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Lancet (London, England) Jan 2022Pharmacotherapy provides an option for adults with overweight and obesity to reduce their bodyweight if lifestyle modifications fail. We summarised the latest evidence...
BACKGROUND
Pharmacotherapy provides an option for adults with overweight and obesity to reduce their bodyweight if lifestyle modifications fail. We summarised the latest evidence for the benefits and harms of weight-lowering drugs.
METHODS
This systematic review and network meta-analysis included searches of PubMed, Embase, and Cochrane Library (CENTRAL) from inception to March 23, 2021, for randomised controlled trials of weight-lowering drugs in adults with overweight and obesity. We performed frequentist random-effect network meta-analyses to summarise the evidence and applied the Grading of Recommendations Assessment, Development, and Evaluation frameworks to rate the certainty of evidence, calculate the absolute effects, categorise interventions, and present the findings. The study was registered with PROSPERO, CRD 42021245678.
FINDINGS
14 605 citations were identified by our search, of which 143 eligible trials enrolled 49 810 participants. Except for levocarnitine, all drugs lowered bodyweight compared with lifestyle modification alone; all subsequent numbers refer to comparisons with lifestyle modification. High to moderate certainty evidence established phentermine-topiramate as the most effective in lowering weight (odds ratio [OR] of ≥5% weight reduction 8·02, 95% CI 5·24 to 12·27; mean difference [MD] of percentage bodyweight change -7·97, 95% CI -9·28 to -6·66) followed by GLP-1 receptor agonists (OR 6·33, 95% CI 5·00 to 8·00; MD -5·76, 95% CI -6·30 to -5·21). Naltrexone-bupropion (OR 2·69, 95% CI 2·11 to 3·43), phentermine-topiramate (2·40, 1·69 to 3·42), GLP-1 receptor agonists (2·17, 1·71 to 2·77), and orlistat (1·72, 1·44 to 2·05) were associated with increased adverse events leading to drug discontinuation. In a post-hoc analysis, semaglutide, a GLP-1 receptor agonist, showed substantially larger benefits than other drugs with a similar risk of adverse events as other drugs for both likelihood of weight loss of 5% or more (OR 9·82, 95% CI 7·09 to 13·61) and percentage bodyweight change (MD -11·41, 95% CI -12·54 to -10·27).
INTERPRETATION
In adults with overweight and obesity, phentermine-topiramate and GLP-1 receptor agonists proved the best drugs in reducing weight; of the GLP-1 agonists, semaglutide might be the most effective.
FUNDING
1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University.
Topics: Adult; Anti-Obesity Agents; Humans; Network Meta-Analysis; Obesity; Overweight; Randomized Controlled Trials as Topic; Treatment Outcome; Weight Loss
PubMed: 34895470
DOI: 10.1016/S0140-6736(21)01640-8 -
Lancet (London, England) Apr 2024Pharmacotherapy provides an option for adults with overweight and obesity to reduce their bodyweight if lifestyle modifications fail. We summarised the latest evidence... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Pharmacotherapy provides an option for adults with overweight and obesity to reduce their bodyweight if lifestyle modifications fail. We summarised the latest evidence for the benefits and harms of weight-lowering drugs.
METHODS
This systematic review and network meta-analysis included searches of PubMed, Embase, and Cochrane Library (CENTRAL) from inception to March 23, 2021, for randomised controlled trials of weight-lowering drugs in adults with overweight and obesity. We performed frequentist random-effect network meta-analyses to summarise the evidence and applied the Grading of Recommendations Assessment, Development, and Evaluation frameworks to rate the certainty of evidence, calculate the absolute effects, categorise interventions, and present the findings. The study was registered with PROSPERO, CRD 42021245678.
