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BMJ (Clinical Research Ed.) Apr 2023To compare the benefits and harms of drug treatments for adults with type 2 diabetes, adding non-steroidal mineralocorticoid receptor antagonists (including finerenone)... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To compare the benefits and harms of drug treatments for adults with type 2 diabetes, adding non-steroidal mineralocorticoid receptor antagonists (including finerenone) and tirzepatide (a dual glucose dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist) to previously existing treatment options.
DESIGN
Systematic review and network meta-analysis.
DATA SOURCES
Ovid Medline, Embase, and Cochrane Central up to 14 October 2022.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Eligible randomised controlled trials compared drugs of interest in adults with type 2 diabetes. Eligible trials had a follow-up of 24 weeks or longer. Trials systematically comparing combinations of more than one drug treatment class with no drug, subgroup analyses of randomised controlled trials, and non-English language studies were deemed ineligible. Certainty of evidence was assessed following the GRADE (grading of recommendations, assessment, development and evaluation) approach.
RESULTS
The analysis identified 816 trials with 471 038 patients, together evaluating 13 different drug classes; all subsequent estimates refer to the comparison with standard treatments. Sodium glucose cotransporter-2 (SGLT-2) inhibitors (odds ratio 0.88, 95% confidence interval 0.83 to 0.94; high certainty) and GLP-1 receptor agonists (0.88, 0.82 to 0.93; high certainty) reduce all cause death; non-steroidal mineralocorticoid receptor antagonists, so far tested only with finerenone in patients with chronic kidney disease, probably reduce mortality (0.89, 0.79 to 1.00; moderate certainty); other drugs may not. The study confirmed the benefits of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing cardiovascular death, non-fatal myocardial infarction, admission to hospital for heart failure, and end stage kidney disease. Finerenone probably reduces admissions to hospital for heart failure and end stage kidney disease, and possibly cardiovascular death. Only GLP-1 receptor agonists reduce non-fatal stroke; SGLT-2 inhibitors are superior to other drugs in reducing end stage kidney disease. GLP-1 receptor agonists and probably SGLT-2 inhibitors and tirzepatide improve quality of life. Reported harms were largely specific to drug class (eg, genital infections with SGLT-2 inhibitors, severe gastrointestinal adverse events with tirzepatide and GLP-1 receptor agonists, hyperkalaemia leading to admission to hospital with finerenone). Tirzepatide probably results in the largest reduction in body weight (mean difference -8.57 kg; moderate certainty). Basal insulin (mean difference 2.15 kg; moderate certainty) and thiazolidinediones (mean difference 2.81 kg; moderate certainty) probably result in the largest increases in body weight. Absolute benefits of SGLT-2 inhibitors, GLP-1 receptor agonists, and finerenone vary in people with type 2 diabetes, depending on baseline risks for cardiovascular and kidney outcomes (https://matchit.magicevidence.org/230125dist-diabetes).
CONCLUSIONS
This network meta-analysis extends knowledge beyond confirming the substantial benefits with the use of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing adverse cardiovascular and kidney outcomes and death by adding information on finerenone and tirzepatide. These findings highlight the need for continuous assessment of scientific progress to introduce cutting edge updates in clinical practice guidelines for people with type 2 diabetes.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42022325948.
Topics: Adult; Humans; Diabetes Mellitus, Type 2; Sodium-Glucose Transporter 2 Inhibitors; Mineralocorticoid Receptor Antagonists; Network Meta-Analysis; Glucagon-Like Peptide-1 Receptor; Quality of Life; Kidney Failure, Chronic; Heart Failure; Randomized Controlled Trials as Topic
PubMed: 37024129
DOI: 10.1136/bmj-2022-074068 -
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 -
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 -
BMJ (Clinical Research Ed.) Jan 2021To evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying... (Meta-Analysis)
Meta-Analysis
Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.
OBJECTIVE
To evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk.
DESIGN
Network meta-analysis.
DATA SOURCES
Medline, Embase, and Cochrane CENTRAL up to 11 August 2020.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Randomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose lowering treatment in adults with type 2 diabetes with follow up of 24 weeks or longer. Studies were screened independently by two reviewers for eligibility, extracted data, and assessed risk of bias.
MAIN OUTCOME MEASURES
Frequentist random effects network meta-analysis was carried out and GRADE (grading of recommendations assessment, development, and evaluation) used to assess evidence certainty. Results included estimated absolute effects of treatment per 1000 patients treated for five years for patients at very low risk (no cardiovascular risk factors), low risk (three or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular disease and kidney disease). A guideline panel provided oversight of the systematic review.
