-
BMJ (Clinical Research Ed.) Jan 2024To evaluate the comparative efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycaemic control, body weight, and lipid profile in adults... (Meta-Analysis)
Meta-Analysis
Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis.
OBJECTIVE
To evaluate the comparative efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycaemic control, body weight, and lipid profile in adults with type 2 diabetes.
DESIGN
Systematic review and network meta-analysis.
DATA SOURCES
PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase from database inception to 19 August 2023.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Eligible randomised controlled trials enrolled adults with type 2 diabetes who received GLP-1RA treatments and compared effects with placebo or any GLP-1RA drug, with a follow-up duration of at least 12 weeks. Trials with a crossover design, non-inferiority studies comparing GLP-1RA and other drug classes without a placebo group, using withdrawn drugs, and non-English studies were deemed ineligible.
RESULTS
76 eligible trials involving 15 GLP-1RA drugs and 39 246 participants were included in this network meta-analysis; all subsequent estimates refer to the comparison with placebo. All 15 GLP-1RAs effectively lowered haemoglobin A and fasting plasma glucose concentrations. Tirzepatide induced the largest reduction of haemoglobin A concentrations (mean difference -2.10% (95% confidence interval -2.47% to -1.74%), surface under the cumulative ranking curve 94.2%; high confidence of evidence), and fasting plasma glucose concentrations (-3.12 mmol/L (-3.59 to -2.66), 97.2%; high confidence), and proved the most effective GLP-1RA drug for glycaemic control. Furthermore, GLP-1RAs were shown to have strong benefits to weight management for patients with type 2 diabetes. CagriSema (semaglutide with cagrilintide) resulted in the highest weight loss (mean difference -14.03 kg (95% confidence interval -17.05 to -11.00); high confidence of evidence), followed by tirzepatide (-8.47 kg (-9.68 to -7.26); high confidence). Semaglutide was effective in lowering the concentration of low density lipoprotein (-0.16 mmol/L (-0.30 to -0.02)) and total cholesterol (-0.48 mmol/L (-0.84 to -0.11)). Moreover, this study also raises awareness of gastrointestinal adverse events induced by GLP-1RAs, and concerns about safety are especially warranted for high dose administration.
CONCLUSIONS
GLP-1RAs are efficacious in treating adults with type 2 diabetes. Compared with the placebo, tirzepatide was the most effective GLP-1RA drug for glycaemic control by reducing haemoglobin A and fasting plasma glucose concentrations. GLP-1RAs also significantly improved weight management for type 2 diabetes, with CagriSema performing the best for weight loss. The results prompt safety concerns for GLP-1RAs, especially with high dose administration, regarding gastrointestinal adverse events.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42022342845.
Topics: Adult; Humans; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide-1 Receptor Agonists; Glycated Hemoglobin; Glycemic Control; Hypoglycemic Agents; Network Meta-Analysis; Weight Loss; Lipid Metabolism
PubMed: 38286487
DOI: 10.1136/bmj-2023-076410 -
BMJ (Clinical Research Ed.) Feb 2024To identify the optimal dose and modality of exercise for treating major depressive disorder, compared with psychotherapy, antidepressants, and control conditions. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To identify the optimal dose and modality of exercise for treating major depressive disorder, compared with psychotherapy, antidepressants, and control conditions.
DESIGN
Systematic review and network meta-analysis.
METHODS
Screening, data extraction, coding, and risk of bias assessment were performed independently and in duplicate. Bayesian arm based, multilevel network meta-analyses were performed for the primary analyses. Quality of the evidence for each arm was graded using the confidence in network meta-analysis (CINeMA) online tool.
DATA SOURCES
Cochrane Library, Medline, Embase, SPORTDiscus, and PsycINFO databases.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Any randomised trial with exercise arms for participants meeting clinical cut-offs for major depression.
