression of diabetic nephropathy in hypertensive patients with type 2 diabetes (22-24). Therefore, therapy that interferes with the reninangiotensinaldosterone system should probably be initiated when microalbuminuria develops in order to reduce albumin excretion and the associated risk for overt nephropathy. All previous studies on this subject investigated hypertensive patients. Therefore, we conducted a multicenter randomized, double-blind, placebo-controlled, clinical trial with forced dose titration to investigate the effects of losartan on urinary albumin excretion rate in normotensive patients with type 2 diabetes and microalbuminuria. Secondary objectives were to determine the time course of the antiproteinuric effect, the optimal dose of losartan, effects on creatinine clearance and blood pressure, and the safety and tolerability of losartan in normotensive patients. Methods Study Design In 19 outpatient clinics in the Netherlands, we conducted a 20-week randomized, placebo-controlled trial. The trial consisted of a 5-week screening and washout period, a 10-week double-blind treatment period, and a 5-week placebo washout period. The study was performed according to the guidelines of good clinical practice and was approved by the institutional review board at each center. All patients gave written informed consent. Patients From March 1999 through August 2001, all outpatients with type 2 diabetes mellitus, microalbuminuria, and a sitting blood pressure of 150/90 mm Hg or less were invited to participate. Type 2 diabetes mellitus was defined as diabetes diagnosed at age older than 30 years or controlled by diet or blood glucoselowering agents for at least 6 months. Microalbuminuria was defined as a urinary albumin excretion rate of 20 to 200 g/min. The current definition of normotension is a blood pressure less than 140/90 mm Hg, with a blood pressurelowering target of less than 130/80 mm Hg in hypertensive adults with diabetes mellitus (25, 26); however, we developed the protocol for this study in 1998, when normotension was defined as a sitting blood pressure of 160/90 mm Hg or less. Because of this and the fact that the mean baseline blood pressures appeared to be 135.9/78.8 mm Hg for the losartan group and 138.3/80.3 mm Hg for the placebo group, our study sample can be considered normotensive. We excluded patients with a myocardial infarction in the preceding 6 months, cerebrovascular events within the past year, unstable angina pectoris, or symptomatic heart failure; patients with electrocardiographic abnormalities (atrioventricular conduction disturbances, sick sinus syndrome, atrial fibrillation, or other clinically significant rhythm disturbances), acute renal failure, chronic glomerulonephritis, polycystic kidney disease, or a serum creatinine level greater than 150 mol/L (1.7 mg/dL); and patients with a glycosylated hemoglobin level greater than 10% or other relevant laboratory abnormalities. Concomitant use of antihypertensive agents, ophthalmic preparations containing -blocking agents, steroids, or lithium was not allowed. Eligible patients were included in the screening and washout period (weeks 5 to 0). In patients not taking blood pressurelowering or renoprotective medication, microalbuminuria was assessed by two sequential 24-hour urine collections before the randomization visit (week 0). Patients could be randomly assigned if the average of these two measurements confirmed microalbuminuria as defined above. Eligible patients who were receiving ACE inhibitors, angiotensin-receptor antagonists, or other antihypertensive agents first entered a 5-week washout period. In these patients, microalbuminuria was assessed after this period. If therapy with such medication had been initiated to normalize known hypertension, the patient was excluded. Interventions Patients who met all study criteria were randomly assigned in a double-blind fashion to receive losartan, 50 mg once daily, or matching placebo (week 0). After 5 weeks of treatment, patients initially assigned to receive 50 mg of losartan had fixed-dose titration to 100 mg of losartan; patients initially assigned to receive placebo continued to receive placebo. Treatment was continued at this dose for another 5 weeks, after which all patients were switched to single-blind placebo for the last 5 weeks. At the end of this washout period, patients returned for their final visit (week 15). The study sponsor, Merck, Sharpe & Dohme, provided each center with the study medication and randomly assigned the patients in blocks of four. The investigators dispensed the study medication and provided the patient with the first available allocation number. In each center, the allocation numbers were assigned in consecutive order. The patients had an equal probability of assignment to either group. The randomization list was inaccessible to all investigators. No randomization code was broken, so all investigators and participants remained blinded to treatment assignment during the entire study. Throughout the study, patients received the standard of care for diabetes. They were instructed not to change their physical exercise patterns significantly because doing so may influence proteinuria. Outcomes The primary end point was the change in urinary albumin excretion rate from baseline to week 10. Secondary end points were change in albumin excretion rate at week 5, change in creatinine clearance from baseline to week 10, and change in systolic and diastolic blood pressures at weeks 5 and 10. Tertiary end points were safety and tolerability of losartan. Measurements At each visit, the same investigator measured blood pressure and pulse. Blood pressure was measured by a sphygmomanometer, with the patient seated for 5 minutes before the first measurement. Three replicate measurements, obtained 1 minute apart, were averaged. In each center, microalbuminuria was measured just before every visit in two sequential 24-hour urine collections by using an immunonephelometric assay on an automated analyzer (Beckman Coulter, Brea, California). The measurements of the two samples were averaged. Complete laboratory evaluations (biochemistry, hematology) were conducted at weeks 0 and 10; at weeks 5 and 15, only renal function and electrolytes were checked. A virtual central laboratory recalculated all laboratory results, including microalbuminuria, and corrected them for possible bias. At weeks 0, 5, 10, and 15, adverse events were recorded, and medication use and adherence were checked by counting pills. Patients were considered adherent if at least 75% of the study drug had been taken. Statistical Analysis Primary and secondary end points were analyzed in the full-analysis study sample, which consisted of all patients randomly assigned (intention-to-treat analysis). The statistical method used was the generalized linear mixed model for longitudinal data, which compares the differences in trends over time between both treatment groups (27). Baseline values were used as covariates in this model, and outcomes were adjusted by using treatment, visit, center, and the corresponding interaction terms as fixed effects. A generalized linear mixed model was also applied to evaluate whether the observed changes in albumin excretion rate were consistent across different baseline blood pressures. Furthermore, an

