Novel Image-Guided Flexible-Probe Transbronchial Microwave Ablation for Stage 1 Lung Cancer.

BACKGROUND: Image-guided percutaneous thermal ablation is an established treatment option for early-stage lung cancer in medically inoperable patients but carries a high risk of pleura-related complications, particularly pneumothorax. OBJECTIVE: This study aimed to determine if image-guided transbronchial microwave ablation (tMWA) is a feasible approach to treat peripheral stage 1 lung cancer. METHOD: A prospective, single-arm, multicenter study sought to enroll 40 adults who were medically inoperable or declined surgery for peripheral stage 1 lung tumors (≤20 mm). Ablation was performed using navigational bronchoscopy and a flexible MWA probe, guided by cone-beam CT with augmented fluoroscopy. Follow-up at 1, 6, and 12 months included CT imaging of the ablation zone and possible tumor recurrence, adverse events (AEs), pulmonary function, and quality of life. RESULTS: Across 2 sites, 11 tumors (10 NSCLC, 1 carcinoid) were treated in 10 enrolled patients. Median tumor diameter was 13 × 14 mm (7-19 mm) and median minimum ablative margin was 11 mm (5-19 mm). Technical success and technique efficacy were achieved in all patients. No tumor recurrence was seen during 12-month follow-up. No pneumothorax, pleural effusion, or bronchopleural fistula were noted. Minor AEs included scant hemoptysis, pain, cough, and dyspnea. Two serious AEs occurred ≤30 days of ablation and included a COPD exacerbation (day 9) and a death of unknown cause (day 15). The death led the sponsor to halt enrollment. Pulmonary function and quality-of-life indices remained stable. CONCLUSIONS: Image-guided tMWA is a technically feasible approach for peripheral early-stage lung cancer but warrants further evaluation of safety and efficacy in larger cohorts.

Challenges in longitudinal exposure-response modeling of data from complex study designs: a case study of modeling CDAI score for ustekinumab in patients with Crohn's disease.

Informative exposure-response modeling of clinical endpoints is important in drug development to identify optimum dose and dosing regimens. Despite much recent progress in mechanism-based longitudinal modeling of clinical data, challenges remain in clinical trials of diseases such as Crohn's disease, where a commonly used composite endpoint Crohn's Disease Activity Index (CDAI) has considerable variation in its administration and scoring between different assessors and complex study designs typically include maintenance phases with randomized withdrawal re-randomizations and other response driven dose adjustments. This manuscript illustrates the complexities of exposure-response modeling of such composite endpoint data through a latent-variable based Indirect Response model framework for CDAI scores using data from three phase III trials of ustekinumab in patients with moderate-to-severe Crohn's Disease. Visual predictive check was used to evaluate model performance. Potential impacts of the study design on model development and evaluation of the E-R relationship in the induction and maintenance phases of treatment are discussed. Certain biases appeared difficult to overcome, and an autocorrelated residual error model was found to provide improvement.

Latent variable indirect response joint modeling of a continuous and a categorical clinical endpoint.

Informative exposure-response modeling of clinical endpoints is important in drug development. There has been much recent progress in latent variable modeling of ordered categorical endpoints, including the application of indirect response (IDR) models and accounting for residual correlations between multiple categorical endpoints. This manuscript describes a framework of latent-variable-based IDR models that facilitate easy simultaneous modeling of a continuous and a categorical clinical endpoint. The model was applied to data from two phase III clinical trials of subcutaneously administered ustekinumab for the treatment of psoriatic arthritis, where Psoriasis Area and Severity Index scores and 20, 50, and 70 % improvement in the American College of Rheumatology response criteria were used as efficacy endpoints. Visual predictive check and external validation showed reasonable parameter estimation precision and model performance.

Efficacy and safety of ustekinumab in Chinese patients with moderate to severe plaque-type psoriasis: results from a phase 3 clinical trial (LOTUS).