FINDINGS
14 605 citations were identified by our search, of which 132 eligible trials enrolled 48 209 participants. All drugs lowered bodyweight compared with lifestyle modification alone; all subsequent numbers refer to comparisons with lifestyle modification. High to moderate certainty evidence established phentermine-topiramate as the most effective in lowering weight (odds ratio [OR] of ≥5% weight reduction 8·02, 95% CI 5·24 to 12·27; mean difference [MD] of percentage bodyweight change -7·98, 95% CI -9·27 to -6·69) followed by GLP-1 receptor agonists (OR 6·33, 95% CI 5·00 to 8·00; MD -5·79, 95% CI -6·34 to -5·25). Naltrexone-bupropion (OR 2·69, 95% CI 2·10 to 3·44), phentermine-topiramate (2·40, 1·68 to 3·44), GLP-1 receptor agonists (2·22, 1·74 to 2·84), and orlistat (1·71, 1·42 to 2·05) were associated with increased adverse events leading to drug discontinuation. In a post-hoc analysis, semaglutide, a GLP-1 receptor agonist, showed substantially larger benefits than other drugs with a similar risk of adverse events as other drugs for both likelihood of weight loss of 5% or more (OR 9·82, 95% CI 7·09 to 13·61) and percentage bodyweight change (MD -11·40, 95% CI -12·51 to -10·29).
INTERPRETATION
In adults with overweight and obesity, phentermine-topiramate and GLP-1 receptor agonists proved the best drugs in reducing weight; of the GLP-1 agonists, semaglutide might be the most effective.
FUNDING
1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University.
Topics: Adult; Humans; Overweight; Network Meta-Analysis; Topiramate; Obesity; Weight Loss; Phentermine; Randomized Controlled Trials as Topic
PubMed: 38582569
DOI: 10.1016/S0140-6736(24)00351-9 -
Diabetes, Obesity & Metabolism Sep 2023To compare the benefits and harms of drugs approved for weight management in adults with obesity or overweight. (Meta-Analysis)
Meta-Analysis
AIM
To compare the benefits and harms of drugs approved for weight management in adults with obesity or overweight.
MATERIALS AND METHODS
We performed a systematic review of drugs approved for treating obesity and overweight. We searched MEDLINE, Embase and CENTRAL through 26 February 2023. Random-effects network meta-analysis was applied.
RESULTS
A total of 168 trials (97 938 patients) were included. There was no evidence that drugs approved for weight management had different associations with cardiovascular death (69 trials, 59 037 participants). Naltrexone/bupropion was associated with lower cardiovascular mortality than placebo (odds ratio [OR], 0.62 [95% CI: 0.39, 0.99]; low certainty evidence). All drugs were associated with greater weight loss at 12 months than placebo (33 trials, 37 616 participants), mainly semaglutide (mean difference [MD], -9.02 kg [95% CI: -10.42, -7.63]; moderate certainty) and phentermine/topiramate (MD, -8.10 kg [95% CI: -10.14, -6.05]; high certainty); and with greater waist circumference reduction at 12 months than placebo (24 trials, 35 733 participants), mainly semaglutide (MD, -7.84 cm [95% CI: -9.34, -6.34]; moderate certainty) and phentermine/topiramate (MD, -6.20 cm [95% CI: -7.46, -4.94]; high certainty). Semaglutide and phentermine/topiramate were associated with lower or no difference in the odds of treatment withdrawal compared with all other drugs (87 trials, 70 860 participants).
CONCLUSIONS
Among adults with obesity or overweight, semaglutide and phentermine/topiramate were associated with greater body weight loss and waist circumference reduction at 12 months than all other drugs, and lower or no significant difference in risks of withdrawal. There was no evidence that drugs approved for weight management had different associations with cardiovascular death.
