Overview of new antiobesity drugs

A short overview of new drugs approved for the treatment of obesity (lorcaserin, phentermine/topiramate combination) as well as those with a perspective for approval as antiobesity drugs (cetilistat, naltrexone/bupropion combination, liraglutide) is presented. All these drugs produce significant weight loss accompanied by reductions in cardiometabolic health risks. Although the adverse events were rather rare and tended to decrease with the duration of treatment with most of these medications, the drug-specific safety concerns should be seriously considered. In order to ensure an appropriate, efficient and safe implementation of novel antiobesity drugs into the comprehensive treatment of obesity, it will be necessary to establish a network of physicians and other health-care providers well educated in obesity management.     

The limits and challenges of antiobesity pharmacotherapy

ABSTRACT

Introduction

Pharmacotherapy is a useful adjunct when patients with obesity are unable to achieve adequate benefit from lifestyle interventions.     

Efficacy and safety of lorcaserin in obesity: a systematic review and meta-analysis of randomized controlled trials

ABSTRACT

Background: Lorcaserin is a novel, selective 5-hydroxytryptamine 2C serotonin receptor agonist, approved for the treatment of obesity. Several phase 3 randomized controlled trials (RCTs) trials have shown a significant reduction in body weight with lorcaserin.

Research design and methods: We systematically searched the database of PubMed, Embase, The Cochrane Library and ClinicalTrials.gov up to 31 July 2019 and retrieved all the studies conducted with lorcaserin for ≥1 year that have explicitly reported the efficacy and safety outcomes versus placebo. Subsequently, we studied the effect of lorcaserin on weight reduction, FDA-defined valvulopathy, depression and suicidal risks in RCTs.

Results: The meta-analysis of four RCTs (N = 16,856) demonstrated a significant decrease in body weight (mean ? ?3.076 Kg; 95% CI, ?3.49 to ?2.66; P < 0.00001), compared to placebo. No significant difference in FDA-defined valvulopathy (RR 1.20; 95% CI, 0.89 to 1.63; P = 0.24), depression (RR 1.07; 95% CI, 0.80 to 1.43; P = 0.67) or suicidal risk (RR 1.43; 95% CI, 0.96 to 2.15; P = 0.08) has been observed with lorcaserin compared to placebo.

Conclusions: Lorcaserin reduces body weight modestly, with no obvious serious adverse side effects. The common adverse events noted with lorcaserin include nausea, dizziness, and transient headache.     

抗肥胖药物研究进展

肥胖是全球主要公共卫生问题之一,会导致一系列的健康相关疾病风险,迫切需要有更安全、更有效且耐受性更好的新抗肥胖药物。本文概要介绍抗肥胖药物的现状和研究进展。     

Current pharmacotherapy for obesity: extrapolation of clinical trials data to practice

Introduction: When used prudently and in combination with lifestyle modification, pharmacotherapy has an important role in the management of obesity.

Areas covered: This review covers targets for antiobesity drugs, challenges and limitations, failed translation of basic science to clinical practice, methodological and regulatory issues in clinical trials of pharmacotherapy, efficacy and risks of drugs currently approved for obesity, and clinical practice issues when using antiobesity drugs with emphasis on recently approved drugs.

Expert opinion: Drugs currently approved for long-term therapy of obesity offer modest benefits for most patients, substantial benefits for some and no benefits for others. Numerous methodological problems including exclusion of the type of patients who are most often seen in clinical practices, inadequate enrollment of men and minorities, exclusion of patients taking antidepressants, high dropout rates, lack of follow-up after treatment discontinuation, and less than ideal imputation methods in data analysis limit the interpretation of clinical trials data and generalizability. Single-drug therapies offer small to moderate weight-loss benefits, but are generally better tolerated. Efficacy is enhanced with combination drug therapies, but so are the hazards. Clinicians should base their decisions on the expected and observed benefit-to-risk balance.     

Safety assessment of combination therapies in the treatment of obesity: focus on naltrexone/bupropion extended release and phentermine-topiramate extended release

Introduction: Few studies on combination therapies for the treatment of obesity had been conducted until recently, when two fixed-dose combinations, bupropion-naltrexone ER fixed-dose combination and phentermine-topiramate ER titrated-dose combinations were evaluated in clinical studies that ultimately led to FDA approval.

Areas covered: In this review, we discuss safety concerns about both combinations, the rationale and history of combination therapies for obesity (including phentermine plus fenfluramine), and possible future new combinations.

