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The Journal of Clinical Endocrinology... Mar 2021Risk of cancer is a major concern in the development of drugs for the treatment of obesity and diabetes. In randomized controlled trials (RCTs) of the Liraglutide... (Meta-Analysis)
Meta-Analysis
CONTEXT
Risk of cancer is a major concern in the development of drugs for the treatment of obesity and diabetes. In randomized controlled trials (RCTs) of the Liraglutide Clinical Development Program, subjects treated with a glucagon-like peptide-1 receptor agonist (GLP-1RA) had a higher absolute number of breast cancer events.
OBJECTIVE
To assess whether patients treated with GLP-1RAs had a higher risk of breast neoplasms.
DATA SOURCES
We searched MEDLINE, Embase, Web of Science, and CENTRAL from July 31, 2019 to February 8, 2020.
STUDY SELECTION
Reviewers assessed abstracts and full-text articles for RCTs of GLP-1RAs in adults with excessive weight and/or diabetes and a minimum follow-up of 24 weeks.
DATA EXTRACTION
Researchers extracted study-level data and assessed within-study risk of bias with the RoB 2.0 tool and quality of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE).
DATA SYNTHESIS
We included 52 trials, of which 50 reported breast cancer events and 11 reported benign breast neoplasms. Overall methodological quality was high. Among 48 267 subjects treated with GLP-1RAs, 130 developed breast cancer compared with 107 of 40 755 controls (relative risk [RR], 0.98; 95% confidence interval [CI], 0.76-1.26). Subset analyses according to follow-up, participant/investigator blinding, and type of GLP-1RA did not reveal any differences. The risk of benign breast neoplasms also did not differ between groups (RR, 0.99; 95% CI, 0.48-2.01). Trial sequential analysis provided evidence that the sample size was sufficient to avoid missing alternative results.
CONCLUSIONS
Treatment with GLP-1RAs for obesity and diabetes does not increase the risk of breast neoplasms.
Topics: Adult; Breast Neoplasms; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Obesity; Risk; Risk Factors
PubMed: 33248445
DOI: 10.1210/clinem/dgaa891 -
The International Journal of... Mar 2013FTY720 (fingolimod) is a known sphingosine-1-phosphate (S1P) receptor agonist, which has been used in clinical trials for treating multiple sclerosis, renal... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND PURPOSE
FTY720 (fingolimod) is a known sphingosine-1-phosphate (S1P) receptor agonist, which has been used in clinical trials for treating multiple sclerosis, renal transplantation, and decreasing reperfusion injury in heart, liver, and kidney. Most of these clinical trials have showed a positive effect. Especially, the trials of MS showed a reduction of relapse rate in FTY720-treated patients. Now, some animal experiments indicated that FTY720 could be a new compound available treatment for stroke patients by exerting neuroprotection via S1P1 mediated antiapoptotic mechanisms. Whether it could be effective in animals is unclear, so we conducted a systematic review to make it clear.
METHODS
We conducted a systematic review and meta-analysis of the efficacy of FTY720 in animal models of focal cerebral ischemia by electronic and manual searches of the literature. Data on study quality, FTY720 dose, time of administration, and outcome measured as infarct volume or functional deficit were extracted. Data from all studies were analyzed by means of a standardized mean difference meta-analysis.
RESULTS
Of the 19 identified studies, 9 were included. Among all the included studies, 178 animals were calculated for infarct size and 194 animals were assessed of neurological deficits. The methodological quality of the studies ranged from 2 to 10 according to a published 11-item quality scale. Of the nine studies selected, only one reported a negative result of FTY720. The result indicated that FTY720 reduced the infarct volume (SMD = -1.31, 95% CI -1.99 to -0.63) and improve the functional outcome (SMD = -1.61, 95% CI -2.17 to -1.05).
CONCLUSIONS
The data we included supporting FTY720 was a candidate drug for stroke, but it should be considered with caution. More good quality experimental studies should be performed to evaluate the safety of FTY720 in the future. Whether FTY720 is effective in aged animals that mimicked human with comorbidities like diabetes and hypertension should also be deliberated.
Topics: Animals; Disease Models, Animal; Fingolimod Hydrochloride; Humans; Propylene Glycols; Receptors, Lysosphingolipid; Recovery of Function; Sphingosine; Stroke; Treatment Outcome
PubMed: 23167788
DOI: 10.3109/00207454.2012.749255 -
Annals of Internal Medicine Jan 2016Once-weekly glucagon-like peptide-1 receptor agonists (GLP-1RAs) are new drugs for the treatment of type 2 diabetes. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Once-weekly glucagon-like peptide-1 receptor agonists (GLP-1RAs) are new drugs for the treatment of type 2 diabetes.
PURPOSE
To summarize evidence for the cardiometabolic efficacy and adverse effects of once-weekly GLP-1RAs in adults with type 2 diabetes.