Topics: Adult; Humans; Overweight; Topiramate; Network Meta-Analysis; Randomized Controlled Trials as Topic; Obesity; Phentermine
PubMed: 37254688
DOI: 10.1111/dom.15138 -
Obesity Reviews : An Official Journal... Nov 2021Anti-obesity medications (AOMs) are efficacious and well tolerated in randomized controlled trials, but findings may not be generalizable to routine clinical practice.... (Review)
Review
Anti-obesity medications (AOMs) are efficacious and well tolerated in randomized controlled trials, but findings may not be generalizable to routine clinical practice. This systematic literature review aimed to identify real-world (RW) evidence for AOMs to treat adults ( ≥ 18 years) with obesity or overweight (BMI ≥ 27 kg/m ). Searches conducted in MEDLINE, Embase, Health Technology Assessment (HTA) Database, National Health Service (NHS) Economic Evaluation Database, and Cochrane Central Register of Controlled Trials for studies of relevant FDA-approved AOMs yielded 41 publications. Weight loss (WL) was consistently observed, with 14% to 58.6% of patients achieving ≥ 5% WL on orlistat, phentermine/topiramate, naltrexone/bupropion, phentermine, or liraglutide in studies of 3-6 months' duration where this was measured. When cardiometabolic risk factors were assessed, AOMs reduced or had no impact on blood pressure, lipids, or glycemia. RW data on the impact of AOMs on existing obesity-related comorbidities and mortality were generally lacking. AOMs were associated with various adverse events, but these were of mild to moderate severity and no unexpected safety signals were reported. A pattern of poor adherence and persistence with AOMs was observed across studies. Overall, the review confirmed the effectiveness of AOMs in RW settings but demonstrated large gaps in the evidence base.
Topics: Adult; Anti-Obesity Agents; Humans; Orlistat; Phentermine; State Medicine; Weight Loss
PubMed: 34423889
DOI: 10.1111/obr.13326 -
Expert Review of Clinical Pharmacology Jan 2020: Obesity poses a significant increase in morbidity and mortality and thus five anti-obesity drugs have been approved currently by US FDA. Several phase 3 trials have... (Meta-Analysis)
Meta-Analysis
: Obesity poses a significant increase in morbidity and mortality and thus five anti-obesity drugs have been approved currently by US FDA. Several phase 3 trials have shown a significant improvement in cardio-metabolic profile including significant weight reduction with these agents compared to placebo.: We systematically searched the database of PubMed, Embase, The Cochrane Library and The ClinicalTrials.gov up to 30 September 2019 and retrieved all the randomized controlled trials (RCTs) that were conducted with these five drugs for ≥1 year and explicitly reported their efficacy versus placebo. Subsequently, we have conducted the meta-analysis to primarily study the effect of these anti-obesity drugs on weight reduction. We additionally reviewed the effect of these drugs on other cardio-metabolic parameters including key adverse events.: This meta-analysis finds a significant reduction in body weight with orlistat (N = 10,435; ∆ -3.07 Kg, 95% CI, -3.76 to -2.37), phentermine plus topiramate (N = 2985; ∆ -9.77 Kg; 95% CI, -11.73 to -7.81), lorcaserin (N = 16,856; ∆ -3.08 Kg; 95% CI, -3.49 to -2.66), naltrexone plus bupropion (N = 3239; ∆ -4.39 Kg; 95% CI, -5.05 to -3.72) and liraglutide (N = 4978; ∆ -5.25 Kg; 95% CI, -6.17 to -4.32), compared to placebo (all p < 0.00001).
Topics: Anti-Obesity Agents; Humans; Obesity; Randomized Controlled Trials as Topic; Weight Loss
PubMed: 31770497
DOI: 10.1080/17512433.2020.1698291 -
Forensic Science International Sep 2022Suicide remains a global public health concern and the increased supply and use of synthetic stimulants globally may have implications for the burden of suicides... (Review)
Review
Suicide remains a global public health concern and the increased supply and use of synthetic stimulants globally may have implications for the burden of suicides attributable to substance use. This systematic review investigated any potential associations of stimulant use detected in post-mortem biological specimens and suicides. We conducted a systematic review and narrative synthesis (CRD42021237966). Medline, EMBASE, TOXLINE, and Scopus databases were searched for terms related to forensic toxicology, post-mortem toxicology, suicide and stimulants. The primary outcome was to estimate the prevalence of stimulant use in suicides. There were 26 studies whichcontributed to prevalence measures; in studies reporting at the individual compound level, suicides involved cocaine (0.1-23%), caffeine (3.2-22%), 3,4-methylenedioxymethamphetamine (0.1-17%), amphetamine (0.2-9.3%), methamphetamine (3.1-7%), and phentermine (0.9-1%). Overall, stimulant use in suicides was over-represented compared to estimates of stimulant use in the general population and has increased over time. Thirteen case reports used to contextualise suicides involving stimulants found no examples of cocaine or methamphetamine mono-intoxication of suicidal intent. This suggests mechanisms other than acute toxicity involved in stimulant-associated suicide. Future research by in-depth psychological autopsies of suicides involving stimulants, in combination with segmental hair analysis to determine the chronicity of stimulant exposure, may contribute to a better understanding of the burden of suicide attributable to stimulant use.