Expert opinion: Combination therapies are a promising new area in obesity treatment, similar to what occurs with diabetes and hypertension. Safety assessment is highly important due to the high number of potential users on a chronic basis.     

针刺治疗偏头痛的系统评价和Meta分析

目的:应用Meta分析方法,系统评价针刺治疗偏头痛的疗效和分析国内外评价疗效差异的原因。方法:检索Pubmed、Cochrane Library、中国生物医学文献数据库(CBM)等数据库,筛选针刺治疗偏头痛的随机对照临床试验(randomized controlled trials,RCT),应用Cochrane协作网提供的Rev Man 5.0软件进行统计分析。结果:本研究共纳入12篇高质量的、以假针刺组为对照的RCT。Meta分析结果显示:针刺治疗结束时,真针刺和假针刺组的有效率分别为49.5%和43.3%,两组之间有统计学差异(OR=1.28,95%CI:1.02~1.61,P=0.03);随访结束时,两组的有效率分别为47.7%和38.5%,两组间无统计学差异(OR=1.33,95%CI:0.70~2.51,P=0.39)。对国内及国外临床试验进行亚组分析发现,在治疗结束及随访结束时,国内试验针刺组的有效率均显著高于假针刺组(P<0.05),而国外临床试验均显示两组间无统计学意义(P>0.05)。结论:上述结果提示在治疗期间针刺对偏头痛具有一定疗效,但治疗停止的随访期间针刺的疗效不显著。国内外临床试验在设计及执行等方面差异较大,今后尚需更多科学严谨的、符合中医特点的高质量RCT来验证针刺治疗偏头痛的疗效。     

Naltrexone for the treatment of obesity: review and update

Since their discovery in the brain and gastrointestinal tract nearly 40 years ago, endogenous opioid peptides have been progressively shown to play a role in the regulation of food intake. Animal and human studies regarding opioid peptides and ingestive behavior are reviewed. While the opioid receptor antagonist naltrexone is associated with minimal weight loss as monotherapy, it does have potential utility in the treatment of obesity when combined with the pro-opiomelanocortin activator bupropion.     

Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials

The objective of this review was to determine the effectiveness, adverse effects and acceptability of folate in the treatment of depression. Electronic databases (Cochrane Controlled Trials Register and the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register) and reference lists were searched, and authors, experts and pharmaceutical companies contacted to identify randomized controlled trials that compared treatment with folic acid or 5'-methyltetrahydrofolic acid to an alternative treatment, for patients with a diagnosis of depressive disorder. Three randomized trials (247 participants) were included. Two studies assessed the use of folate in addition to other treatment, and found that adding folate reduced Hamilton Depression Rating Scale (HDRS) scores on average by a further 2.65 points [95% confidence interval (CI) 0.38-4.93]. Fewer patients treated with folate experienced a reduction in their HDRS score of less than 50% at 10 weeks (relative risk 0.47, 95% CI 0.24-0.92). The remaining study found no statistically significant difference when folate alone was compared with trazodone. The identified trials did not find evidence of any problems with the acceptability or safety of folate. The limited available evidence suggests folate may have a potential role as a supplement to other treatment for depression. It is currently unclear if this is the case both for people with normal folate levels, and for those with folate deficiency.     

Pharmacotherapy for smoking cessation in schizophrenia: a systematic review

ABSTRACT

Introduction

Rates of tobacco smoking are high in people with schizophrenia with greater difficulty of quitting smoking compared to the general population, which also relate to the increased cardiovascular and cancer risks in this co-occurring disorder. Therefore, effective smoking cessation pharmacotherapies addressing tobacco co-morbidity are imperative.     

Effects of telmisartan on fat distribution: a meta-analysis of randomized controlled trials