Low bone mass in Pompe disease Muscular strength as a predictor of bone mineral density

UNLABELLED Pompe disease is an inherited metabolic myopathy caused by deficiency of acid alpha-glucosidase. The introduction of enzyme replacement therapy as treatment for the disease may change prospects for patients and may require that more attention be paid to co-morbidities such as osteoporosis. METHODS Bone mineral status was assessed in children and adults with Pompe disease and compared with reference values by means of dual energy X-ray absorptiometry (DXA) technology (GE Lunar DPX, GE Health Care). Bone mineral density (BMD) of the total body and the lumbar spine (L2-L4) was measured in adults and children; BMD of the femoral neck was measured in adults only. Exclusion criteria were: age<4 years, severe contractures, and inability to transfer the patient. RESULTS 46 patients were enrolled in the study; 36 adults and 10 children. The BMD was significantly lower in Pompe patients than in healthy individuals. Sixty-seven percent of patients had a BMD Z-score below -1, 26% were classified as osteoporosis/low bone mass for chronological age (T-score<-2.5 in adults or Z-score<-2 in children), 66% had a BMD Z-score below -1 of the femoral neck, and 34% had a BMD Z-score below -1 for the lumbar spine. Osteoporosis/low bone mass for chronological age was more frequent in patients who were wheelchair-bound, but was also observed in ambulant patients. We found a significant correlation between proximal muscle strength and total body BMD. Of the 10 children, 8 (all four patients with the classic infantile form) had a low BMD. CONCLUSION Low BMD is a frequent finding in patients with Pompe disease and may be causally related to decreased proximal muscle strength. BMD should be monitored at regular intervals. Children deserve specific attention.

Normotensive women with type 2 diabetes and microalbuminuria are at high risk for macrovascular disease