RESULTS
218 unique studies with a total of 495 arms and 14 170 participants were included. Compared with active controls (eg, usual care, placebo tablet), moderate reductions in depression were found for walking or jogging (n=1210, κ=51, Hedges' g -0.62, 95% credible interval -0.80 to -0.45), yoga (n=1047, κ=33, g -0.55, -0.73 to -0.36), strength training (n=643, κ=22, g -0.49, -0.69 to -0.29), mixed aerobic exercises (n=1286, κ=51, g -0.43, -0.61 to -0.24), and tai chi or qigong (n=343, κ=12, g -0.42, -0.65 to -0.21). The effects of exercise were proportional to the intensity prescribed. Strength training and yoga appeared to be the most acceptable modalities. Results appeared robust to publication bias, but only one study met the Cochrane criteria for low risk of bias. As a result, confidence in accordance with CINeMA was low for walking or jogging and very low for other treatments.
CONCLUSIONS
Exercise is an effective treatment for depression, with walking or jogging, yoga, and strength training more effective than other exercises, particularly when intense. Yoga and strength training were well tolerated compared with other treatments. Exercise appeared equally effective for people with and without comorbidities and with different baseline levels of depression. To mitigate expectancy effects, future studies could aim to blind participants and staff. These forms of exercise could be considered alongside psychotherapy and antidepressants as core treatments for depression.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42018118040.
Topics: Humans; Network Meta-Analysis; Depression; Depressive Disorder, Major; Bayes Theorem; Exercise; Antidepressive Agents; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 38355154
DOI: 10.1136/bmj-2023-075847 -
Endocrine Aug 2023To summarize the more robust evidence about the performance of tools useful for diagnosis of medullary thyroid carcinoma (MTC) such as calcitonin (Ctn) and other... (Review)
Review
PURPOSE
To summarize the more robust evidence about the performance of tools useful for diagnosis of medullary thyroid carcinoma (MTC) such as calcitonin (Ctn) and other circulating markers, ultrasound (US), fine-needle aspiration (FNA), and other imaging procedures.
METHODS
This systematic review of systematic reviews was carried out according to a predefined protocol. A search string was created. An electronical comprehensive search of literature was performed on December 2022. Quality assessment of eligible systematic reviews was performed and main findings were described.
RESULTS
Twenty-three systematic reviews were included and several findings were achieved. Ctn is the most reliable diagnostic marker of MTC with no evidence of improvement with stimulation test. CEA doubling time is more reliable than Ctn in identifying MTC with poorer prognosis. US sensitivity is suboptimal in MTC and only just over half of cases are at high risk according to Thyroid Imaging And Reporting Data Systems. Cytology can correctly detect MTC in just over half of cases and measuring Ctn in washout fluid from FNA is necessary. PET/CT is useful for detecting recurrent MTC.
CONCLUSIONS
Future guidelines of both thyroid nodule management and MTC diagnosis should consider these evidence-based data.
Topics: Thyroid Neoplasms; Thyroid Nodule; Positron Emission Tomography Computed Tomography; Diagnostic Tests, Routine; Calcitonin; Systematic Reviews as Topic; Biopsy, Fine-Needle
PubMed: 36877452
DOI: 10.1007/s12020-023-03326-6 -
Journal of Neurology Oct 2023To compare the efficacy and safety of antiseizure medications (ASMs), both as monotherapies and adjunctive therapies, for idiopathic generalized epilepsies (IGEs) and... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To compare the efficacy and safety of antiseizure medications (ASMs), both as monotherapies and adjunctive therapies, for idiopathic generalized epilepsies (IGEs) and related entities.
METHODS
Two reviewers independently searched PubMed, Embase, and the Cochrane Library for relevant randomized controlled trials from December 2022 to February 2023. Studies on the efficacy and safety of ASM monotherapies or adjunctive therapies for IGEs and related entities-including juvenile myoclonic epilepsy, childhood absence epilepsy (CAE), juvenile absence epilepsy, or generalized tonic-clonic seizures alone (GTCA)-were included. Efficacy outcomes were the proportions of patients remaining seizure free for 1, 3, 6, and 12 months; safety outcomes were the proportions of any treatment-emergent adverse event (TEAE) and TEAEs leading to discontinuation. Network meta-analyses were performed in a random-effects model to obtain odds ratios and 95% confidence intervals. Rankings of ASMs were based on the surface under the cumulative ranking curve (SUCRA). This study is registered with PROSPERO (No. CRD42022372358).