BACKGROUND: Available biologic agents for the treatment of psoriasis in China are limited. OBJECTIVES: The LOTUS study is a phase 3, double-blind, placebo-controlled study that evaluated the efficacy and safety of ustekinumab in Chinese patients with moderate to severe plaque-type psoriasis. PATIENTS AND METHODS: Patients (n=322) were randomized to receive ustekinumab 45 mg or placebo at weeks 0 and 4, with placebo crossover to ustekinumab at week 12; all patients were followed up to week 36. The primary end point was the proportion of patients achieving at least a 75% improvement in the Psoriasis Area and Severity Index (PASI 75) at week 12. Other end points at week 12 included the proportion of patients with a Physician's Global Assessment (PGA) score of 0 or 1 and the change in Dermatology Life Quality Index (DLQI) score from baseline. RESULTS: At week 12, 82.5% of ustekinumab-treated patients achieved PASI 75 responses compared with 11.1% of placebo-treated patients (P<.001). Clinical responses were maintained through week 28, with maximum responses observed at week 24. Significant improvements in PGA and DLQI were observed at week 12 and were generally maintained through week 28. At week 12, adverse events rates were similar between groups (45 mg: 42.5% vs placebo: 38.5%), and serious adverse events were reported in 0.6% of patients in each group. Through week 36, no cases of active tuberculosis, serious infections, malignancies, or major adverse cardiovascular events were reported. CONCLUSIONS: Consistent with results previously reported in global phase 3 studies, ustekinumab was highly effective and generally well tolerated in Chinese patients with moderate to severe psoriasis through 36 weeks.

Long-term safety experience of ustekinumab in patients with moderate to severe psoriasis (Part II of II): results from analyses of infections and malignancy from pooled phase II and III clinical trials.

BACKGROUND: Ustekinumab targets interleukin (IL)-12 and IL-23 in the treatment of moderate to severe psoriasis. OBJECTIVE: We sought to evaluate the impact of ustekinumab on infections and malignancies, both theoretical risks of blocking IL-12 and IL-23, in patients exposed up to 3 years. METHODS: Rates of infections and malignancies were evaluated in cumulative safety data from 3117 ustekinumab-treated patients across 4 studies. RESULTS: During the placebo-controlled periods, rates of overall infections per 100 patient-years were similar among placebo (121.0), ustekinumab 45-mg (145.7), and ustekinumab 90-mg (132.2) groups, with overlapping confidence intervals, and remained stable through 3 years in ustekinumab groups. Rates of serious infections during the placebo-controlled periods were similar between placebo (1.70) and 90-mg (1.97) groups, yet lower in the 45-mg group (0.49). Rates remained stable (90 mg) or decreased (45 mg) over time, and were comparable with those for the US psoriasis population based on a managed care database. Rates of malignancies during the placebo-controlled periods were comparable among groups (placebo: 1.70; 45 mg: 0.99; 90 mg: 0.98) and remained stable over time in ustekinumab groups. Rates of malignancies, excluding nonmelanoma skin cancer, were comparable with rates expected in the general US population based on the Surveillance, Epidemiology, and End Results database. LIMITATIONS: Controlled periods do not extend beyond 12 to 20 weeks. Only 1247 patients were treated for at least 2 years, to date. Comparator database populations may not fully represent the clinical trial population. CONCLUSIONS: The emerging safety profile of ustekinumab remains favorable and does not suggest increased rates of infection or malignancy through 3 years.

Long-term safety experience of ustekinumab in patients with moderate-to-severe psoriasis (Part I of II): results from analyses of general safety parameters from pooled Phase 2 and 3 clinical trials.

BACKGROUND: Ustekinumab targets interleukin (IL)-12 and IL-23 in the treatment of moderate-to-severe psoriasis. OBJECTIVE: To evaluate overall pooled study data to assess the safety profile of ustekinumab through 3 years of treatment. METHODS: Cumulative safety data were pooled from studies in 3117 ustekinumab-treated patients. RESULTS: During the placebo-controlled periods (Phase 2, PHOENIX 1, PHOENIX 2), rates of adverse events (AEs) were comparable among patients treated with placebo (50.4%), with ustekinumab 45 mg (57.6%), or with ustekinumab 90 mg (51.6%); similar findings were observed during the controlled period of the ACCEPT trial (etanercept: 70.0%; ustekinumab 45 mg: 66.0%; and ustekinumab 90 mg: 69.2%). Rates of serious AEs (SAEs) through the controlled periods were low and comparable among all groups (1.2% to 1.9%). Through 3 years, rates of AEs per 100 patient-years of follow-up (/100 patient-yrs) (45 mg: 305.2/100 patient-yrs; 90 mg: 305.9/100 patient-yrs) and SAEs (45 mg: 6.8/100 patient-yrs; 90 mg: 8.2/100 patient-yrs) were comparable between ustekinumab doses. No cases of demyelination or tuberculosis were reported in these trials. No dose response in rates of AEs, overall infections, or SAEs was apparent through 3 years. Rates of AEs, infections, SAEs, and AEs leading to study agent discontinuation remained generally stable or decreased over time. LIMITATIONS: Controlled periods did not extend beyond 12 to 20 weeks. Only 1247 of the 3117 ustekinumab-treated patients were treated for 2 or more years. CONCLUSIONS: The safety profile of continued ustekinumab exposure through up to 3 years is favorable and consistent with previous short-term reports.