DATA SOURCES
Electronic databases (PubMed, Web of Science, Cochrane Central Register of Controlled Trials, U.S. Food and Drug Administration, European Medicines Agency, ClinicalTrials.gov) and congress abstracts from inception through 26 September 2015.
STUDY SELECTION
Randomized, controlled trials (≥ 24 weeks of follow-up) studying albiglutide, dulaglutide, once-weekly exenatide, semaglutide, and taspoglutide and reporting a cardiometabolic (primary outcome, hemoglobin A1c [HbA1c]) or safety outcome.
DATA EXTRACTION
Extraction was done in duplicate, and risk of bias was assessed. No language restriction was applied.
DATA SYNTHESIS
34 trials (21,126 participants) were included. Compared with placebo, all once-weekly GLP-1RAs reduced HbA1c and fasting plasma glucose; taspoglutide, 20 mg, once-weekly exenatide, and dulaglutide, 1.5 mg, reduced body weight. Among once-weekly GLP-1RAs, the greatest differences were found between dulaglutide, 1.5 mg, and taspoglutide, 10 mg, for HbA1c (-0.4% [95% CI, -0.7% to -0.2%]), once-weekly exenatide and albiglutide for fasting plasma glucose (-0.7 mmol/L [CI, -1.1 to -0.2 mmol/L]; -12.6 mg/dL [CI, -19.8 to -3.6 mg/dL]), and taspoglutide, 20 mg, and dulaglutide, 0.75 mg, for body weight (-1.5 kg [CI, -2.2 to -0.8]). Clinically marginal or no differences were found for blood pressure, blood lipid levels, and C-reactive protein levels. Once-weekly exenatide increased heart rate compared with albiglutide and dulaglutide (1.4 to 3.2 beats/min). Among once-weekly GLP-1RAs, the risk for hypoglycemia was similar, whereas taspoglutide, 20 mg, had the greatest risk for nausea (odds ratios, 1.9 to 5.9).
LIMITATION
Data were unavailable for semaglutide, definitions of outcomes were heterogeneous, the last-observation-carried-forward imputation method was used in 73% of trials, and publication bias is possible.
CONCLUSION
Compared with other once-weekly GLP-1RAs, dulaglutide, 1.5 mg; once-weekly exenatide; and taspoglutide, 20 mg, showed a greater reduction of HbA1c, fasting plasma glucose, and body weight. Taspoglutide, 20 mg, had the highest risk for nausea; risk for hypoglycemia among once-weekly GLP-1RAs was similar.
PRIMARY FUNDING SOURCE
Sanofi Aventis (grant to the University of Leicester).
Topics: Blood Glucose; Diabetes Mellitus, Type 2; Drug Administration Schedule; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Hemodynamics; Humans; Hypoglycemia; Hypoglycemic Agents; Nausea; Weight Loss
PubMed: 26642233
DOI: 10.7326/M15-1432 -
Clinical Endocrinology Nov 2022To estimate the proportion of patients with persistent normoprolactinaemia following dopamine agonist (DA) withdrawal and to identify predictors of successful withdrawal... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To estimate the proportion of patients with persistent normoprolactinaemia following dopamine agonist (DA) withdrawal and to identify predictors of successful withdrawal in patients with hyperprolactinaemia.
DESIGN, PATIENTS, AND MEASUREMENTS
A systematic review of observational eligible studies were identified by searching PubMed and Embase. The primary outcome was the proportion of patients with normoprolactinaemia after cessation of DA treatment. Secondary outcome included the proportion of patients with normoprolactinaemia after DA withdrawal using individual patient data. Risk of bias was assessed by using Newcastle-Ottawa Scale. Pooled proportions were estimated using a random effects model in case I ≤ 75% or by reporting range of effects if I > 75%.
RESULTS
Thirty-two observational studies enroling 1563 patients were included. The proportion of patients with persistent normoprolactinaemia ranged from 0% to 75% (I = 84%). Heterogeneity was partly explained by age with more successful withdrawal in patients of higher age. Individual patient data analyses suggested that the proportion of patients with persistent normoprolactinaemia 6 months after DA withdrawal with a low maintenance dose and full regression of the prolactinoma was 87.7% (95% confidence interval [CI] = 60.7-97.1; I = 0%) and 58.4% (95% CI = 23.8-86.3; I = 75%) for microadenomas and macroadenomas, respectively.
CONCLUSIONS
The proportion of patients with persistent normoprolactinaemia following DA withdrawal treatment varied greatly, partly explained by the mean age of participants of the individual studies. Individual patient data analysis suggested that successful withdrawal was likely in patients with full regression of prolactinomas using a low maintenance dose before cessation.