RESULTS
Twenty-eight randomized controlled trials containing 4282 patients were included. As monotherapies, all ASMs were more effective than placebo, and valproate and ethosuximide were significantly better than lamotrigine. According to the SUCRA for efficacy, ethosuximide ranked first for CAE, whereas valproate ranked first for other types of IGEs. As adjunctive therapies, topiramate ranked best for GTCA as well as overall for IGEs, while levetiracetam ranked best for myoclonic seizures. For safety, perampanel ranked best (measured by any TEAE).
CONCLUSIONS
All of the studied ASMs were more effective than placebo. Valproate monotherapy ranked best overall for IGEs, whereas ethosuximide ranked best for CAE. Adjunctive topiramate and levetiracetam were most effective for GTCA and myoclonic seizures, respectively. Furthermore, perampanel had the best tolerability.
Topics: Humans; Child; Valproic Acid; Topiramate; Network Meta-Analysis; Levetiracetam; Ethosuximide; Anticonvulsants; Epilepsy, Generalized; Seizures; Randomized Controlled Trials as Topic
PubMed: 37378757
DOI: 10.1007/s00415-023-11834-8 -
JAMA Network Open Oct 2023There is a plethora of treatment options for patients with de Quervain tenosynovitis (DQT), but there are limited data on their effectiveness and no definitive... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
There is a plethora of treatment options for patients with de Quervain tenosynovitis (DQT), but there are limited data on their effectiveness and no definitive management guidelines.
OBJECTIVE
To assess and compare the effectiveness associated with available treatment options for DQT to guide musculoskeletal practitioners and inform guidelines.
DATA SOURCES
Medline, Embase, PubMed, Cochrane Central, Scopus, OpenGrey.eu, and WorldCat.org were searched for published studies, and the World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, The European Union Clinical Trials Register, and the ISRCTN registry were searched for unpublished and ongoing studies from inception to August 2022.
STUDY SELECTION
All randomized clinical trials assessing the effectiveness of any intervention for the management of DQT.
DATA EXTRACTION AND SYNTHESIS
This study was prospectively registered on PROSPERO and conducted and reported per Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions (PRISMA-NMA) and PRISMA in Exercise, Rehabilitation, Sport Medicine and Sports Science (PERSIST) guidance. The Cochrane Risk of Bias tool and the Grading of Recommendations, Assessment, Development, and Evaluations tool were used for risk of bias and certainty of evidence assessment for each outcome.
MAIN OUTCOMES AND MEASURES
Pairwise and network meta-analyses were performed for patient-reported pain using a visual analogue scale (VAS) and for function using the quick disabilities of the arm, shoulder, and hand (Q-DASH) scale. Mean differences (MD) with their 95% CIs were calculated for the pairwise meta-analyses.
RESULTS
A total of 30 studies with 1663 patients (mean [SD] age, 46 [7] years; 80% female) were included, of which 19 studies were included in quantitative analyses. From the pairwise meta-analyses, based on evidence of moderate certainty, adding thumb spica immobilization for 3 to 4 weeks to a corticosteroid injection (CSI) was associated with statistically but not clinically significant functional benefits in the short-term (MD, 10.5 [95% CI, 6.8-14.1] points) and mid-term (MD, 9.4 [95% CI, 7.0-11.9] points). In the network meta-analysis, interventions that included ultrasonography-guided CSI ranked at the top for pain. CSI with thumb spica immobilization had the highest probability of being the most effective intervention for short- and mid-term function.
CONCLUSIONS AND RELEVANCE
This network meta-analysis found that adding a short period of thumb spica immobilization to CSI was associated with statistically but not clinically significant short- and mid-term benefits. These findings suggest that administration of CSI followed by 3 to 4 weeks immobilization should be considered as a first-line treatment for patients with DQT.
Topics: Humans; Female; Middle Aged; Male; Network Meta-Analysis; Tenosynovitis; Bias; Exercise; Pain
PubMed: 37889490
DOI: 10.1001/jamanetworkopen.2023.37001 -
Nutrients Jul 2023Dietary patterns play a critical role in diabetes management, while the best dietary pattern for Type 2 diabetes (T2DM) patients is still unclear. The aim of this... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Dietary patterns play a critical role in diabetes management, while the best dietary pattern for Type 2 diabetes (T2DM) patients is still unclear. The aim of this network meta-analysis was to compare the impacts of various dietary approaches on the glycemic control of T2DM patients.
