Efficacy and Safety of Long-Term Fluoxetine Treatment of Obesity - Maximizing Success

Obesity is a major health care concern because of its associated medical complications and increased mortality. Despite a myriad of short-term weight loss strategies and the motivation of improving health, patients have difficulty maintaining reduced weight. Pharmacologic agents, such as fluoxetine, a selective serotonin uptake inhibitor, have been investigated as adjunctive therapy to standard weight management programs. Extended therapy with fluoxetine has demonstrated clinically meaningful benefits on weight loss and obesity-associated medical conditions in double-blind placebo-controlled studies. However, the magnitude of these benefits for individuals vary. Such findings are consistent with the belief that the obesity syndrome has differing etiologies. Accordingly not all patients are likely to benefit from a particular therapy. Studies should identify patient subgroups that are more likely to respond to a specific therapy. In this study of 719 fluoxetine-treated and 722 placebo treated patients in four multicenter, randomized, double-blind, long-term clinical trials, we investigated possible predictors of a beneficial long-term outcome from fluoxetine therapy. Patients' age, current smoking activity, and baseline uric acid concentration were predictors of a meaningful long-term treatment effect. Further review of the weight loss patterns of patients achieving long-term success provided the basis for a treatment monitor. Use of the predictors and the treatment monitor are strategies to maximize the benefits of therapy through improved patient selection and monitoring during a therapeutic program.     

Fluoxetine: A Randomized Clinical Trial in the Maintenance of Weight Loss

Because current weight-reduction treatments have considerable recidivism, a therapy that could help patients maintain weight loss would be of benefit. A six-center, randomized, double-blind trial compared the effects of the specific serotonin uptake inhibitor, fluoxetine hydrochloride, and placebo on maintenance of weight loss. Obese outpatients who had lost ≤3.6 kg after 8 weeks of single-blind fluoxetine 60 mg/day in the qualification phase (N=317 [70.4% of patients entered]; mean ± standard deviation [SD] weight loss, 6.8 ± 2.8 kg) were randomly assigned to fluoxetine 20 mg/day (N=104), fluoxetine 60 mg/day (N=106), or placebo (N=107) for 40 weeks (maintenance phase). Patients received minimal nutrition/dietary counseling. Qualification phase clinic visits were biweekly; maintenance phase visits were monthly for 4 months, then bimonthly for 6 months. Patients treated with fluoxetine 60 mg/day continued to lose weight for 8 additional weeks (16 weeks total; maximum mean ± SD weight loss, 7.2 ± 4.6 kg); those treated with fluoxetine 20 mg/day or placebo began to regain weight. Mean weights remained below baseline values at week 48 (all groups); treatment differences were not statistically significant. Study completion rates were comparable (fluoxetine 20 mg/day, 67.3%; fluoxetine 60 mg/day, 56.6%; placebo, 67.3%; p = 0.175). Among commonly reported adverse events (>10% incidence), only asthenia was reported statistically significantly (p< 0.050) more frequently with fluoxetine than with placebo. Few patients discontinued for any single adverse event. Fluoxetine 60 mg/day was effective for a longer period than fluoxetine 20 mg/day or placebo in maintaining weight loss. Overall, fluoxetine was safe and well tolerated.     

Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression.