Topics: Amphetamine; Central Nervous System Stimulants; Cocaine; Humans; Methamphetamine; Suicide
PubMed: 35908335
DOI: 10.1016/j.forsciint.2022.111391 -
Obesity (Silver Spring, Md.) Jul 2023The study aim was to review the economic evaluation literature of commercially available and effective nonsurgical weight-loss interventions to investigate whether there... (Review)
Review
OBJECTIVE
The study aim was to review the economic evaluation literature of commercially available and effective nonsurgical weight-loss interventions to investigate whether there is evidence to support claims of cost-effectiveness (i.e., good value for money) or cost savings (i.e., a positive return on investment).
METHODS
Relevant databases were systematically reviewed to identify economic evaluations of commercially available weight-loss products and services shown to result in clinically significant weight loss. Five weight-loss medications (orlistat, liraglutide, naltrexone-bupropion, semaglutide, and phentermine-topiramate), two meal replacement programs (Jenny Craig, Optifast), and one behavioral intervention (Weight Watchers [WW]) that met inclusion criteria were identified. After screening, 32 relevant comparisons of cost-effectiveness or cost savings across 20 studies were identified.
RESULTS
Ten of twenty pharmaceutical comparisons showed evidence of cost-effectiveness based on established thresholds. Four of twelve nonpharmaceutical comparisons provided evidence of cost-effectiveness, and five made claims of cost savings. However, methodological concerns cast doubt on the robustness of these claims.
CONCLUSIONS
Evidence of cost-effectiveness for commercially available, evidence-based, nonsurgical weight-loss interventions is mixed. There is no evidence for cost-saving weight-loss medications and only weak evidence for behavioral and weight-loss interventions. Results provide a call to action to generate more robust evidence of the economic value proposition for these interventions.
Topics: Humans; Anti-Obesity Agents; Weight Loss; Orlistat; Cost-Benefit Analysis; Liraglutide
PubMed: 37231621
DOI: 10.1002/oby.23760 -
The Cochrane Database of Systematic... Jan 2021This is the third update of this review, first published in July 2009. All major guidelines on treatment of hypertension recommend weight loss; anti-obesity drugs may be... (Meta-Analysis)
Meta-Analysis
BACKGROUND
This is the third update of this review, first published in July 2009. All major guidelines on treatment of hypertension recommend weight loss; anti-obesity drugs may be able to help in this respect.
OBJECTIVES
Primary objectives: To assess the long-term effects of pharmacologically-induced reduction in body weight in adults with essential hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events).. Secondary objectives: To assess the long-term effects of pharmacologically-induced reduction in body weight in adults with essential hypertension on change from baseline in systolic and diastolic blood pressure, and on body weight reduction.
SEARCH METHODS
For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to March 2020: the Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. The searches had no language restrictions. We contacted authors of relevant papers about further published and unpublished work.
SELECTION CRITERIA
Randomised controlled trials of at least 24 weeks' duration in adults with hypertension that compared approved long-term weight-loss medications to placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risks of bias, and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using a fixed-effect meta-analysis. When heterogeneity was present, we used the random-effects method and investigated the cause of the heterogeneity.