METHODS
Relevant studies were retrieved from PubMed, Embase, Web of Knowledge, Cochrane Central Register of Controlled Trials (CENTRAL), and other additional records (1949 to 31 July 2022). Eligible RCTs were those comparing different dietary approaches against each other or a control diet in individuals with T2DM for at least 6 months. We assessed the risk of bias of included studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. In order to determine the pooled effect of each dietary approach relative to each other, we performed a network meta-analysis (NMA) for interventions for both HbA1c and fasting glucose, which enabled us to estimate the relative intervention effects by combing both direct and indirect trial evidence.
RESULTS
Forty-two RCTs comprising 4809 patients with T2DM were included in the NMA, comparing 10 dietary approaches (low-carbohydrate, moderate-carbohydrate, ketogenic, low-fat, high-protein, Mediterranean, Vegetarian/Vegan, low glycemic index, recommended, and control diets). In total, 83.3% of the studies were at a lower risk of bias or had some concerns. Findings of the NMA revealed that the ketogenic, low-carbohydrate, and low-fat diets were significantly effective in reducing HbA1c (viz., -0.73 (-1.19, -0.28), -0.69 (-1.32, -0.06), and -1.82 (-2.93, -0.71)), while moderate-carbohydrate, low glycemic index, Mediterranean, high-protein, and low-fat diets were significantly effective in reducing fasting glucose (viz., -1.30 (-1.92, -0.67), -1.26 (-2.26, -0.27), -0.95 (-1.51, -0.38), -0.89 (-1.60, -0.18) and -0.75 (-1.24, -0.27)) compared to a control diet. The clustered ranking plot for combined outcomes indicated the ketogenic, Mediterranean, moderate-carbohydrate, and low glycemic index diets had promising effects for controlling HbA1c and fasting glucose. The univariate meta-regressions showed that the mean reductions of HbA1c and fasting glucose were only significantly related to the mean weight change of the subjects.
CONCLUSIONS
For glycemic control in T2DM patients, the ketogenic diet, Mediterranean diet, moderate-carbohydrate diet, and low glycemic index diet were effective options. Although this study found the ketogenic diet superior, further high-quality and long-term studies are needed to strengthen its credibility.
Topics: Humans; Diabetes Mellitus, Type 2; Network Meta-Analysis; Glycated Hemoglobin; Blood Glucose; Glycemic Control; Randomized Controlled Trials as Topic; Diet, Mediterranean
PubMed: 37513574
DOI: 10.3390/nu15143156 -
Journal of Gastrointestinal Surgery :... Aug 2023Postoperative ileus is common after gastrointestinal surgery. This network meta-analysis aimed to compare the effectiveness of gum chewing and coffee and caffeine intake... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Postoperative ileus is common after gastrointestinal surgery. This network meta-analysis aimed to compare the effectiveness of gum chewing and coffee and caffeine intake on ileus-related outcomes.
METHODS
A systematic literature review was performed to identify randomized controlled trials (RCTs) comparing noninvasive treatments for ileus after gastrointestinal surgery. The main analyses included random effects network meta-analyses using frequentist methods with simultaneous direct and indirect comparisons of time to first flatus, time to first defecation, and length of stay. Bayesian network meta-analysis using Markov chains was also used.
RESULTS
A total of 32 RCTs comparing 4999 patients were included in this network meta-analysis. Time to flatus was reduced by gum chewing (mean difference compared to control (MD): -11 h, 95% confidence interval (95% CI) - 16 to - 5 h, P < 0.001). Time to defecation was reduced by gum chewing and coffee, with MDs of -18 h (95% CI - 23 to - 13 h, P < 0.001) and -13 h (95% CI - 24 to - 1 h, P < 0.001), respectively. Length of stay was reduced by coffee and gum chewing with MDs of - 1.5 days (95% CI: - 2.5 to - 0.6 days, P < 0.001) and - 0.9 days (95% CI: - 1.3 to - 0.4 days, P < 0.001), respectively.