An update on the long-term safety experience of ustekinumab: results from the psoriasis clinical development program with up to four years of follow-up.

BACKGROUND: The efficacy and safety profile of ustekinumab with up to three years of exposure suggested a favorable benefit-risk profile in patients with moderate to severe psoriasis. OBJECTIVE: To evaluate the safety of ustekinumab in patients with moderate to severe psoriasis treated for up to four years. METHODS: Safety data were pooled across four Phase II/III randomized controlled trials. Rates over time and cumulative rates of adverse events (AEs), AEs leading to treatment discontinuation, serious adverse events (SAEs), serious infections, malignancies, and major adverse cardiovascular events (MACE) (i.e., cardiovascular death, myocardial infarction [MI], or stroke as adjudicated by an independent panel of academic cardiologists) were evaluated. Observed rates of AEs of interest were compared with those expected in the general (malignancies, MI, and stroke) and psoriasis (serious infections, MI, and stroke) populations. RESULTS: Overall, 3,117 patients were followed for up to four years (6,791 patient-years). Rates of AEs, AEs leading to treatment discontinuation, and SAEs remained stable over time, whereas cumulative rates were generally comparable between patients who received 45 mg and 90 mg of ustekinumab. The rates of AEs of interest also remained stable over time, and cumulative rates per 100 patient-years were 0.80 and 1.32 (serious infections), 0.70 and 0.53 (nonmelanoma skin cancer), 0.63 and 0.61 (other malignancies), and 0.56 and 0.46 (MACE) in patients treated with 45 mg and 90 mg, respectively. Rates of AEs of interest were consistent with those in the general and psoriasis populations. CONCLUSION: The safety profile of long-term ustekinumab treatment with up to four years of continuous use remains consistent with previous reports, with no evidence of cumulative toxicity.

Effect of rosiglitazone on HDL metabolism in subjects with metabolic syndrome and low HDL.

Treatment with the peroxisome proliferator-activated receptor γ agonist rosiglitazone has been reported to increase HDL-cholesterol (HDL-C) levels, although the mechanism responsible for this is unknown. We sought to determine the effect of rosiglitazone on HDL apolipoprotein A-I (apoA-I) and apoA-II metabolism in subjects with metabolic syndrome and low HDL-C. Subjects were treated with placebo followed by rosiglitazone (8 mg) once daily. At the end of each 8 week treatment, subjects (n = 15) underwent a kinetic study to measure apoA-I and apoA-II production rate (PR) and fractional catabolic rate. Rosiglitazone significantly reduced fasting insulin and high-sensitivity C-reactive protein (hsCRP) and increased apoA-II levels. Mean apoA-I and HDL-C levels were unchanged following rosiglitazone treatment, although there was considerable individual variability in the HDL-C response. Rosiglitazone had no effect on apoA-I metabolism, whereas the apoA-II PR was increased by 23%. The change in HDL-C in response to rosiglitazone was significantly correlated with the change in apoA-II concentration but not to changes in apoA-I, measures of glucose homeostasis, or hsCRP. Treatment with rosiglitazone significantly increased apoA-II production in subjects with metabolic syndrome and low HDL-C but had no effect on apoA-I metabolism. The change in HDL-C in response to rosiglitazone treatment was unrelated to effects on apoA-I, instead being related to the change in the metabolism of apoA-II.

Informative dropout modeling of longitudinal ordered categorical data and model validation: application to exposure-response modeling of physician's global assessment score for ustekinumab in patients with psoriasis.