OBJECTIVE--A comprehensive meta-analysis of clinical trial data was performed to assess the possible association of fluoxetine and suicidality (suicidal acts and ideation). DESIGN--Retrospective analysis of pooled data from 17 double blind clinical trials in patients with major depressive disorder comparing fluoxetine (n = 1765) with a tricyclic antidepressant (n = 731) or placebo (n = 569), or both. MAIN OUTCOME MEASURES--Multiple data sources were searched to identify patients with suicidal acts. Suicidal ideation was assessed with item 3 of the Hamilton depression rating scale, which systematically rates suicidality. Emergence of substantial suicidal ideation was defined as a change in the rating of this item from 0 or 1 at baseline to 3 or 4 during double blind treatment; worsening was defined as any increase from baseline; improvement was defined as a decrease from baseline at the last visit during the treatment. RESULTS--Suicidal acts did not differ significantly in comparisons of fluoxetine with placebo (0.2% v 0.2%, p = 0.494, Mantel-Haenszel adjusted incidence difference) and with tricyclic antidepressants (0.7% v 0.4%, p = 0.419). The pooled incidence of suicidal acts was 0.3% for fluoxetine, 0.2% for placebo, and 0.4% for tricyclic antidepressants, and fluoxetine did not differ significantly from either placebo (p = 0.533, Pearson''s chi 2) or tricyclic antidepressants (p = 0.789). Suicidal ideation emerged marginally significantly less often with fluoxetine than with placebo (0.9% v 2.6%, p = 0.094) and numerically less often than with tricyclic antidepressants (1.7% v 3.6%, p = 0.102). The pooled incidence of emergence of substantial suicidal ideation was 1.2% for fluoxetine, 2.6% for placebo, and 3.6% for tricyclic antidepressants. The incidence was significantly lower with fluoxetine than with placebo (p = 0.042) and tricyclic antidepressants (p = 0.001). Any degree of worsening of suicidal ideation was similar with fluoxetine and placebo (15.4% v 17.9%, p = 0.196) and with fluoxetine and tricyclic antidepressants (15.6% v 16.3%, p = 0.793). The pooled incidence of worsening of suicidal ideation was 15.3% for fluoxetine, 17.9% for placebo, and 16.3% for tricyclic antidepressants. The incidence did not differ significantly with fluoxetine and placebo (p = 0.141) or tricyclic antidepressants (p = 0.542). Suicidal ideation improved significantly more with fluoxetine than with placebo (72.0% v 54.8%, p less than 0.001) and was similar to the improvement with tricyclic antidepressants (72.5% v 69.8%, p = 0.294). The pooled incidence of improvement of suicidal ideation was 72.2% for fluoxetine, 54.8% for placebo, and 69.8% for tricyclic antidepressants. The incidence with fluoxetine was significantly greater than with placebo (p less than 0.001) and did not differ from that with tricyclic antidepressants (p = 0.296). CONCLUSIONS--Data from these trials do not show that fluoxetine is associated with an increased risk of suicidal acts or emergence of substantial suicidal thoughts among depressed patients.     

Serotoninergic Manipulation,Meal-Induced Satiety and Eating Pattern: Effect of Fluoxetine in Obese Female Subjects

Twelve nondepressed healthy female obese subjects (BMI > 30kg/m²) took part in a study which conformed to a double-blind randomized crossover design. Each subject acted as her own control across 2 weeks of treatment with either 60 mg of the 5-HT reuptake inhibitor fluoxetine or matching placebo. On days 7 and 14 of both treatment phases subjects were provided with fixed energy lunch meals high in either CHO or fat. The effect of these meals on satiety during the fluoxetine and placebo phases was assessed by a battery of procedures. Subjects felt less hungry after consuming the high CHO meal than after consuming the high-fat meal. They also felt less hungry when taking fluoxetine than when taking the placebo. Analysis of energy intake from the test meal revealed a main effect of prior lunch meal type (high CHO or high fat) and a main effect of drug treatment. Subjects consumed an average of 574 kcal following the high CHO meal compared to 689 kcal following the high-fat meal. Subjects also consumed an average of 532 kcal when taking fluoxetine compared to 730 kcal when taking the placebo. Fluoxetine did not exert any significant effects on macronutrient selection. Mean daily energy intake, calculated from food diary records, was 1881 kcal when subjects were taking the placebo compared to 1460 kcal when taking fluoxetine (a reduction of 22.4%). Fluoxetine treatment produced a significant weight loss of 1.97 kg over the two weeks of treatment compared to a weight loss of only 0.04 kg on placebo.     

Where do we stand with IPF treatment?