RESULTS
764 trials including 421 346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment. Both classes of drugs lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). Notable differences were found between the two agents: SGLT-2 inhibitors reduced admission to hospital for heart failure more than GLP-1 receptor agonists, and GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect). SGLT-2 inhibitors caused genital infection (high certainty), whereas GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty). Low certainty evidence suggested that SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight. Little or no evidence was found for the effect of SGLT-2 inhibitors or GLP-1 receptor agonists on limb amputation, blindness, eye disease, neuropathic pain, or health related quality of life. The absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 3 to 40 fewer deaths in 1000 patients over five years; see interactive decision support tool (https://magicevidence.org/match-it/200820dist/#!/) for all outcomes.
CONCLUSIONS
In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with some differences in benefits and harms. Absolute benefits are determined by individual risk profiles of patients, with clear implications for clinical practice, as reflected in the BMJ Rapid Recommendations directly informed by this systematic review.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42019153180.
Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Mortality; Network Meta-Analysis; Randomized Controlled Trials as Topic; Renal Insufficiency; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 33441402
DOI: 10.1136/bmj.m4573 -
The Lancet. Diabetes & Endocrinology Oct 2019Glucagon-like peptide-1 (GLP-1) receptor agonists differ in their structure and duration of action and have been studied in trials of varying sizes and with different... (Meta-Analysis)
Meta-Analysis
Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.
BACKGROUND
Glucagon-like peptide-1 (GLP-1) receptor agonists differ in their structure and duration of action and have been studied in trials of varying sizes and with different patient populations, with inconsistent effects on cardiovascular outcomes reported. We aimed to synthesise the available evidence by doing a systematic review and meta-analysis of cardiovascular outcome trials of these drugs.
METHODS
We searched MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials for eligible placebo-controlled trials reporting major adverse cardiovascular events (MACE; ie, cardiovascular death, stroke, or myocardial infarction) up to June 15, 2019. We did a meta-analysis using a random-effects model to estimate overall hazard ratios (HRs) for MACE, its components, death from any cause, hospital admission for heart failure, kidney outcomes, and key safety outcomes (severe hypoglycaemia, pancreatitis, and pancreatic cancer). We also examined MACE in several subgroups based on patient characteristics (history of cardiovascular disease, BMI, age, baseline HbA1c, and baseline estimated glomerular filtration rate), trial duration, treatment dosing interval, and structural homology.
FINDINGS
Of 27 publications screened, seven trials, with a combined total of 56 004 participants, were included: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide). Overall, GLP-1 receptor agonist treatment reduced MACE by 12% (HR 0·88, 95% CI 0·82-0·94; p<0·0001). There was no statistically significant heterogeneity across the subgroups examined. HRs were 0·88 (95% CI 0·81-0·96; p=0·003) for death from cardiovascular causes, 0·84 (0·76-0·93; p<0·0001) for fatal or non-fatal stroke, and 0·91 (0·84-1·00; p=0·043) for fatal or non-fatal myocardial infarction. GLP-1 receptor agonist treatment reduced all-cause mortality by 12% (0·88, 0·83-0·95; p=0·001), hospital admission for heart failure by 9% (0·91, 0·83-0·99; p=0·028), and a broad composite kidney outcome (development of new-onset macroalbuminuria, decline in estimated glomerular filtration rate [or increase in creatinine], progression to end-stage kidney disease, or death attributable to kidney causes) by 17% (0·83, 0·78-0·89; p<0·0001), mainly due to a reduction in urinary albumin excretion. There was no increase in risk of severe hypoglycaemia, pancreatitis, or pancreatic cancer.
INTERPRETATION
Treatment with GLP-1 receptor agonists has beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes.
FUNDING
None.
Topics: Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 31422062
DOI: 10.1016/S2213-8587(19)30249-9 -
Diabetologia Aug 2022Tirzepatide is a novel dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) currently under review for marketing... (Meta-Analysis)
Meta-Analysis Review
AIMS/HYPOTHESIS
Tirzepatide is a novel dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) currently under review for marketing approval. Individual trials have assessed the clinical profile of tirzepatide vs different comparators. We conducted a systematic review and meta-analysis to assess the efficacy and safety of tirzepatide for type 2 diabetes.