CONCLUSION
Coffee and gum chewing were proven to be effective noninvasive approaches for shortening the postoperative length of hospital stay and time to first defecation, especially in open gastrointestinal surgery; thus these actions should be recommended after gastrointestinal surgery.
Topics: Humans; Defecation; Coffee; Network Meta-Analysis; Mastication; Flatulence; Ileus; Postoperative Complications; Digestive System Surgical Procedures; Chewing Gum; Length of Stay; Gastrointestinal Motility
PubMed: 37277676
DOI: 10.1007/s11605-023-05702-z -
Clinical Oral Implants Research Sep 2023The aim of this study was to review available evidence for Type 1A (immediate implant placement and immediate loading) of single tooth replacement in the maxillary... (Meta-Analysis)
Meta-Analysis Review
Selection criteria for immediate implant placement and immediate loading for single tooth replacement in the maxillary esthetic zone: A systematic review and meta-analysis.
OBJECTIVES
The aim of this study was to review available evidence for Type 1A (immediate implant placement and immediate loading) of single tooth replacement in the maxillary esthetic zone.
MATERIALS AND METHODS
An electronic search was conducted utilizing the databases of MEDLINE, Embase, and Cochrane to identify publications reporting on the outcomes of Type 1A for single tooth replacement in the maxillary esthetic zone. The success and survival rates of the included articles were reported, which were further categorized according to the clinical criteria reported in Type 1A. Mean survival rates were univariately compared between risk groups and additionally between studies published before and since 2012 using bias-corrected and study size-weighed bootstrap tests. A study time-correcting meta-analysis was then performed to obtain an overall effect for the study pool.
RESULTS
A total of 3118 publications were identified in the search, with a total of 68 articles included. A mean number of implants per study were 37.2 and mean follow-up was 2.8 years. All the included studies utilizing Type 1A report highly selective inclusion and exclusion criteria. Univariate risk group comparison determined that studies before 2012 report a significantly lower mean survival rate (difference of -1.9 percentage points [PP], 95% CI: [-0.3, -4.0], p = .02), facial gap dimension had an impact on survival rates (+3.1 PP [0.2, 5.3] for width >2 mm, p = .04), as well as presence of endodontic infection (+2.6 PP [0.9, 5.1], p = .004).
CONCLUSIONS
Type 1A has a high survival rate in studies reporting strict patient and site selection criteria. Further research is required to assess esthetic and functional success with Type 1A treatments.
Topics: Humans; Patient Selection; Dental Implants; Esthetics, Dental; Databases, Factual
PubMed: 37750515
DOI: 10.1111/clr.14109 -
JAMA Network Open Jul 2023Plant-based diets are known to improve cardiometabolic risk in the general population, but their effects on people at high risk of cardiovascular diseases (CVDs) remain... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Plant-based diets are known to improve cardiometabolic risk in the general population, but their effects on people at high risk of cardiovascular diseases (CVDs) remain inconclusive.
OBJECTIVE
To assess the association of vegetarian diets with major cardiometabolic risk factors, including low-density lipoprotein cholesterol (LDL-C), hemoglobin A1c (HbA1c), systolic blood pressure (SBP), and body weight in people with or at high risk of CVDs.
DATA SOURCES
This meta-analysis was registered before the study was conducted. Systematic searches performed included Embase, MEDLINE, CINAHL, and CENTRAL from inception until July 31, 2021.
STUDY SELECTION
Eligible randomized clinical trials (RCTs) that delivered vegetarian diets in adults with or at high risk of CVDs and measured LDL-C, HbA1c or SBP were included. Of the 7871 records screened, 29 (0.4%; 20 studies) met inclusion criteria.
DATA EXTRACTION AND SYNTHESIS
Two reviewers independently extracted data including demographics, study design, sample size, and diet description, and performed risk of bias assessment. A random-effects model was used to assess mean changes in LDL-C, HbA1c, SBP, and body weight. The overall certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool.
MAIN OUTCOMES AND MEASURES
Mean differences between groups in changes (preintervention vs postintervention) of LDL-C, HbA1c, and SBP; secondary outcomes were changes in body weight and energy intake.