Despite receiving ‘weak no’ recommendations in the updated guidelines on treating patients with Idiopathic Pulmonary Fibrosis (IPF), two key treatment options are pirfenidone and N-acetylcysteine (NAC), and both are used in clinical practice. The efficacy of pirfenidone is supported by a number of Phase III trials as well as a Cochrane meta-analysis. Tolerability data are also provided by clinical trials and a long-term extension phase of these studies. Pirfenidone is approved in Europe for the treatment of patients with mild-to-moderate IPF. NAC-based therapy has no such approval, but is commonly used to treat patients. A Phase III trial suggested some benefit of the NAC, prednisone and azathioprine regimen for IPF patients, but the study had many limitations. A further study to investigate this regimen, compared with a placebo alone arm, was recently stopped due to increased mortality in the triple-therapy arm. Discussion of these data and recent findings highlight the importance of a further update to the existing guidelines, so that IPF specialists can provide the most up-to-date advice and treatment to patients in clinical practice.     

A controlled study of fluoxetine and cognitive-behavioural counselling in the treatment of postnatal depression.

OBJECTIVE: To study the effectiveness of fluoxetine and cognitive-behavioural counselling in depressive illness in postnatal women: to compare fluoxetine and placebo, six sessions and one session of counselling, and combinations of drugs and counselling. DESIGN: Randomised, controlled treatment trial, double blind in relation to drug treatment, with four treatment cells: fluoxetine or placebo plus one or six sessions of counselling. SUBJECTS: 87 women satisfying criteria for depressive illness 6-8 weeks after childbirth, 61 (70%) of whom completed 12 weeks of treatment. SETTING: Community based study in south Manchester. MAIN OUTCOME MEASURES: Psychiatric morbidity after 1, 4, and 12 weeks, measured as mean scores and 95% confidence limits on the revised clinical interview schedule, the Edinburgh postnatal depression scale and the Hamilton depression scale. RESULTS: Highly significant improvement was seen in all four treatment groups. The improvement in subjects receiving fluoxetine was significantly greater than in those receiving placebo. The improvement after six sessions of counselling was significantly greater than after a single session. Interaction between counselling and fluoxetine was not statistically significant. These differences were evident after one week, and improvement in all groups was complete after four weeks. CONCLUSIONS: Both fluoxetine and cognitive-behavioural counselling given as a course of therapy are effective treatments for non-psychotic depression in postnatal women. After an initial session of counselling, additional benefit results from either fluoxetine or further counselling but there seems to be no advantage in receiving both. The choice of treatment may therefore be made by the women themselves.     

Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration

Background

Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance. Yet, the efficacy of the antidepressants may also depend on the severity of initial depression scores. The purpose of this analysis is to establish the relation of baseline severity and antidepressant efficacy using a relevant dataset of published and unpublished clinical trials.

Methods and Findings

We obtained data on all clinical trials submitted to the US Food and Drug Administration (FDA) for the licensing of the four new-generation antidepressants for which full datasets were available. We then used meta-analytic techniques to assess linear and quadratic effects of initial severity on improvement scores for drug and placebo groups and on drug–placebo difference scores. Drug–placebo differences increased as a function of initial severity, rising from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression, reaching conventional criteria for clinical significance only for patients at the upper end of the very severely depressed category. Meta-regression analyses indicated that the relation of baseline severity and improvement was curvilinear in drug groups and showed a strong, negative linear component in placebo groups.

Conclusions

Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.     

Physical Activity and Long-Term Maintenance of Weight Loss

To examine the effect of exercise on the long-term maintenance of weight loss, two types of literature were reviewed - correlational studies of predictors of long-term weight loss, and randomized trials comparing diet, exercise, and the combination of diet plus exercise. Both literatures were striking in the consistency with which activity emerged as a determinant of long-term maintenance of weight loss. The benefits of exercise for long-term weight maintenance were observed with different types of populations, diets, and exercise interventions. Several possible explanations for these positive effects of diet plus exercise are presented, and suggestions made for future research on ways to maximize the benefit of this approach to weight control. Since adherence to exercise may ultimately prove to be the cornerstone for long-term weight maintenance, studying ways to improve exercise adherence is recommended.     