METHODS
We searched PubMed, Embase, Cochrane and ClinicalTrials.gov up until 27 October 2021 for randomised controlled trials with a duration of at least 12 weeks that compared once-weekly tirzepatide 5, 10 or 15 mg with placebo or other glucose-lowering drugs in adults with type 2 diabetes irrespective of their background glucose-lowering treatment. The primary outcome was change in HbA from baseline. Secondary efficacy outcomes included change in body weight, proportion of individuals reaching the HbA target of <53 mmol/mol (<7.0%), ≤48 mmol/mol (≤6.5%) or <39 mmol/mol (<5.7%), and proportion of individuals with body weight loss of at least 5%, 10% or 15%. Safety outcomes included hypoglycaemia, gastrointestinal adverse events, treatment discontinuation due to adverse events, serious adverse events, and mortality. We used version 2 of the Cochrane risk-of-bias tool for randomised trials to assess risk of bias for the primary outcome.
RESULTS
Seven trials (6609 participants) were included. A dose-dependent superiority in lowering HbA was evident with all three tirzepatide doses vs all comparators, with mean differences ranging from -17.71 mmol/mol (-1.62%) to -22.35 mmol/mol (-2.06%) vs placebo, -3.22 mmol/mol (-0.29%) to -10.06 mmol/mol (-0.92%) vs GLP-1 RAs, and -7.66 mmol/mol (-0.70%) to -12.02 mmol/mol (-1.09%) vs basal insulin regimens. Tirzepatide was more efficacious in reducing body weight; reductions vs GLP-1 RAs ranged from 1.68 kg with tirzepatide 5 mg to 7.16 kg with tirzepatide 15 mg. Incidence of hypoglycaemia with tirzepatide was similar vs placebo and lower vs basal insulin. Nausea was more frequent with tirzepatide vs placebo, especially with tirzepatide 15 mg (OR 5.60 [95% CI 3.12, 10.06]), associated with higher incidence of vomiting (OR 5.50 [95% CI 2.40, 12.59]) and diarrhoea (OR 3.31 [95% CI 1.40, 7.85]). Odds of gastrointestinal events were similar between tirzepatide and GLP-1 RAs, except for diarrhoea with tirzepatide 10 mg (OR 1.51 [95% CI 1.07, 2.15]). Tirzepatide 15 mg led to higher discontinuation rate of study medication due to adverse events regardless of comparator, while all tirzepatide doses were safe in terms of serious adverse events and mortality.
CONCLUSIONS/INTERPRETATION
A dose-dependent superiority on glycaemic efficacy and body weight reduction was evident with tirzepatide vs placebo, GLP-1 RAs and basal insulin. Tirzepatide did not increase the odds of hypoglycaemia but was associated with increased incidence of gastrointestinal adverse events. Study limitations include presence of statistical heterogeneity in the meta-analyses for change in HbA and body weight, assessment of risk of bias solely for the primary outcome, and generalisation of findings mainly to individuals who are overweight or obese and already on metformin-based background therapy. PROSPERO registration no. CRD42021283449.
Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diarrhea; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulins; Treatment Outcome
PubMed: 35579691
DOI: 10.1007/s00125-022-05715-4 -
Obesity Reviews : An Official Journal... Jun 2022Clinical trials have investigated the weight loss effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) in adults with obesity without diabetes mellitus, but... (Meta-Analysis)
Meta-Analysis Review
Effect of glucagon-like peptide-1 receptor agonists on body weight in adults with obesity without diabetes mellitus-a systematic review and meta-analysis of randomized control trials.
Clinical trials have investigated the weight loss effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) in adults with obesity without diabetes mellitus, but results for weight loss efficacy were varied. We aimed to provide an up-to-date systematic review and meta-analysis for overall weight loss effect of GLP-1 RA in adults with obesity and overweight without diabetes mellitus. We retrieved eligible randomized control trials that assessed the weight loss effect of GLP-1 RA in adults (≥18 years old) without type 1/type 2 diabetes up to September 30, 2021, using Pubmed and Embase. Of 36 clinical trials assessed for eligibility, 12 trials were included, with a combined total of 11,459 participants. Compared with control groups, a more significant weight loss was seen in GLP-1 RA groups with an overall mean difference of -7.1 kg (95% CI -9.2 to -5.0) (I = 99%). The overall analysis results showed that GLP-1 RA improved glycemic control without increasing the risk of hypoglycemic events. Better control of blood pressure and plasma levels of LDL, HDL, and triglycerides was seen with GLP-1 RA treatment. Subgroup analysis showed greater treatment effect of semaglutide than liraglutide. Vomiting, nausea, dyspepsia, diarrhea, constipation, and abdominal pain were GLP-1 RA-associated common adverse effects.