The physician's global assessment (PGA) score is a 6-point measure of psoriasis severity that is widely used in clinical trials to assess response to psoriasis treatment. The objective of this study was to perform exposure-response modeling using the PGA score as a pharmacodynamic endpoint following treatment with ustekinumab in patients with moderate-to-severe psoriasis who participated in two Phase 3 studies (PHOENIX 1 and PHOENIX 2). Patients were randomly assigned to receive ustekinumab 45 or 90 mg or placebo, followed by active treatment or placebo crossover to ustekinumab, dose intensification or randomized withdrawal and long-term extension periods. A novel joint longitudinal-dropout model was developed from serum ustekinumab concentrations, PGA scores, and patient dropout information. The exposure-response component employed a semi-mechanistic drug model, integrated with disease progression and placebo effect under the mixed-effect logistic regression framework. This allowed potential tolerance to be investigated with a mechanistic approach. The dropout component of the joint model allowed the examination of its potential influence on the exposure-response relationship. The flexible Weibull dropout hazard function was used. Visual predictive check of the joint longitudinal-dropout model required special handling, and a conditional approach was proposed. The conditional approach was extended to external model validation. Finally, appropriate interpretation of model validation is discussed. This longitudinal-dropout model can serve as a basis to support future alternative dosing regimens for ustekinumab in patients with moderate-to-severe plaque psoriasis.

Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia.

BACKGROUND: Patients with homozygous familial hypercholesterolemia have markedly elevated cholesterol levels, which respond poorly to drug therapy, and a very high risk of premature cardiovascular disease. Inhibition of the microsomal triglyceride transfer protein may be effective in reducing cholesterol levels in these patients. METHODS: We conducted a dose-escalation study to examine the safety, tolerability, and effects on lipid levels of BMS-201038, an inhibitor of the microsomal triglyceride transfer protein, in six patients with homozygous familial hypercholesterolemia. All lipid-lowering therapies were suspended 4 weeks before treatment. The patients received BMS-201038 at four different doses (0.03, 0.1, 0.3, and 1.0 mg per kilogram of body weight per day), each for 4 weeks, and returned for a final visit after a 4-week drug washout period. Analysis of lipid levels, safety laboratory analyses, and magnetic resonance imaging of the liver for fat content were performed throughout the study. RESULTS: All patients tolerated titration to the highest dose, 1.0 mg per kilogram per day. Treatment at this dose decreased low-density lipoprotein (LDL) cholesterol levels by 50.9% and apolipoprotein B levels by 55.6% from baseline (P<0.001 for both comparisons). Kinetic studies showed a marked reduction in the production of apolipoprotein B. The most serious adverse events were elevation of liver aminotransferase levels and accumulation of hepatic fat, which at the highest dose ranged from less than 10% to more than 40%. CONCLUSIONS: Inhibition of the microsomal triglyceride transfer protein by BMS-201038 resulted in the reduction of LDL cholesterol levels in patients with homozygous familial hypercholesterolemia, owing to reduced production of apolipoprotein B. However, the therapy was associated with elevated liver aminotransferase levels and hepatic fat accumulation.

Flaxseed and cardiovascular risk factors: results from a double blind, randomized, controlled clinical trial.

OBJECTIVE: Flaxseed is a rich source of alpha linolenic acid (ALA), fiber and lignans, making it a potentially attractive functional food for modulating cardiovascular risk. We studied the effects of flaxseed on markers of cardiovascular risk in hypercholesterolemic adults. METHODS: Sixty-two men and post-menopausal women with pre-study low density lipoprotein cholesterol (LDL-C) between 130 and 200 mg/dl were randomized to 40g/day of ground flaxseed-containing baked products or matching wheat bran products for 10 weeks while following a low fat, low cholesterol diet. Fasting lipoproteins, measures of insulin resistance, inflammation, oxidative stress, and safety were assessed at 0, 5 and 10 weeks. RESULTS: Flaxseed was well-tolerated, and increased serum levels of ALA (p < 0.001). Compared to wheat, flaxseed significantly reduced LDL-C at 5 weeks (-13%, p < 0.005), but not at 10 weeks (-7%, p = 0.07). Flaxseed reduced lipoprotein a (Lp[a]) by a net of 14% (p = 0.02), and reduced the homeostatic model assessment of insulin resistance (HOMA-IR) index by 23.7% (p = 0.03) compared to wheat at 10 weeks, but did not affect markers of inflammation (IL-6, Hs-CRP) or oxidative stress (ox LDL, urinary isoprostanes) at any time points. In men, flaxseed reduced HDL-C concentrations by a net of 16% (p = 0.03) and 9% (p = 0.05) at 5 and 10 weeks, respectively. CONCLUSIONS: Ground flaxseed has a modest but short lived LDL-C lowering effect, yet reduces Lp(a) and improves insulin sensitivity in hyperlipidemic adults. The HDL-C lowering effect of flaxseed in men warrants additional study.