Navafenterol (AZD8871) in patients with mild asthma: a randomised placebo-controlled phase I study evaluating the safety,tolerability, pharmacokinetics,and pharmacodynamics of single ascending doses of this novel inhaled long-acting dual-pharmacology bronchodilator

Nintedanib is an approved therapy for idiopathic pulmonary fibrosis (IPF). Some patients treated with nintedanib experience weight loss. Exploratory data suggest that low body mass index or weight loss are associated with worse outcomes in patients with IPF. We investigated whether BMI at baseline or weight loss over 52 weeks was associated with FVC decline, or influenced the effect of nintedanib, in patients with IPF. Using pooled data from the two INPULSIS trials, we analysed the rate of decline in FVC (mL/yr) over 52 weeks in patients treated with nintedanib and placebo in subgroups by baseline BMI (< 25; ≥25 to < 30; ≥30 kg/m2) and by weight loss over 52 weeks (≤5; > 5%) using random coefficient regression. In the placebo group, the mean rate of FVC decline over 52 weeks was numerically greater in patients with lower baseline BMI (− 283.3 [SE 22.4], − 207.9 [20.9] and − 104.5 [21.4] in patients with BMI < 25 kg/m2, ≥25 to < 30 kg/m2 and ≥ 30 kg/m2, respectively). Nintedanib reduced the rate of FVC decline versus placebo in all subgroups by BMI, with a consistent treatment effect across subgroups (interaction p = 0.31). In the placebo group, the mean rate of FVC decline was numerically greater in patients with > 5% than ≤5% weight loss over 52 weeks (− 312.7 [SE 32.2] versus − 199.5 [SE 14.4] mL/year). Nintedanib reduced the rate of FVC decline versus placebo in both subgroups by weight loss, with a greater treatment effect in patients with > 5% weight loss (interaction p = 0.0008). The adverse event profile of nintedanib was similar across subgroups. In patients with IPF, lower BMI and weight loss may be associated with faster decline in FVC. Nintedanib reduces the rate of FVC decline both in patients who lose weight on treatment and those who do not. ClinicalTrials.gov ; Nos. NCT01335464 and NCT01335477 ; URL: www.clinicaltrials.gov .     

Hypertriglyceridemia and the fibrate trials

Epidemiological studies published since 1996 have established that hypertriglyceridemia can predict risk of cardiovascular disease in a manner statistically independent of HDL cholesterol. Nevertheless, the relationship of concentrations of plasma triglycerides to risk of cardiovascular disease remains less than straightforward, partly because triglycerides are carried in lipoproteins of different atherogenicity, partly because hypertriglyceridemia is associated with non-lipid atherogenic and thrombogenic processes. For example, the association of highest risk of cardiovascular disease to moderate rather than to severe hypertriglyceridemia can be understood in terms of the distribution of triglycerides between different classes of plasma lipoproteins. It is counter-intuitive to most clinicians, however, and hence it can result in the misdirection of clinical efforts including drug therapy.Fibrates lower plasma triglycerides, and raise HDL, efficiently and with few immediate side-effects. Central to their mode of action is activation of certain nuclear receptors in cells. There is no necessary connection, however, between that fascinating biochemistry and clinical benefit as defined by reductions in rates of death by coronary artery disease. A review of trials of cholesterol-lowering by diet and drugs, published between 1966 and 1996, included 12 trials of therapy with fibrates or placebo in more than 21000 patients. Overall, these trials indicated no benefit in terms of reduction in risk of coronary deaths. The period since 1996 has seen the publication of four additional trials of treatment of 6144 patients with fibrates or placebo. Two of them were major trials. The VA-HIT was very encouraging, because treatment with gemfibrozil produced a signficant reduction in the combined incidence of fatal and non-fatal coronary events. There was no significant reduction in coronary deaths, however. The results of BIP were frankly disappointing, because they demonstrated no significant effect of treatment with bezafibrate on either the primary end-point of the trial or on rates of coronary death.Clinical indications for the use of fibrates can obviously not be based on biochemical insights, however intriguing in their own right, but they have also not been satisfactorily defined by the randomized clinical trials published to date. Hope remains, however, that some clarification will result from ongoing trials of fibrate treatment of patients with type II diabetes.     