Objectives: Several meta-analyses have confirmed the positive metabolic effects of telmisartan, an angiotensin II receptor blocker that can also act as a partial peroxisome proliferator-activated receptor-γ agonist, compared to those of other angiotensin II receptor blockers. These effects include decreased fasting glucose, glycosylated hemoglobin, interleukin-6, and tumor necrosis factor-α levels. However, no systemic analysis of telmisartan’s effects on body fat distribution has been performed. We performed a meta-analysis of randomized controlled telmisartan trials to investigate its effects on body weight, fat distribution, and visceral adipose reduction. Research design and methods: A literature search was performed using Embase, MEDLINE, and the Cochrane Library between January 1966 and November 2013. Randomized controlled trials in English and meeting the following criterion were included: random assignment of hypertensive participants with overweight/obesity, metabolic syndrome, or glucose intolerance to telmisartan or control therapy group. Results: Of 651 potentially relevant reports, 15 satisfied the inclusion criterion. While visceral fat area was significantly lower in the telmisartan group than in the control group (weighted mean difference?=??18.13?cm², 95% C.I.?=??27.16 to ?9.11, P_χ²?=?0.19, I²?=?41%), subcutaneous fat area was similar (weighted mean difference =2.94?cm², 95% C.I.?=??13.01 to 18.89, P_χ²?=?0.30, I²?=?17%). Total cholesterol levels were significantly different between the groups (standardized mean difference?=??0.24, 95% C.I.?=??0.45 to ?0.03, P_χ²?=?0.0002, I²?=?67%). Limitations: Limitations include: (1) limited number of studies, especially those evaluating fat distribution; (2) different imaging modalities to assess visceral fat area (V.F.A.) and subcutaneous fat area (S.F.A.); (3) observed heterogeneity. Conclusion: The findings suggest that telmisartan affected fat distribution, inducing visceral fat reduction, and thus could be useful in hypertensive patients with obesity/overweight, metabolic syndrome, or glucose intolerance.     

Paclitaxel-based versus docetaxel-based regimens in metastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials

Abstract

Objectives:

Docetaxel and paclitaxel show significant clinical activity in metastatic breast cancer (MBC) and have been approved for MBC by the U.S. Food and Drug Administration, but it is still unclear whether a paclitaxel-based regimen improves outcomes over a docetaxel-based regimen in patients with MBC. We therefore performed a meta-analysis of randomized controlled trials to compare the safety and efficacy of these two regimens in MBC.     

Alpha-lipoic acid effect on leptin and adiponectin concentrations: a systematic review and meta-analysis of randomized controlled trials

New evidence suggests that dysregulation of adipocytokines caused by excess adiposity plays an important role in the pathogenesis of various obesity comorbidities. Our aim in this meta-analysis was to determine the effect of alpha-lipoic acid (ALA) supplementation on serum levels of leptin and adiponectin. We searched Scopus, PubMed, Google Scholar, and ISI Web of Science from inception up to July 2019. Mean difference for leptin and adiponectin were calculated by subtracting the change from baseline in each study group. Summary estimates for the overall effect of ALA on serum leptin and adiponectin concentrations were calculated using random effects model. Results were presented as weighted mean difference (WMD) and their 95% confidence intervals (CI). Between-study heterogeneity was examined using the I2 statistics. Eight studies were included in systematic review and seven studies in meta-analysis. The overall effect suggested a significant decrement in serum leptin concentrations (WMD = − 3.63; 95% CI, − 5.63, − 1.64 μg/ml; I2 = 80.7%) and a significant increase in serum levels of adiponectin (WMD = 1.98 μg/ml; 95% CI, 0.92, 3.04; I2 = 95.7%). Subgroup analyses based on age showed a significant reduction in leptin levels only in younger adults, and subgroup analysis based on duration indicated in studies with a duration of more than 8 weeks adiponectin levels increased significantly and leptin levels decreased significantly. Our results revealed ALA decreased leptin and increased adiponectin especially in studies lasted more than 8 weeks. We still need more studies with different ALA dose, intervention duration, and separately on male and female.     

Efficacy of indirect dopamine agonists for psychostimulant dependence: a systematic review and meta-analysis of randomized controlled trials

Psychostimulant dependence is characterized by dopamine deficit, which could be reversed with indirect dopamine agonists (IDAs). A systematic review and meta-analysis of randomized, parallel-group, placebo-controlled clinical trials assessing the efficacy of IDAs in psychostimulant-dependent individuals were conducted. The study outcomes were psychostimulant abstinence, assessed by means of urinalysis, and retention in treatment. Risk of bias was determined using a Cochrane Collaboration instrument. Twenty-nine studies fulfilled the inclusion criteria, involving 2,467 participants. Compared with placebo, IDAs increased psychostimulant abstinence (standardized mean difference = 0.20; 95% confidence interval, 0.06-0.35; p = .005) but did not increase retention in treatment. Efficacy was larger in comorbid heroin-dependent individuals and was positively related with treatment length. No study was considered fully free of bias. IDAs appear to be efficacious for reducing psychostimulant use but did not improve retention. Efforts should be undertaken to reduce the risk of bias of clinical trials with psychostimulant-dependent individuals.     