Topics: Adolescent; Adult; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Obesity; Weight Loss
PubMed: 35194917
DOI: 10.1111/obr.13435 -
JAMA Apr 2018Combined use of inhaled corticosteroids and long-acting β-agonists (LABAs) as the controller and the quick relief therapy termed single maintenance and reliever therapy... (Meta-Analysis)
Meta-Analysis Review
Association of Inhaled Corticosteroids and Long-Acting β-Agonists as Controller and Quick Relief Therapy With Exacerbations and Symptom Control in Persistent Asthma: A Systematic Review and Meta-analysis.
IMPORTANCE
Combined use of inhaled corticosteroids and long-acting β-agonists (LABAs) as the controller and the quick relief therapy termed single maintenance and reliever therapy (SMART) is a potential therapeutic regimen for the management of persistent asthma.
OBJECTIVE
To conduct a systematic review and meta-analysis of the effects of SMART in patients with persistent asthma.
DATA SOURCES AND STUDY SELECTION
The databases of MEDLINE via OVID, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews were searched from database inception through August 2016 and updated through November 28, 2017. Two reviewers selected randomized clinical trials or observational studies evaluating SMART vs inhaled corticosteroids with or without a LABA used as the controller therapy and short-acting β-agonists as the relief therapy for patients aged 5 years or older with persistent asthma and reporting on an outcome of interest.
DATA EXTRACTION AND SYNTHESIS
Meta-analyses were conducted using a random-effects model to calculate risk ratios (RRs), risk differences (RDs), and mean differences with corresponding 95% CIs. Citation screening, data abstraction, risk assessment, and strength of evidence grading were completed by 2 independent reviewers.
MAIN OUTCOMES AND MEASURES
Asthma exacerbations.
RESULTS
The analyses included 16 randomized clinical trials (N = 22 748 patients), 15 of which evaluated SMART as a combination therapy with budesonide and formoterol in a dry-powder inhaler. Among patients aged 12 years or older (n = 22 524; mean age, 42 years; 14 634 [65%] were female), SMART was associated with a reduced risk of asthma exacerbations compared with the same dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.68 [95% CI, 0.58 to 0.80]; RD, -6.4% [95% CI, -10.2% to -2.6%]) and a higher dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.77 [95% CI, 0.60 to 0.98]; RD, -2.8% [95% CI, -5.2% to -0.3%]). Similar results were seen when SMART was compared with inhaled corticosteroids alone as the controller therapy. Among patients aged 4 to 11 years (n = 341; median age, 8 [range, 4-11] years; 69 [31%] were female), SMART was associated with a reduced risk of asthma exacerbations compared with a higher dose of inhaled corticosteroids as the controller therapy (RR, 0.55 [95% CI, 0.32 to 0.94]; RD, -12.0% [95% CI, -22.5% to -1.5%]) or the same dose of inhaled corticosteroids and LABA as the controller therapy (RR, 0.38 [95% CI, 0.23 to 0.63]; RD, -23.2% [95% CI, -33.6% to -12.1%]).
CONCLUSIONS AND RELEVANCE
In this meta-analysis of patients with persistent asthma, the use of single maintenance and reliever therapy compared with inhaled corticosteroids as the controller therapy (with or without a long-acting β-agonist) and short-acting β-agonists as the relief therapy was associated with a lower risk of asthma exacerbations. Evidence for patients aged 4 to 11 years was limited.
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-Agonists; Anti-Asthmatic Agents; Asthma; Bias; Budesonide; Delayed-Action Preparations; Drug Therapy, Combination; Formoterol Fumarate; Humans; Maintenance Chemotherapy; Risk Assessment
PubMed: 29554195
DOI: 10.1001/jama.2018.2769 -
JAMA Internal Medicine May 2022Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been widely recommended for glucose control and cardiovascular risk reduction in patients with type 2... (Meta-Analysis)
Meta-Analysis
Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases: A Systematic Review and Meta-analysis of Randomized Clinical Trials.
IMPORTANCE
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been widely recommended for glucose control and cardiovascular risk reduction in patients with type 2 diabetes, and more recently, for weight loss. However, the associations of GLP-1 RAs with gallbladder or biliary diseases are controversial.
OBJECTIVE
To evaluate the association of GLP-1 RA treatment with gallbladder and biliary diseases and to explore risk factors for these associations.
DATA SOURCES
MEDLINE/PubMed, EMBASE, Web of Science, and Cochrane Library (inception to June 30, 2021), websites of clinical trial registries (July 10, 2021), and reference lists. There were no language restrictions.