Effects of Pramlintide in Patients with Type 2 Diabetes Mellitus: An Analysis Using Daily Insulin Dose Tertiles

ObjectiveThe purpose of the analysis was to investigate if the efficacy and tolerability of 6 months of pramlintide therapy in patients with type 2 diabetes mellitus (T2DM) differed with increasing levels of concomitant insulin doses, using data from 3 previously described clinical trials.MethodsIn this post hoc analysis, data from 2 pooled, placebo-controlled pivotal trials and 1 clinical practice trial were evaluated by baseline insulin use tertile in patients with T2DM.ResultsIn the pivotal trials, both glycated hemoglobin (A1C) and body weight decreased similarly across tertiles with pramlintide. A1C decreased slightly and body weight remained relatively unchanged across tertiles with placebo. Similarly, in the clinical practice trial, pramlintide was associated with decreases in A1C, body weight, and total daily insulin use across the tertiles. Overall, the most common adverse events were gastrointestinal in nature, and the rate of severe hypoglycemia was low.ConclusionThese results suggest that pramlintide therapy was associated with improved A1C and decreased body weight, with a low rate of severe hypoglycemia, among patients with T2DM, regardless of baseline insulin use. (Endocr Pract. 2014;20:1070-1075)     

A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial)

Background

There have been increasing concerns regarding the safety and efficacy of neuroleptics in people with dementia, but there are very few long-term trials to inform clinical practice. The aim of this study was to determine the impact of long-term treatment with neuroleptic agents upon global cognitive decline and neuropsychiatric symptoms in patients with Alzheimer disease.

Methods and Findings

Design: Randomised, blinded, placebo-controlled parallel two-group treatment discontinuation trial.Setting: Oxfordshire, Newcastle and Gateshead, London and Edinburgh, United Kingdom.Participants: Patients currently prescribed the neuroleptics thioridazine, chlorpromazine, haloperidol trifluoperazine or risperidone for behavioural or psychiatric disturbance in dementia for at least 3 mo.Interventions: Continue neuroleptic treatment for 12 mo or switch to an identical placebo.Outcome measures: Primary outcome was total Severe Impairment Battery (SIB) score. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory (NPI).Results: 165 patients were randomised (83 to continue treatment and 82 to placebo, i.e., discontinue treatment), of whom 128 (78%) commenced treatment (64 continue/64 placebo). Of those, 26 were lost to follow-up (13 per arm), resulting in 51 patients per arm analysed for the primary outcome. There was no significant difference between the continue treatment and placebo groups in the estimated mean change in SIB scores between baseline and 6 mo; estimated mean difference in deterioration (favouring placebo) −0.4 (95% confidence interval [CI] −6.4 to 5.5), adjusted for baseline value (p = 0.9). For neuropsychiatric symptoms, there was no significant difference between the continue treatment and placebo groups (n = 56 and 53, respectively) in the estimated mean change in NPI scores between baseline and 6 mo; estimated mean difference in deterioration (favouring continue treatment) −2.4 (95% CI −8.2 to 3.5), adjusted for baseline value (p = 0.4). Both results became more pronounced at 12 mo. There was some evidence to suggest that those patients with initial NPI ≥ 15 benefited on neuropsychiatric symptoms from continuing treatment.

Conclusions

For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this benefit must be weighed against the side effects of therapy.Trial registration: Cochrane Central Registry of Controlled Trials/National Research Register (#ISRCTN33368770).     