MAIN RESULTS
This third update of the review added one new trial, investigating the combination of naltrexone/bupropion versus placebo. Two medications, which were included in the previous versions of this review (rimonabant and sibutramine) are no longer considered relevant for this update, since their marketing approval was withdrawn in 2010 and 2009, respectively. The number of included studies in this review update is therefore six (12,724 participants in total): four RCTs comparing orlistat to placebo, involving a total of 3132 participants with high blood pressure and a mean age of 46 to 55 years; one trial comparing phentermine/topiramate to placebo, involving 1305 participants with high blood pressure and a mean age of 53 years; and one trial comparing naltrexone/bupropion to placebo, involving 8283 participants with hypertension and a mean age of 62 years. We judged the risks of bias to be unclear for the trials investigating orlistat or naltrexone/bupropion. and low for the trial investigating phentermine/topiramate. Only the study of naltrexone/bupropion included cardiovascular mortality and morbidity as predefined outcomes. There were no differences in the rates of all-cause or cardiovascular mortality, major cardiovascular events, or serious adverse events between naltrexone/bupropion and placebo. The incidence of overall adverse events was significantly higher in participants treated with naltrexone/bupropion. For orlistat, the incidence of gastrointestinal side effects was consistently higher compared to placebo. The most frequent side effects with phentermine/topiramate were dry mouth and paraesthesia. After six to 12 months, orlistat reduced systolic blood pressure compared to placebo by mean difference (MD) -2.6 mm Hg (95% confidence interval (CI) -3.8 to -1.4 mm Hg; 4 trials, 2058 participants) and diastolic blood pressure by MD -2.0 mm Hg (95% CI -2.7 to -1.2 mm Hg; 4 trials, 2058 participants). After 13 months of follow-up, phentermine/topiramate decreased systolic blood pressure compared to placebo by -2.0 to -4.2 mm Hg (1 trial, 1030 participants) (depending on drug dosage), and diastolic blood pressure by -1.3 to -1.9 mm Hg (1 trial, 1030 participants) (depending on drug dosage). There was no difference in the change in systolic or diastolic blood pressure between naltrexone/bupropion and placebo (1 trial, 8283 participants). We identified no relevant studies investigating liraglutide or lorcaserin in people with hypertension.
AUTHORS' CONCLUSIONS
In people with elevated blood pressure, orlistat, phentermine/topiramate and naltrexone/bupropion reduced body weight; the magnitude of the effect was greatest with phentermine/topiramate. In the same trials, orlistat and phentermine/topiramate, but not naltrexone/bupropion, reduced blood pressure. One RCT of naltrexone/bupropion versus placebo showed no differences in all-cause mortality or cardiovascular mortality or morbidity after two years. The European Medicines Agency refused marketing authorisation for phentermine/topiramate due to safety concerns, while for lorcaserin the application for European marketing authorisation was withdrawn due to a negative overall benefit/risk balance. In 2020 lorcaserin was also withdrawn from the US market. Two other medications (rimonabant and sibutramine) had already been withdrawn from the market in 2009 and 2010, respectively.