RESULTS
Twenty RCTs involving 1878 participants (range of mean age, 28-64 years) were included, and mean duration of intervention was 25.4 weeks (range, 2 to 24 months). Four studies targeted people with CVDs, 7 focused on diabetes, and 9 included people with at least 2 CVD risk factors. Overall, relative to all comparison diets, meta-analyses showed that consuming vegetarian diets for an average of 6 months was associated with decreased LDL-C, HbA1c, and body weight by 6.6 mg/dL (95% CI, -10.1 to -3.1), 0.24% (95% CI, -0.40 to -0.07), and 3.4 kg (95% CI, -4.9 to -2.0), respectively, but the association with SBP was not significant (-0.1 mm Hg; 95% CI, -2.8 to 2.6). The GRADE assessment showed a moderate level of evidence for LDL-C and HbA1c reduction.
CONCLUSIONS AND RELEVANCE
In this study, consuming a vegetarian diet was associated with significant improvements in LDL-C, HbA1c and body weight beyond standard therapy in individuals at high risk of CVDs. Additional high-quality trials are warranted to further elucidate the effects of healthy plant-based diets in people with CVDs.
Topics: Adult; Humans; Middle Aged; Cardiovascular Diseases; Cholesterol, LDL; Glycated Hemoglobin; Vegetarians; Research Design; Body Weight
PubMed: 37490288
DOI: 10.1001/jamanetworkopen.2023.25658 -
The Cochrane Database of Systematic... Jan 2024Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biological agents. Although each one of these therapies reduces relapse frequency and slows disability accumulation compared to no treatment, their relative benefit remains unclear. This is an update of a Cochrane review published in 2015.
OBJECTIVES
To compare the efficacy and safety, through network meta-analysis, of interferon beta-1b, interferon beta-1a, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, immunoglobulins, cladribine, cyclophosphamide, diroximel fumarate, fludarabine, interferon beta 1-a and beta 1-b, leflunomide, methotrexate, minocycline, mycophenolate mofetil, ofatumumab, ozanimod, ponesimod, rituximab, siponimod and steroids for the treatment of people with RRMS.
SEARCH METHODS
CENTRAL, MEDLINE, Embase, and two trials registers were searched on 21 September 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. A top-up search was conducted on 8 August 2022.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that studied one or more of the available immunomodulators and immunosuppressants as monotherapy in comparison to placebo or to another active agent, in adults with RRMS.
DATA COLLECTION AND ANALYSIS
Two authors independently selected studies and extracted data. We considered both direct and indirect evidence and performed data synthesis by pairwise and network meta-analysis. Certainty of the evidence was assessed by the GRADE approach.
MAIN RESULTS
We included 50 studies involving 36,541 participants (68.6% female and 31.4% male). Median treatment duration was 24 months, and 25 (50%) studies were placebo-controlled. Considering the risk of bias, the most frequent concern was related to the role of the sponsor in the authorship of the study report or in data management and analysis, for which we judged 68% of the studies were at high risk of other bias. The other frequent concerns were performance bias (34% judged as having high risk) and attrition bias (32% judged as having high risk). Placebo was used as the common comparator for network analysis. Relapses over 12 months: data were provided in 18 studies (9310 participants). Natalizumab results in a large reduction of people with relapses at 12 months (RR 0.52, 95% CI 0.43 to 0.63; high-certainty evidence). Fingolimod (RR 0.48, 95% CI 0.39 to 0.57; moderate-certainty evidence), daclizumab (RR 0.55, 95% CI 0.42 to 0.73; moderate-certainty evidence), and immunoglobulins (RR 0.60, 95% CI 0.47 to 0.79; moderate-certainty evidence) probably result in a large reduction of people with relapses at 12 months. Relapses over 24 months: data were reported in 28 studies (19,869 participants). Cladribine (RR 0.53, 95% CI 0.44 to 0.64; high-certainty evidence), alemtuzumab (RR 0.57, 95% CI 0.47 to 0.68; high-certainty evidence) and natalizumab (RR 0.56, 95% CI 0.48 to 0.65; high-certainty