Baseline predictors of response and discontinuation of tumor necrosis factor-alpha blocking therapy in ankylosing spondylitis: a prospective longitudinal observational cohort study

Introduction  

Identifying ankylosing spondylitis (AS) patients who are likely to benefit from tumor necrosis factor-alpha (TNF-α) blocking therapy is important, especially in view of the costs and potential side effects of these agents. Recently, the AS Disease Activity Score (ASDAS) has been developed to assess both subjective and objective aspects of AS disease activity. However, data about the predictive value of the ASDAS with respect to clinical response to TNF-α blocking therapy are lacking. The aim of the present study was to identify baseline predictors of response and discontinuation of TNF-α blocking therapy in AS patients in daily clinical practice.     

No Specific Effect of Fluoxetine Treatment on Fasting Glucose,Insulin, Lipid Levels,and Blood Pressure in Healthy Men with Abdominal Obesity

In this paper we investigated the effect of fluoxetine (60 mg/d) on serum lipids, glucose and insulin concentrations and blood pressure by means of a randomized, double-blind placebo controlled trial. Thirty-eight overweight BMI: 26–30 kg/m²), nondiabetic, nonhypertensive men with an abdominal fat distribution (waist/hip ratio: >0.97) received dietary advice and placebo or fluoxetine for 12 weeks. The changes in serum parameters and blood pressure in the fluoxetine treated group were not different from the placebo treated group, despite a significantly larger weight loss in the fluoxetine group. In both groups serum total-cholesterol concentrations, serum LDL-cholesterol concentrations and tlie HDL/LDL ratio were significantly improved after treatment. Reductions in fasting glucose concentration and systolic blood pressure were only significant in the placebo group. A reduction of serum triglycerides and an increase of HDL-cholesterol were found in the fluoxetine treated group. In the total study population the changes in serum lipids seemed to be more strongly related to the change in total body fat or subcutaneous abdominal fat (assessed by MRI) compared to the change in visceral fat. The improvement of most of the serum lipids was related to tlie change in total body fat independent of the mechanism for attaining this fat loss. Our results indicate that fluoxetine treatment has no specific effect beyond that expected for weight loss on serum lipid, glucose and insulin concentrations, and blood pressure in overweight men.     

Percutaneous closure of a patent foramen ovale after cryptogenic stroke

A patent foramen ovale is a common intracardiac finding that is located between the left and right atrium. It can cause right-to-left shunting and has a high prevalence in patients who suffer a cryptogenic stroke. Earlier trials did not show superiority of percutaneous patent foramen ovale closure with standard medical therapy over standard medical therapy alone in the treatment of cryptogenic stroke. Interestingly, several meta-analyses show positive results regarding closure, suggesting underpowering of the individual trials. Recently, two large prospective trials and one long-term follow-up study showed benefit of percutaneous closure over standard medical therapy in treatment of cryptogenic stroke. A larger right-to-left shunt or the presence of an atrial septal aneurysm were predictors for a recurrent event. Therefore, percutaneous patent foramen ovale closure after cryptogenic stroke should be recommended over antiplatelet therapy alone in patients younger than 55 years of age with a high-risk patent foramen ovale.     

Is Liraglutide A Useful Addition to Diabetes Therapy?

ObjectiveTo evaluate liraglutide as an antidiabetic agent.MethodsThe pertinent English-language medical literature was reviewed for the period from 1985 to April 2010 with use of data from MEDLINE.ResultsLiraglutide is a glucagonlike peptide-1 receptor analogue that stimulates insulin secretion, reduces postprandial glucagon release, causes a mild delay in gastric emptying, and may slightly decrease appetite. Mean reductions in hemoglobin A1c levels with liraglutide therapy range from 1.0% to 1.5% in comparison with baseline and are 1.0% and 1.3% in comparison with placebo. Head-to-head trials suggest that liraglutide may be more effective than glimepiride, rosiglitazone, insulin glargine, and exenatide. Some of the previous trials, however, are limited by use of submaximal doses of comparator drugs and an open-label design. The use of liraglutide is associated with a mean weight loss of 0.2 to 3.2 kg relative to baseline and 0.1 to 2.6 kg relative to placebo. Liraglutiderelated hypoglycemia is generally mild, but its incidence and severity substantially increase in conjunction with sulfonylureas. Gastrointestinal adverse effects such as nausea, diarrhea, or vomiting occurred in 44% to 56% of patients who received liraglutide versus 17% to 19% with placebo. Premature withdrawal from trials occurred in 4% to 15% of liraglutide-treated patients (mainly attributable to gastrointestinal adverse effects), in comparison with 3% to 5% of those receiving placebo.ConclusionThe 2 main advantages of liraglutide are mild degrees of weight loss and hypoglycemia. Important limitations, however, are the frequent occurrence of gastrointestinal adverse effects, the requirement of subcutaneous injection once daily, and the lack of long-term efficacy and safety data. Liraglutide may be a useful add-on therapy in patients with type 2 diabetes uncontrolled with metformin, when hypoglycemia, weight gain, or both are major concerns. (Endocr Pract. 2010;16:1028-1037)     