Benzodiazepine augmentation of antipsychotic drugs in schizophrenia: A meta-analysis and cochrane review of randomized controlled trials

Applying various psychopharmacological combination and augmentation strategies in schizophrenia is common clinical practice. This meta-analysis evaluated the efficacy of benzodiazepines added to antipsychotics. The Cochrane Schizophrenia Group trial register (until February 2011) and PubMed/Medline (until July 2012) were searched for randomized controlled trials (RCTs) with a minimum duration of one week that compared benzodiazepine augmentation of antipsychotics with a control group receiving antipsychotic monotherapy in schizophrenia and schizophrenia-like psychoses. Study selection and data extraction were conducted independently by at least two authors. The primary outcome was response to treatment. Secondary outcomes were positive and negative schizophrenic symptoms, anxiety symptoms, and dropouts due to any reason, inefficacy of treatment, and adverse events. Pooled risk ratios (RRs) with the 95% confidence intervals (CIs) were calculated using a random-effects model, with number-needed-to-treat/harm (NNT/H) calculations where appropriate. Overall, 16 relevant RCTs with 1045 participants were identified. Benzodiazepine augmentation was not associated with statistically significantly more responders (N=6; n=511; RR 0.97, 95% CI 0.77–1.22). Adjunctive benzodiazepines were well accepted and tolerated according to dropout-rates and adverse effects apart from dizziness (N=3; n=190; RR 2.58, 95% CI 1.08–6.15) and somnolence (N=2; n=118; RR 3.30, 95% CI 1.04–10.40). There is no evidence for antipsychotic efficacy of additional benzodiazepine medication in schizophrenia. Therefore, benzodiazepines should be considered primarily for desired ultra short-term sedation of acutely agitated patients but not for augmentation of antipsychotics in the medium- and long-term pharmacotherapy of schizophrenia and related disorders.     

Compound glycyrrhizin plus conventional therapy for psoriasis vulgaris: a systematic review and meta-analysis of randomized controlled trials

Background: Psoriasis vulgaris is a chronic skin condition affecting patients’ quality of life. Long-term use of conventional therapy increases risk of unwanted side effects. Compound glycyrrhizin in conjunction with conventional therapy has been used in clinical practice, but the evidence for such practice has not been evaluated systematically.

Objective: This review aims to evaluate the efficacy and safety of compound glycyrrhizin in combination with conventional therapy for psoriasis vulgaris.

Methods: PubMed, Excerpta Medica dataBASE (Embase), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Central Register of Controlled Trials, Allied and Complementary Medicine Database (AMED), CiNii, Chinese Biomedical Literature, China National Knowledge Infrastructure, Chinese Scientific Journals Full Text Database and Wanfang Data were searched from their respective inceptions to July 2015. Randomized controlled trials comparing compound glycyrrhizin plus conventional therapy to conventional therapy alone for psoriasis vulgaris were included. Data analysis was performed using Review Manager 5.3.

Results: Eleven randomized controlled trials were included in this review. Meta-analysis of the 11 randomized controlled trials indicated that the addition of compound glycyrrhizin increased the number of patients achieving Psoriasis Area and Severity Index (PASI) 60 (RR: 1.30 [1.21, 1.40], I² = 6%), when compared with conventional therapy alone. Comparable numbers of patients experienced adverse events in the two groups.

Conclusions: Compound glycyrrhizin in conjunction with conventional therapy enhances clinical response, and compound glycyrrhizin as add-on therapy does not appear to pose any additional risk in the treatment of psoriasis vulgaris. However, the findings should be interpreted with caution of methodological flaws in the included studies.

PROSPERO registration number: CRD42015027763.     

A systematic review and meta-analysis of randomized controlled trials of cardiovascular toxicity of medical cannabinoids

BackgroundSeveral systematic reviews (SRs) have summarized the potential effectiveness of medical cannabinoids, but it is unclear to what extent safety-related outcomes were incorporated.ObjectiveThe objective of this study was to evaluate the cardiovascular toxicity associated with medical use of cannabinoids.MethodsA 2-stage systematic review (SR) approach was undertaken to assess the current evidence on cannabinoid-associated cardiovascular events reported among randomized controlled trials (RCTs). First, we searched for SRs in multiple sources until June 2019. Second, RCTs identified from the SRs were included if they assessed medical cannabis and reported cardiovascular events. The outcomes of interest were all types of cardiovascular events. Data were extracted by 2 independent reviewers. Study quality was assessed using the Cochrane risk of bias. A statistical test of heterogeneity was performed. The summary risk ratios (RRs) and 95% CIs were calculated using a random-effects model.ResultsA total of 47 studies involving 2800 patients were included. The median duration of cannabinoid use was 15.8 days (range 1 to 322), and 45% of the studies excluded patients with underlying cardiovascular diseases. Cannabinoid use was significantly associated with increased risks of orthostatic hypotension (RR 3.16 [95% CI 2.27–4.40], I² = 2.3%) and hypotension (3.55 [1.45–8.71], I² = 31.8%), with a trend of increased risk of tachycardia (1.94 [0.81–4.64], I² = 48.6%). No study reported serious cardiovascular events.ConclusionsCannabinoid use was associated with tachycardia, hypotension, and orthostatic hypotension. There is a paucity of data for other cardiovascular events among medical cannabis users. More data, especially regarding long-term effects among patients with existing cardiovascular diseases, are needed.     