A randomized trial of a low-carbohydrate diet for obesity.

BACKGROUND: Despite the popularity of the low-carbohydrate, high-protein, high-fat (Atkins) diet, no randomized, controlled trials have evaluated its efficacy. METHODS: We conducted a one-year, multicenter, controlled trial involving 63 obese men and women who were randomly assigned to either a low-carbohydrate, high-protein, high-fat diet or a low-calorie, high-carbohydrate, low-fat (conventional) diet. Professional contact was minimal to replicate the approach used by most dieters. RESULTS: Subjects on the low-carbohydrate diet had lost more weight than subjects on the conventional diet at 3 months (mean [+/-SD], -6.8+/-5.0 vs. -2.7+/-3.7 percent of body weight; P=0.001) and 6 months (-7.0+/-6.5 vs. -3.2+/-5.6 percent of body weight, P=0.02), but the difference at 12 months was not significant (-4.4+/-6.7 vs. -2.5+/-6.3 percent of body weight, P=0.26). After three months, no significant differences were found between the groups in total or low-density lipoprotein cholesterol concentrations. The increase in high-density lipoprotein cholesterol concentrations and the decrease in triglyceride concentrations were greater among subjects on the low-carbohydrate diet than among those on the conventional diet throughout most of the study. Both diets significantly decreased diastolic blood pressure and the insulin response to an oral glucose load. CONCLUSIONS: The low-carbohydrate diet produced a greater weight loss (absolute difference, approximately 4 percent) than did the conventional diet for the first six months, but the differences were not significant at one year. The low-carbohydrate diet was associated with a greater improvement in some risk factors for coronary heart disease. Adherence was poor and attrition was high in both groups. Longer and larger studies are required to determine the long-term safety and efficacy of low-carbohydrate, high-protein, high-fat diets.

Effects of pioglitazone on lipoproteins, inflammatory markers, and adipokines in nondiabetic patients with metabolic syndrome.

OBJECTIVE: The purpose of this research was to evaluate the short-term effects of pioglitazone (PIO) on high-density lipoprotein cholesterol (HDL-C) and other metabolic parameters in nondiabetic patients with metabolic syndrome (MetSyn). METHODS AND RESULTS: Sixty nondiabetic adults with low HDL-C and MetSyn were randomized to PIO or matching placebo for 12 weeks. PIO increased HDL-C by 15% and 14% at 6 and 12 weeks, respectively, compared with placebo (P<0.001). Changes in HDL-C were correlated to changes in adiponectin (r=0.34; P=0.01) but not to changes in insulin resistance. PIO did not affect serum triglycerides or low-density lipoprotein (LDL) cholesterol concentrations but reduced the number of small LDL particles by 18% (P<0.001). PIO reduced median C-reactive protein levels by 31% (P<0.001) and mean resistin levels by 10% (P=0.02) while increasing mean serum levels of adiponectin by 111% (P<0.001) compared with placebo. PIO did not affect weight and modestly decreased insulin resistance. CONCLUSIONS: In nondiabetic patients with low HDL-C and MetSyn, PIO significantly raised HDL-C and favorably affected lipoprotein particle size, markers of inflammation, and adipokines without changes in triglycerides, LDL-C, or weight. These results suggest that PIO has direct effects on HDL, which may contribute to its antiatherogenic effects.

Effects of rosiglitazone on lipids, adipokines, and inflammatory markers in nondiabetic patients with low high-density lipoprotein cholesterol and metabolic syndrome.