Eradication of Helicobacter pylori does not reduce the incidence of gastroduodenal ulcers in patients on long-term NSAID treatment: double-blind, randomized, placebo-controlled trial

BACKGROUND: Helicobacter pylori and nonsteroidal antiinflammatory drugs (NSAIDs) are the major causes of gastroduodenal ulcers. Studies on the benefit of eradication of H. pylori in NSAID users yielded conflicting results. OBJECTIVE: To investigate whether H. pylori eradication in patients on long-term NSAIDs reduces the incidence of gastroduodenal ulcers. METHODS: Patients on long-term NSAID treatment and who are H. pylori positive on serologic testing, were randomly assigned to either H. pylori eradication (omeprazole, amoxicillin, and clarithromycin) or placebo. Primary endpoint was the presence of endoscopic gastric or duodenal ulcers 3 months after randomization. RESULTS: One hundred sixty-five (48%) of a total of 347 patients were on gastroprotective medication. At endoscopy, gastroduodenal ulcers were diagnosed in 6 (4%) and 8 (5%) patients in the eradication and placebo group, respectively (p = .65). During follow-up of 12 months, no symptomatic ulcers or ulcer complications developed. No significant differences were found in the development of gastroduodenal erosions, dyspepsia, or in quality of life. CONCLUSION: H. pylori eradication therapy in patients on long-term NSAID treatment had no beneficial effect on the occurrence of ulcers, erosions, or dyspepsia. Ulcer rates in both study arms are remarkably low, in both patients with and without gastroprotective therapy.     

Review and Meta‐analysis of Pharmacotherapy for Binge‐eating Disorder

This study evaluated available controlled treatment studies to determine utility of pharmacotherapy for binge‐eating disorder (BED). The authors identified randomized placebo‐controlled trials testing pharmacotherapy‐only treatments and controlled trials testing pharmacotherapy with psychotherapy treatments. Meta‐analysis was performed on placebo‐controlled trials with data for attrition, remission, and weight loss. Qualitative review was performed on remaining controlled treatment literature. A total of 33 studies were considered of which 14 studies with a total of 1,279 patients were included in the meta‐analysis of pharmacotherapy‐only treatment and 8 studies with a total of 683 patients were included in the qualitative review of pharmacotherapy combined with psychotherapy interventions. No evidence suggested significant differences between medication and placebo for attrition. Evidence suggested that pharmacological treatments have a clinically significant advantage over placebo for achieving short‐term remission from binge eating (48.7% vs. 28.5%) and for weight loss, although weight losses are not substantial. No data exist to allow evaluation of longer‐term effects of pharmacotherapy‐only treatment for BED. Combining medications with psychotherapy interventions failed to significantly enhance binge outcomes, although specific medications (orlistat, topiramate) enhanced weight losses achieved with cognitive behavioral therapy and behavioral weight loss. In summary, BED patients can be advised that certain pharmacotherapies may enhance likelihood of stopping binge eating short term, but that longer‐term effects are unknown. Although some weight loss may occur, it is unlikely to be substantial with available medications. Combining medications with cognitive or behavioral treatments is unlikely to enhance binge outcomes, but specific medications (orlistat, topiramate) may enhance weight losses, albeit modestly.     