STUDY SELECTION
Randomized clinical trials (RCTs) comparing the use of GLP-1 RA drugs with placebo or with non-GLP-1 RA drugs in adults.
DATA EXTRACTION AND SYNTHESIS
Two reviewers independently extracted data according to the PRISMA recommendations and assessed the quality of each study with the Cochrane Collaboration risk-of-bias tool. Pooled relative risks (RRs) were calculated using random or fixed-effects models, as appropriate. The quality of evidence for each outcome was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework.
MAIN OUTCOMES AND MEASURES
The primary outcome was the composite of gallbladder or biliary diseases. Secondary outcomes were biliary diseases, biliary cancer, cholecystectomy, cholecystitis, and cholelithiasis. Data analyses were performed from August 5, 2021, to September 3, 2021.
RESULTS
A total of 76 RCTs involving 103 371 patients (mean [SD] age, 57.8 (6.2) years; 41 868 [40.5%] women) were included. Among all included trials, randomization to GLP-1 RA treatment was associated with increased risks of gallbladder or biliary diseases (RR, 1.37; 95% CI, 1.23-1.52); specifically, cholelithiasis (RR, 1.27; 95% CI, 1.10-1.47), cholecystitis (RR, 1.36; 95% CI, 1.14-1.62), and biliary disease (RR, 1.55; 95% CI, 1.08-2.22). Use of GLP-1 RAs was also associated with increased risk of gallbladder or biliary diseases in trials for weight loss (n = 13; RR, 2.29; 95% CI, 1.64-3.18) and for type 2 diabetes or other diseases (n = 63; RR, 1.27; 95% CI, 1.14-1.43; P <.001 for interaction). Among all included trials, GLP-1 RA use was associated with higher risks of gallbladder or biliary diseases at higher doses (RR, 1.56; 95% CI, 1.36-1.78) compared with lower doses (RR, 0.99; 95% CI, 0.73-1.33; P = .006 for interaction) and with longer duration of use (RR, 1.40; 95% CI, 1.26-1.56) compared with shorter duration (RR, 0.79; 95% CI, 0.48-1.31; P = .03 for interaction).
CONCLUSIONS AND RELEVANCE
This systematic review and meta-analysis of RCTs found that use of GLP-1 RAs was associated with increased risk of gallbladder or biliary diseases, especially when used at higher doses, for longer durations, and for weight loss.
TRIAL REGISTRATION
PROSPERO Identifier: CRD42021271599.
Topics: Adult; Cholecystitis; Cholelithiasis; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Weight Loss
PubMed: 35344001
DOI: 10.1001/jamainternmed.2022.0338 -
Obesity Reviews : An Official Journal... Jun 2021Pharmacological options for management of obesity and type 2 diabetes mellitus (T2DM) in children are limited. We aimed to synthesize published randomized controlled... (Meta-Analysis)
Meta-Analysis Review
Pharmacological options for management of obesity and type 2 diabetes mellitus (T2DM) in children are limited. We aimed to synthesize published randomized controlled trial (RCT) evidence on the efficacy of glucagon-like peptide-1 (GLP-1) agonists in T2DM, pre-diabetes, and obesity in children aged <18 years. Inclusion criteria were RCTs of any GLP-1 agonist, solely or in conjunction with other drugs, for the treatment of obesity, pre-diabetes, and/or T2DM in children aged <18 years old. Nine studies met the inclusion criteria (two for T2DM, one for pre-diabetes, and six for obesity without diabetes). In total, 286 children were allocated to GLP-1 agonist therapy. Compared with controls, GLP-1 agonist therapy reduced HbA1c by -0.30% (95% confidence interval [CI] -0.57, -0.04) with a larger effect in children with (pre-)diabetes (-0.72%; 95% CI -1.17, -0.28; three studies) than in children with obesity (-0.08%; 95% CI -0.13, -0.02; four studies). Conversely, GLP-1 agonist therapy reduced body weight more in children with obesity (-2.74 kg; 95% CI -3.77, -1.70; six studies) than in children with T2DM (-0.97 kg; 95% CI -2.01, 0.08; two studies). Adverse effects included gastrointestinal symptoms and minor hypoglycemic episodes, but not severe hypoglycemia. GLP-1 agonists are efficacious in treating children with obesity and/or T2DM. Effect sizes are comparable with those reported in adults.
Topics: Adolescent; Child; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Pediatric Obesity; Randomized Controlled Trials as Topic
PubMed: 33354917
DOI: 10.1111/obr.13177