evidence) result in a large decrease of people with relapses at 24 months. Fingolimod (RR 0.54, 95% CI 0.48 to 0.60; moderate-certainty evidence), dimethyl fumarate (RR 0.62, 95% CI 0.55 to 0.70; moderate-certainty evidence), and ponesimod (RR 0.58, 95% CI 0.48 to 0.70; moderate-certainty evidence) probably result in a large decrease of people with relapses at 24 months. Glatiramer acetate (RR 0.84, 95%, CI 0.76 to 0.93; moderate-certainty evidence) and interferon beta-1a (Avonex, Rebif) (RR 0.84, 95% CI 0.78 to 0.91; moderate-certainty evidence) probably moderately decrease people with relapses at 24 months. Relapses over 36 months findings were available from five studies (3087 participants). None of the treatments assessed showed moderate- or high-certainty evidence compared to placebo. Disability worsening over 24 months was assessed in 31 studies (24,303 participants). Natalizumab probably results in a large reduction of disability worsening (RR 0.59, 95% CI 0.46 to 0.75; moderate-certainty evidence) at 24 months. Disability worsening over 36 months was assessed in three studies (2684 participants) but none of the studies used placebo as the comparator. Treatment discontinuation due to adverse events data were available from 43 studies (35,410 participants). Alemtuzumab probably results in a slight reduction of treatment discontinuation due to adverse events (OR 0.39, 95% CI 0.19 to 0.79; moderate-certainty evidence). Daclizumab (OR 2.55, 95% CI 1.40 to 4.63; moderate-certainty evidence), fingolimod (OR 1.84, 95% CI 1.31 to 2.57; moderate-certainty evidence), teriflunomide (OR 1.82, 95% CI 1.19 to 2.79; moderate-certainty evidence), interferon beta-1a (OR 1.48, 95% CI 0.99 to 2.20; moderate-certainty evidence), laquinimod (OR 1.49, 95 % CI 1.00 to 2.15; moderate-certainty evidence), natalizumab (OR 1.57, 95% CI 0.81 to 3.05), and glatiramer acetate (OR 1.48, 95% CI 1.01 to 2.14; moderate-certainty evidence) probably result in a slight increase in the number of people who discontinue treatment due to adverse events. Serious adverse events (SAEs) were reported in 35 studies (33,998 participants). There was probably a trivial reduction in SAEs amongst people with RRMS treated with interferon beta-1b as compared to placebo (OR 0.92, 95% CI 0.55 to 1.54; moderate-certainty evidence).
AUTHORS' CONCLUSIONS
We are highly confident that, compared to placebo, two-year treatment with natalizumab, cladribine, or alemtuzumab decreases relapses more than with other DMTs. We are moderately confident that a two-year treatment with natalizumab may slow disability progression. Compared to those on placebo, people with RRMS treated with most of the assessed DMTs showed a higher frequency of treatment discontinuation due to AEs: we are moderately confident that this could happen with fingolimod, teriflunomide, interferon beta-1a, laquinimod, natalizumab and daclizumab, while our certainty with other DMTs is lower. We are also moderately certain that treatment with alemtuzumab is associated with fewer discontinuations due to adverse events than placebo, and moderately certain that interferon beta-1b probably results in a slight reduction in people who experience serious adverse events, but our certainty with regard to other DMTs is lower. Insufficient evidence is available to evaluate the efficacy and safety of DMTs in a longer term than two years, and this is a relevant issue for a chronic condition like MS that develops over decades. More than half of the included studies were sponsored by pharmaceutical companies and this may have influenced their results. Further studies should focus on direct comparison between active agents, with follow-up of at least three years, and assess other patient-relevant outcomes, such as quality of life and cognitive status, with particular focus on the impact of sex/gender on treatment effects.
Topics: Adult; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Glatiramer Acetate; Interferon beta-1a; Fingolimod Hydrochloride; Natalizumab; Interferon beta-1b; Cladribine; Alemtuzumab; Dimethyl Fumarate; Daclizumab; Network Meta-Analysis; Immunologic Factors; Recurrence
PubMed: 38174776
DOI: 10.1002/14651858.CD011381.pub3