Weight loss produced by tesofensine in patients with Parkinson's or Alzheimer's disease

Objective: Tesofensine (TE) is a norepinephrine, dopamine, and serotonin reuptake inhibitor. We conducted a meta‐analysis of TE's effect on body weight in trials investigating its potential for treatment of Parkinson's or Alzheimer's disease. Methods and Procedures: Four randomized, double‐blind, multicenter trials compared TE (n = 740) and placebo (n = 228), two in each disease. Patients received oral TE or placebo once daily for 14 weeks without any weight loss program. Results were adjusted for baseline values, age, and study. Results: In the placebo group, 14% were obese and 21% were in the TE group. In the total cohort, weight change after 14 weeks was +0.5, ?0.5, ?0.9, ?1.8, ?2.8% in the placebo, 0.125, 0.25, 0.5 and 1.0 mg in the TE groups, respectively (P = 0.015 for dose effect). In the obese subgroup, weight changes were ?0.2, ?1.7, ?1.6, ?1.5, ?3.7%, and 2.1, 8.2, 14.1, 20.9, 32.1% of the obese patients achieved ≥5% weight loss (P < 0.001 for 0.25, 0.5, and 1.0 mg vs. placebo for both end points). Changes in heart rate were ?0.4, 2.1, 4.2, 6.0, and 6.8 bpm after 14 weeks (TE vs. placebo: P < 0.001 from 0.25 mg), but no effect on blood pressure was observed. Discussion: TE produced a placebo‐subtracted weight loss of ～4% for >14 weeks without any diet and lifestyle therapy, which is similar to that of sibutramine, but with no effect on blood pressure. On the basis of these results, TE is now being developed for obesity management.     

Sibutramine Produces Dose-Related Weight Loss

BRAY, GEORGE A., GEORGE L. BLACKBURN, JAMES M. FERGUSON, FRANK L. GREENWAY, ADESH K. JAIN, CARL M. MENDEL, JOSEPH MEN-DELS, DONNA H. RYAN, SHERWYN L. SCHWARTZ, MONTE L. SCHEINBAUM, AND TIMOTHY B. SEATON. Sibutramine produces dose-related weight loss. Obes Res. Objective Sibutramine is a weight control drug that inhibits the reuptake of both serotonin and norepinephrine. In animals, it reduces food intake and increases thermogenesis and preliminary data in human beings showed weight loss. This paper reports a 24-week dose-ranging study to determine the effect of sibutramine on body weight of patients with obesity. Research Methods and Procedures Seven clinical centers screened 1463 patients with obesity and randomized 1047 to 24 weeks of treatment with 1 of 6 doses of sibutramine (1, 5, 10, 15, 20, or 30 mg) or placebo once daily. Six hundred eighty-three patients completed the study. A two-week placebo run-in period was used to initiate a standardized program of diet, physical activity, and lifestyle changes. Results Weight loss was dose-related and statistically significant vs. placebo (p <0.05) across all time-points for a 5 mglday to 30 mglday dosage of sibutramine. At week 24, percent weight loss from baseline for completers was: placebo, 1.2%; 1 mg, 2.7%; 5 mg, 3.9%; 10 mg, 6.1%; 15 mg, 7.4%; 20 mg, 8.8%; and 30 mg, 9.4%. Weight loss achieved at week 4 was predictive of weight loss achieved at week 24. Patients losing weight demonstrated an increase in serum high density lipoprotein cholesterol and reductions in serum triglycerides, total cholesterol, low density lipoprotein cholesterol, and uric acid. Small mean increases in blood pressure and pulse rate (with considerable individual variability) were observed in patients treated with sibutramine. The most frequent adverse events were dry mouth, anorexia, and insomnia. Discussion Sibutramine administered once daily for 24 weeks in the weight loss phase of treatment for uncomplicated obesity produced dose-related weight loss and was well tolerated. Improvements in serum lipids and uric acid accompany sibutramine-induced weight loss. Most of the adverse events observed on sibutramine are related to its pharmacology, including small mean increases in blood pressure and heart rate.