OBJECTIVE—The excess risk of macrovascular disease and death associated with diabetes seems higher in women than in men. The pathogenesis for this risk difference has not been fully elucidated. We investigated whether female sex was associated with macrovascular disease and death, independently of known risk factors related to type 2 diabetes, nephropathy, or retinopathy in normotensive patients with type 2 diabetes and microalbuminuria. RESEARCH DESIGN AND METHODS—We conducted a prospective, prolonged follow-up study of a subgroup of 67 diabetic patients (46 men and 21 women) without established cardiovascular disease who participated in a larger clinical trial. Data were collected on current and past health, medication use, blood pressure, renal function, and HbA1c during the follow-up period of 4.7 ± 0.8 (means ± SE) years. The end point was a composite of death, cardiovascular disease, cerebrovascular events, and peripheral artery disease. RESULTS—Of the women, eight (38.1%) met the end point compared with six (13.4%) of the men (P = 0.02 for difference in event-free survival). The hazard ratio of women relative to men was 3.19 (95% CI 1.11–9.21), which further increased after adjusting for age, systolic blood pressure, BMI, smoking, total-to-HDL cholesterol ratio, urinary albumin excretion, and retinopathy. CONCLUSIONS—In our study population of normotensive patients with type 2 diabetes and microalbuminuria, female sex was associated with increased risk of fatal and nonfatal cardiovascular disease, independent of the classical cardiovascular risk factors, the severity of nephropathy or presence of retinopathy, or health care utilization.

Glucose in prediabetic and diabetic range and outcome after stroke

Newly diagnosed disturbed glucose metabolism is highly prevalent in patients with stroke. Limited data are available on their prognostic value on outcome after stroke. We aimed to assess the association of glucose in the prediabetic and diabetic range with unfavourable short‐term outcome after stroke.

The IGF‐I system and the renal and haemodynamic effects of losartan in normotensive patients with type 2 diabetes mellitus: a randomized clinical trial

Objective  Losartan has been shown to protect the diabetic kidney, at least partly independent of changes in blood pressure. Imbalances in the IGF‐I system are associated with the development of diabetic nephropathy. We investigated whether renal as well as haemodynamic effects of losartan are associated with changes in the IGF‐I system in normotensive patients with type 2 diabetes mellitus (T2DM).

Metformin and sitAgliptin in patients with impAired glucose tolerance and a recent TIA or minor ischemic Stroke (MAAS): study protocol for a randomized controlled trial

BackgroundImpaired glucose tolerance is present in one third of patients with a TIA or ischemic stroke and is associated with a two-fold risk of recurrent stroke. Metformin improves glucose tolerance, but often leads to side effects.The aim of this study is to explore the feasibility, safety, and effects on glucose metabolism of metformin and sitagliptin in patients with TIA or minor ischemic stroke and impaired glucose tolerance. We will also assess whether a slow increase in metformin dose and better support and information on this treatment will reduce the incidence of side effects in these patients.Methods/DesignThe Metformin and sitAgliptin in patients with impAired glucose tolerance and a recent TIA or minor ischemic Stroke trial (MAAS trial) is a phase II, multicenter, randomized, controlled, open-label trial with blinded outcome assessment. Non-diabetic patients (n = 100) with a recent (<6 months) TIA, amaurosis fugax or minor ischemic stroke (modified Rankin scale ≤ 3) and impaired glucose tolerance, defined as 2-hour post-load glucose levels between 7.8 and 11.0 mmol/L after repeated standard oral glucose tolerance test, will be included. Patients with renal or liver impairment, heart failure, chronic hypoxic lung disease stage III–IV, history of lactate acidosis or diabetic ketoacidosis, pregnancy or breastfeeding, pancreatitis and use of digoxin will be excluded. The patients will be randomly assigned in a 1:1:2 ratio to metformin, sitagliptin or “no treatment.” Patients allocated to metformin will start with 500 mg twice daily, which will be slowly increased during a 6-week period to a twice daily dose of 1000 mg. Patients allocated to sitagliptin will be treated with a daily fixed dose of 100 mg. The study has been registered as NTR 3196 in The Netherlands Trial Register. Primary outcomes include percentage still on treatment, percentage of (serious) adverse events, and the baseline adjusted difference in 2-hour post-load glucose levels at 6 months.DiscussionThis study will give more information about the feasibility and safety of metformin and sitagliptin as well as the effect on 2-hour post-load glucose levels at 6 months in patients with TIA or ischemic stroke and impaired glucose tolerance.Trial registration numberNTR3196, Date of registration: 15 December 2011.

Metabolic Syndrome and Preeclampsia: A cohort study

To evaluate the association between different pre‐eclampsia (PE) phenotypes and the development of metabolic syndrome postpartum, in order to identify the subgroup of formerly pre‐eclamptic women with a worse cardiovascular risk profile requiring tailored postpartum follow‐up.