BACKGROUND: PPAR-gamma agonists improve insulin sensitivity and glycemic control in type 2 diabetes and may reduce atherosclerosis progression. Thus, PPAR-gamma agonists may be an effective therapy for metabolic syndrome. However, the full spectrum of potentially antiatherogenic mechanisms of PPAR-gamma agonists have not been fully tested in nondiabetic patients with metabolic syndrome. METHODS AND RESULTS: We performed a prospective, double-blinded, placebo-controlled study of 60 nondiabetic subjects with low high-density lipoprotein cholesterol (HDL-C) level and metabolic syndrome to rosiglitazone 8 mg daily or placebo for 12 weeks. We found no significant effect of rosiglitazone on HDL-C (+5.5% versus +5.8%, P=0.89), and an increase in total cholesterol (+8% versus -1%; P=0.03). Nevertheless, rosiglitazone significantly increased adiponectin (+168% versus +25%; P<0.001), and lowered resistin (-6% versus +4%; P=0.009), C-reactive protein (-32% versus +36%, P=0.002), interleukin (IL)-6 (-22% versus +4%, P<0.001), and soluble tumor-necrosis factor-alpha receptor-2 (-5% versus +7%, P<0.001). CONCLUSIONS: These findings suggest that rosiglitazone, presumably through its PPAR-gamma agonist properties, has direct effects on inflammatory markers and adipokines in the absence of favorable lipid effects. These findings may help explain the mechanism underlying the possible antiatherosclerotic effects of rosiglitazone.

The triglyceride-high-density lipoprotein axis: an important target of therapy?

Coronary heart disease is the single largest cause of morbidity and mortality in the United States. The link between elevated low-density lipoprotein cholesterol (LDL-C) levels and coronary heart disease (CHD) has been clearly established. However, triglycerides (TG) are increasingly believed to be independently associated with CHD, while high-density lipoprotein cholesterol (HDL-C) is inversely associated with CHD risk. High TG and low HDL often occur together, often with normal levels of LDL-C, and can be described as abnormalities of the TG-HDL axis. This lipid abnormality is a fundamental characteristic of patients with the metabolic syndrome, a condition strongly associated with the development of both type 2 diabetes and CHD. Patients with high TG and low HDL-C should be aggressively treated with therapeutic lifestyle changes. For high-risk patients, lipid-modifying therapy that specifically addresses the TG-HDL axis should also be considered. Current pharmacologic treatment options for such patients include statins, fibrates, niacin, fish oils, and combinations thereof. Several new pharmacologic approaches to treating the TG-HDL axis are currently being investigated. More clinical trial data is needed to test the hypothesis that pharmacologic therapy targeting the TG-HDL axis reduces atherosclerosis and cardiovascular events.

Flaxseed and cardiovascular risk.

Flaxseed has recently gained attention in the area of cardiovascular disease primarily because it is the richest known source of both alpha-linolenic acid (ALA) and the phytoestrogen, lignans, as well as being a good source of soluble fiber. Human studies have shown that flaxseed can modestly reduce serum total and low-density lipoprotein cholesterol concentrations, reduce postprandial glucose absorption, decrease some markers of inflammation, and raise serum levels of the omega-3 fatty acids, ALA and eicosapentaenoic acid. Data on the antiplatelet, antioxidant, and hypotensive effects of flaxseed, however, are inconclusive. More research is needed to define the role of this functional food in reducing cardiovascular risk.

Guggulipid for the treatment of hypercholesterolemia: a randomized controlled trial.