Topics: Adult; Anti-Obesity Agents; Appetite Depressants; Bias; Blood Pressure; Body Weight; Bupropion; Diet, Reducing; Drug Combinations; Female; Fructose; Humans; Hypertension; Lactones; Male; Middle Aged; Naltrexone; Orlistat; Phentermine; Piperidines; Pyrazoles; Randomized Controlled Trials as Topic; Safety-Based Drug Withdrawals; Time; Topiramate
PubMed: 33454957
DOI: 10.1002/14651858.CD007654.pub5 -
Obesity Reviews : An Official Journal... Apr 2023Weight-lowering pharmacotherapies provide an option for weight management; however, their effects on physical activity, function, and cardiorespiratory fitness are not... (Meta-Analysis)
Meta-Analysis Review
Weight-lowering pharmacotherapies provide an option for weight management; however, their effects on physical activity, function, and cardiorespiratory fitness are not fully understood. We conducted a systematic review and meta-analysis of randomized controlled trials to investigate the effect of licensed weight loss pharmacotherapies on physical activity, physical function, and cardiorespiratory fitness in individuals with obesity. Fourteen trials met our prespecified inclusion criteria: Five investigated liraglutide, four semaglutide, three naltrexone/bupropion, and two phentermine/topiramate. All 14 trials included a self-reported measure of physical function, with the pooled findings suggesting an improvement favoring the pharmacotherapy intervention groups (SMD: 0.27; 95% CI: 0.22 to 0.32) and effects generally consistent across different therapies. Results were also consistent when stratified by the two most commonly used measures: The Short-Form 36-Item Questionnaire (SF-36) (0.24; 0.17 to 0.32) and the Impact of Weight on Quality Of Life-Lite (IWQOL-Lite) (0.29; 0.23 to 0.35). Meta-regression confirmed a significant association between pharmacotherapy induced weight loss and improved physical function for IWQOL-Lite (p = 0.003). None of the studies reported a physical activity outcome, and only one study reported objectively measured cardiorespiratory fitness. Improvements in self-reported physical function were observed with weight loss therapy, but the effect on physical activity or objectively measured physical function and fitness could not be determined.
Topics: Humans; Quality of Life; Randomized Controlled Trials as Topic; Obesity; Exercise; Weight Loss; Physical Fitness
PubMed: 36721366
DOI: 10.1111/obr.13553 -
Obesity (Silver Spring, Md.) Jun 2021The study objective was to examine the association between phentermine/topiramate therapy and weight loss and adverse events in adults with overweight or obesity by... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The study objective was to examine the association between phentermine/topiramate therapy and weight loss and adverse events in adults with overweight or obesity by meta-analysis and systematic review.
METHODS
Medical Subject Headings and free-text terms were selected to search for eligible trials in PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase up to April 18, 2020. The quality of randomized controlled trials was evaluated by the Cochrane risk-of-bias tool. Meta-analysis was performed using random-effect models.
RESULTS
Phentermine/topiramate therapy resulted in an average weight loss of 7.73 kg (95% CI: 6.60-8.85) in general compared with placebo. The weight loss was related to the dose of phentermine/topiramate. Compared with placebo, the average weight loss was 3.55 kg (95% CI: 2.22-4.88) for 3.75/23 mg, 7.27 kg (95% CI: 6.40-8.13) for 7.5/46 mg, and 8.25 kg (95% CI: 6.92-9.79) for 15/92 mg. For phentermine/topiramate participants in different weight-loss subgroups, the weight loss of participants with ≥5%, ≥10%, and ≥15% baseline weight loss was 3.18 (95% CI: 2.75-3.67), 5.32 (95% CI: 4.53-6.25), and 5.65 (95% CI: 3.55-9.01), respectively. Compared with placebo, the adverse events associated with the treatment mainly included dysgeusia (odds ratio [OR] = 8.86, 95% CI: 5.65-13.89), paresthesia (OR = 8.51, 95% CI: 6.20-11.67), dry mouth (OR = 6.71, 95% CI: 5.03-8.94), disturbance in attention (OR = 4.48, 95% CI: 2.39-8.41), irritability (OR = 4.10, 95% CI: 2.29-7.33), hypoesthesia (OR = 3.81, 95% CI: 1.32-11.00), constipation (OR = 2.43, 95% CI: 2.02-2.93), and dizziness (OR = 2.26, 95% CI: 1.72-2.98). Phentermine/topiramate also reduced waist circumference, blood pressure, blood sugar levels, and lipid levels.
CONCLUSIONS
Phentermine/topiramate has considerable benefit in reducing body weight, and the efficacy was closely related to the dosage. However, it increased the risk of nervous system-related adverse events.
Topics: Adult; Blood Pressure; Body Weight; Drug Therapy, Combination; Female; Fructose; Humans; Male; Middle Aged; Obesity; Overweight; Phentermine; Randomized Controlled Trials as Topic; Topiramate; Treatment Outcome; Weight Loss
PubMed: 33864346
DOI: 10.1002/oby.23152