Assessment of efficacy and safety of volanesorsen for treatment of metabolic complications in patients with familial partial lipodystrophy: Results of the BROADEN study: Volanesorsen in FPLD; The BROADEN Study.

BACKGROUND: Volanesorsen, an antisense oligonucleotide, is designed to inhibit hepatic apolipoprotein C-III synthesis and reduce plasma apolipoprotein C-III and triglyceride concentrations. OBJECTIVE: The present study assessed efficacy and safety of volanesorsen in patients with familial partial lipodystrophy (FPLD) and concomitant hypertriglyceridemia and diabetes. METHODS: BROADEN was a randomized, placebo-controlled, phase 2/3, 52-week study with open-label extension and post-treatment follow-up periods. Patients received weekly subcutaneous volanesorsen 300 mg or placebo. The primary endpoint was percent change from baseline in fasting triglycerides at 3 months. Secondary endpoints included relative percent change in hepatic fat fraction (HFF), visceral adiposity, and glycated hemoglobin levels. RESULTS: Forty patients (11 men, 29 women) were enrolled, majority of whom were aged <65 years (mean, 47 years) and White. Least squares mean (LSM) percent change in triglycerides from baseline to 3 months was -88% (95% CI, -134 to -43) in the volanesorsen group versus -22% (95% CI, -61 to 18) in the placebo group, with a difference in LSM of -67% (95% CI, -104 to -30; P=0.0009). Volanesorsen induced a significant LSM relative reduction in HFF of 53% at month 12 versus placebo (observed mean [SD]: 9.7 [7.65] vs. 18.0 [8.89]; P=0.0039). No statistically significant changes were noted in body volume measurements (fat, liver, spleen, visceral/subcutaneous adipose tissue) or glycated hemoglobin. Serious adverse events in patients assigned to volanesorsen included 1 case each of sarcoidosis, anaphylactic reaction, and systemic inflammatory response syndrome. CONCLUSION: In BROADEN, volanesorsen significantly reduced serum triglyceride levels and hepatic steatosis in patients with FPLD.

Distinguishing the economic costs associated with type 1 and type 2 diabetes.

The objective was to estimate the economic costs of diagnosed type 1 (T1DM) and type 2 (T2DM) diabetes mellitus in the United States in 2007. Medical claims were analyzed to estimate the proportion of diagnosed diabetes cases and excess medical costs by diabetes type. Indirect costs associated with T1DM and T2DM were estimated by using findings from the literature on diagnosed diabetes, as well as differences in health per case of T1DM and T2DM. This study builds on the Cost of Diabetes Model developed for the American Diabetes Association to estimate the economic burden of diagnosed diabetes. T1DM accounts for an estimated 5.7% (1.0 million) of the 17.5 million people with diagnosed diabetes. Approximately $14.9 billion (8.6%) of the economic burden of diagnosed diabetes is associated with T1DM, including medical costs of $10.5 billion and indirect costs of $4.4 billion. Costs associated with T2DM are $159.5 billion, including medical costs of $105.7 billion and indirect costs of $53.8 billion. The economic burden per case of diabetes is greater for T1DM than for T2DM, and the difference increases with age. The prevalence of T2DM is significantly greater than the prevalence of T1DM, so T2DM is responsible for most of the economic burden of diabetes. Estimates for T1DM are sensitive to the criteria used to identify people with diabetes using claims data; estimates for T2DM are relatively stable. Improved coding of diabetes type in medical claims and identification of diabetes type in survey data could lead to more precise estimates of the economic burden by diabetes type.

The effect of oral alpha-lipoic acid on oxidative stress in adolescents with type 1 diabetes mellitus.

BACKGROUND: Oxidative stress has been implicated in the pathophysiology of diabetic complications. Alpha-lipoic acid (LA), a potent antioxidant, has been shown to be an effective treatment for diabetic neuropathy when given intravenously. Recently, an oral controlled-release formulation of alpha-lipoic acid (CRLA) was developed, and a pharmacokinetic study demonstrated that CRLA maintained significant plasma levels for 67% longer than a common quick-release formulation. OBJECTIVE: To determine if CRLA is an effective antioxidant in type 1 diabetes mellitus (T1D) by measuring its effects on markers of oxidative damage and total antioxidant status. METHODS: Forty pubertal and postpubertal adolescents with T1D underwent a double-blind, randomized, placebo-controlled study of CRLA for 3 months. 8-hydroxy-2'-deoxyguanosine, 2-thiobarbituric acid-reactive substances, protein carbonyl, total reactive antioxidant potential, hemoglobin A1c (HbA1c), and spot random urine collected for albumin to creatinine ratio were measured before and after treatment. RESULTS: There was no significant change in any measurement of oxidative damage, total antioxidant status, HbA1c, or microalbuminuria prevalence after treatment with either placebo or CRLA. CONCLUSION: In this pilot study, CRLA was not an effective treatment for decreasing oxidative damage in T1D, although efficacy may have been limited by issues with compliance.

Oral urea for the treatment of chronic syndrome of inappropriate antidiuresis in children.

We report the successful use of oral urea in the management of children with chronic syndrome of inappropriate antidiuretic hormone secretion (SIAD). We performed a retrospective review of four children with chronic SIAD. After initial attempts at management with fluid restriction, each was started on a 30% to 50% oral urea solution, and the dose was titrated until normal serum sodium was achieved. Fluid intake was liberalized after serum sodium normalization. All four children normalized their serum sodium. No side effects or toxicities were experienced. Oral urea is a safe, effective treatment for chronic SIAD in children.

Nephrogenic syndrome of inappropriate antidiuresis.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia. We describe two infants whose clinical and laboratory evaluations were consistent with the presence of SIADH, yet who had undetectable arginine vasopressin (AVP) levels. We hypothesized that they had gain-of-function mutations in the V2 vasopressin receptor (V2R). DNA sequencing of each patient's V2R gene (AVPR2) identified missense mutations in both, with resultant changes in codon 137 from arginine to cysteine or leucine. These novel mutations cause constitutive activation of the receptor and are the likely cause of the patients' SIADH-like clinical picture, which we have termed "nephrogenic syndrome of inappropriate antidiuresis."