CONTEXT: Herbal extracts from Commiphora mukul (guggul) have been widely used in Asia as cholesterol-lowering agents, and their popularity is increasing in the United States. Recently, guggulsterones, the purported bioactive compounds of guggul, have been shown to be potent antagonists of 2 nuclear hormone receptors involved in cholesterol metabolism, establishing a plausible mechanism of action for the hypolipidemic effects of these extracts. However, there are currently no published safety or efficacy data on the use of guggul extracts in Western populations. OBJECTIVE: To study the short-term safety and efficacy of 2 doses of a standardized guggul extract (guggulipid, containing 2.5% guggulsterones) in healthy adults with hyperlipidemia eating a typical Western diet. DESIGN: Double-blind, randomized, placebo-controlled trial using a parallel design, conducted March 2000-August 2001. PARTICIPANTS AND SETTING: A total of 103 ambulatory, community-dwelling, healthy adults with hypercholesterolemia in the Philadelphia, Pa, metropolitan area. INTERVENTION: Oral, 3 times daily doses of standard-dose guggulipid (1000 mg), high-dose guggulipid (2000 mg), or matching placebo. MAIN OUTCOME MEASURES: Percentage change in levels of directly measured low-density lipoprotein cholesterol (LDL-C) after 8 weeks of therapy. Secondary outcome measures included levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, and directly measured very low-density lipoprotein cholesterol (VLDL-C), as well as adverse events reports and laboratory safety measures including electrolyte levels and hepatic and renal function. RESULTS: Compared with participants randomized to placebo (n = 36), in whom levels of LDL-C decreased by 5%, both standard-dose guggulipid (n = 33) and high-dose guggulipid (n = 34) raised levels of LDL-C by 4% (P =.01 vs placebo) and 5% (P =.006 vs placebo), respectively, at 8 weeks, for a net positive change of 9% to 10%. There were no significant changes in levels of total cholesterol, HDL-C, triglycerides, or VLDL-C in response to treatment with guggulipid in the intention-to-treat analysis. While guggulipid was generally well tolerated, 6 participants treated with guggulipid developed a hypersensitivity rash compared with none in the placebo group. CONCLUSIONS: Despite plausible mechanisms of action, guggulipid did not appear to improve levels of serum cholesterol over the short term in this population of adults with hypercholesterolemia, and might in fact raise levels of LDL-C. Guggulipid also appeared to cause a dermatologic hypersensitivity reaction in some patients.

A randomized trial of the effects of an almond-enriched, hypocaloric diet in the treatment of obesity.

BACKGROUND: Increased consumption of nuts has been advocated because of their health benefits, but the role of nuts in the treatment of obesity is unclear given their high energy density. OBJECTIVE: This study was designed to evaluate the effects of a hypocaloric, almond-enriched diet (AED) compared with a hypocaloric nut-free diet (NFD) on body weight and cardiovascular disease risk factors in the context of an 18-mo behavioral weight-management program. DESIGN: Overweight and obese individuals [n = 123; age = 46.8 y, BMI (in kg/m(2)) = 34.0] were randomly assigned to consume an AED or NFD and instructed in traditional behavioral methods of weight control. Anthropometric and metabolic measurements were made at baseline, 6 mo, and 18 mo. RESULTS: Those in the AED group lost slightly but significantly less weight than did those in the NFD group at 6 mo (-5.5 compared with -7.4 kg; P = 0.04), but there were no differences at 18 mo. No significant differences in body composition were found between the groups at 6 or 18 mo. The AED, compared with the NFD, was associated with greater reductions in total cholesterol (P = 0.03), total:HDL cholesterol (P = 0.02), and triglycerides (P = 0.048) at 6 mo, and no differences were observed between the groups at 18 mo. CONCLUSIONS: The AED and NFD groups experienced clinically significant and comparable weight loss at 18 mo. Despite smaller weight loss in the AED group at 6 mo, the AED group experienced greater improvements in lipid profiles. This trial was registered at clinicaltrials.gov as NCT00194428.

Chromium picolinate does not improve key features of metabolic syndrome in obese nondiabetic adults.

BACKGROUND: The use of chromium-containing dietary supplements is widespread among patients with type 2 diabetes. Chromium's effects in patients at high risk for developing diabetes, especially those with metabolic syndrome, is unknown. The objective of this study was to determine the effects of chromium picolinate (CrPic) on glucose metabolism in patients with metabolic syndrome. METHOD: A double-blind, placebo-controlled, randomized trial was conducted at a U.S. academic medical center. Sixty three patients with National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III)-defined metabolic syndrome were included. The primary end point was a change in the insulin sensitivity index derived from a frequently sampled intravenous glucose tolerance test. Prespecified secondary end points included changes in other measurements of glucose metabolism, oxidative stress, fasting serum lipids, and high sensitivity C-reactive protein. RESULTS: After 16 weeks of CrPic treatment, there was no significant change in insulin sensitivity index between groups (P = 0.14). However, CrPic increased acute insulin response to glucose (P 0.02). CrPic had no significant effect on other measures of glucose metabolism, body weight, serum lipids, or measures of inflammation and oxidative stress. CONCLUSION: CrPic at 1000 microg/day does not improve key features of the metabolic syndrome in obese nondiabetic patients.