Assessment of pharmacist-led patient counseling in randomized controlled trials: a systematic review

Background Pharmacists’ counseling has improved health-related outcomes in many acute and chronic conditions. Several studies have shown how pharmacists have been contributing to reduce morbidity and mortality related to drug-therapy (MMRDT). However, there still is a lack of reviews that assemble evidence-based clinical pharmacists’ counseling. Equally, there is also a need to understand structure characteristics, processes and technical contents of these clinical services. Aim of the review To review the structure, processes and technical contents of pharmacist counseling or education reported in randomized controlled trials (RCT) that had positive health-related outcomes. Methods We performed a systematic search in specialized databases to identify RCT published between 1990 and 2013 that have evaluated pharmacists’ counseling or educational interventions to patients. Methodological quality of the trials was assessed using the Jadad scale. Pharmacists’ interventions with positive clinical outcomes (p < 0.05) were evaluated according to patients’ characteristics, setting and timing of intervention, reported written and verbal counseling. Results 753 studies were found and 101 RCT matched inclusion criteria. Most of the included RCTs showed a Jadad score between two (37 studies) and three (32 studies). Pharmacists were more likely to provide counseling at ambulatories (60 %) and hospital discharge (25 %); on the other hand pharmacists intervention were less likely to happen when dispensing a medication. Teaching back and explanations about the drug therapy purposes and precautions related to its use were often reported in RCT, whereas few studies used reminder charts, diaries, group or electronic counseling. Most of studies reported the provision of a printed material (letter, leaflet or medication record card), regarding accessible contents and cultural-concerned informations about drug therapy and disease. Conclusion Pharmacist counseling is an intervention directed to patients’ health-related needs that improve inter-professional and inter-institutional communication, by collaborating to integrate health services. In spite of reducing MMRDT, we found that pharmacists’ counseling reported in RCT should be better explored and described in details, hence collaborating to improve medication-counseling practice among other countries and settings.     

Additive effect of α-ketoacids in chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials

α-Ketoacids (KAs) are widely used in chronic kidney disease (CKD), but their efficacy is not clear. Therefore, we conducted a systematic review of the benefits of KAs. Two reviewers independently searched MEDLINE, EMBASE, the Cochrane library (http://www.cochrane.org), CNKI, and Wan Fang databases from inception to May 31, 2016 for randomized controlled trials (RCTs) comparing KAs plus low protein diet (LPD) with LPD only on CKD patients. Statistical analyses were performed using both a random effects model and a fixed effects model with Rev Man 5.3, followed by sensitivity analysis. We identified 21 randomized controlled trials that enrolled a total of 1448 patients. 726 had received LPD plus KAs and 722 had received only LPD. Compared with simply using of LPD, combining with KAs could decrease serum creatinine (95% CI, 0.46–0.96; P<0.00001), serum cholesterol (95% CI, 0.24–0.77; P = 0.02), serum LDL cholesterol (95% CI, 0.12–0.54; P = 0.31), and serum triglyceride (95% CI, 0.28–0.83; P = 0.02) while increasing serum HDL cholesterol (95% CI, -1.73–0.07; P<0.00001). Likewise, a decrease in P^3– (95% CI, 0.90–1.26; P<0.00001) and PTH (95% CI, 0.70–1.21; P = 0.007) were observed. No hypercalcemia and other ARD or toxicity was reported, which indicated the safety of KAs. Nevertheless, the studies were pooled with considerable heterogeneity. In patients with CKD, there was low-quality evidence suggesting that KAs may perform an additive effect on the improvement of renal function, lipid profile, as well as the correction of calcium-phosphate metabolism disorders. On account of the considerable heterogeneity of the meta-analysis and the costly price and adherence of KAs administration, KAs’ roles in the management of mild or moderate CKD patients may need more RCTs of large scale and high quality to confirm.