Topics: Dopamine Agonists; Humans; Hyperprolactinemia; Pituitary Neoplasms; Prolactinoma; Withholding Treatment
PubMed: 35261059
DOI: 10.1111/cen.14714 -
Psychological Medicine Aug 2014A meta-analysis of the serotonin1A (5-HT1A) receptor partial agonist of the azapirone class as an anxiolytic drug for the treatment of major depressive disorder (MDD)... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A meta-analysis of the serotonin1A (5-HT1A) receptor partial agonist of the azapirone class as an anxiolytic drug for the treatment of major depressive disorder (MDD) has not previously been reported.
METHOD
We carried out a systematic review of the literature available in PubMed, the Cochrane Library database and PsycINFO up to 12 October 2013, and conducted a meta-analysis of randomized controlled trials (RCTs) comparing 5-HT1A agonists with placebo and RCTs of 5-HT1A agonist augmentation therapies for MDD treatment. We calculated the risk ratio (RR), number needed to treat (NNT)/number needed to harm (NNH) and 95% confidence intervals (CIs).
RESULTS
Fifteen RCTs comparing 5-HT1A agonists with placebo (total n = 2469, four studies with buspirone, seven with gepirone, three with ipsapirone and one with zalospirone) were identified. Pooled 5-HT1A agonists had significantly more responders (RR 0.74, 95% CI 0.65-083, p < 0.00001, NNT = 6, 12 trials, n = 1816) than placebo. Pooled 5-HT1A agonists were superior to placebo in discontinuation due to inefficacy (RR 0.49, p = 0.02, NNH = 16, p = 0.03, 10 trials, n = 1494) but were inferior to placebo in discontinuation due to side-effects (RR 1.88, p < 0.0001, NNH = 17, p = 0.001, 13 trials, n = 2196). However, all-cause discontinuation was similar in both groups (RR 0.99, p = 0.85, 14 trials, n = 2402). Four 5-HT1A agonist augmentation studies were identified (total n = 365, three buspirone studies and one tandospirone study). There were no statistically significant effects of 5-HT1A agonist augmentation therapies on response rate (RR 0.98, p = 0.85, four trials, n = 341). 5-HT1A agonist-related side-effects including gastrointestinal symptoms, dizziness, insomnia, palpitation, paresthesia and sweating were greater than with placebo (p < 0.00001 to p = 0.03).
CONCLUSIONS
Our results suggest that 5-HT1A agonist has a more beneficial effect on MDD than placebo, but has several side-effects.
Topics: Depressive Disorder, Major; Humans; Serotonin 5-HT1 Receptor Agonists
PubMed: 24262766
DOI: 10.1017/S0033291713002857 -
CNS Drugs Dec 2018About 30% of regular cannabis users report withdrawal symptoms on cessation of prolonged use, such as irritability, insomnia, decreased appetite, depressed mood,... (Review)
Review
BACKGROUND
About 30% of regular cannabis users report withdrawal symptoms on cessation of prolonged use, such as irritability, insomnia, decreased appetite, depressed mood, anxiety, and restlessness. However, among highly dependent and/or in-treatment users, the incidence of withdrawal can be even higher, reaching up to 50-95% of individuals. This syndrome was only recognized by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) as a diagnosis with specific criteria in 2013. The treatment options are poor, with high rates of relapse and non-responders. In this scenario, agonist replacement therapy with cannabinoids has demonstrated potential as a promising therapeutic intervention, with a series of studies having been carried out in recent years.
OBJECTIVE
This review sought to summarize trials with cannabinoid agonist replacement therapy for cannabis withdrawal symptoms with the aim of evaluating the efficacy of this pharmacological intervention.
DATA SOURCES
We entered the following search terms on the PubMed, Web of Science and PsycINFO databases: (marijuana OR marihuana OR cannabis OR THC OR tetrahydrocannabinol OR hashish OR pot) AND (treatment OR medication) AND (withdrawal OR abstinence) AND (dronabinol OR nabilone OR nabiximols OR sativex OR cesamet OR synthetic cannabinoid). The date of the most recent search was September 2017.
STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS
Original trials, published in English, performed on humans and dealing with cannabis users who were treated for cannabis withdrawal symptoms using synthetic cannabinoids were all included in the present systematic review. Quality and risk of bias across studies were assessed using a Cochrane tool.
STUDY APPRAISAL AND SYNTHESIS METHODS
The first, second, and last authors read the abstracts of all studies found in the search (n = 243). The inclusion and exclusion criteria were applied, and 233 articles were excluded. The first and second authors independently developed a data extraction sheet based on the included articles.
RESULTS
The present review included ten original articles. Despite the limited number of studies and methodological differences, our findings demonstrate that the use of dronabinol, nabilone, or nabiximols, either alone or in combination with other drugs, shows promise in reducing cannabis withdrawal symptoms, probably with a dose-dependent effect. This has also been considered a safe group of medications with good tolerability and few adverse effects.
LIMITATIONS
No method of handling data and combining results of studies was carried out, representing a limitation of the review.
CONCLUSIONS AND IMPLICATION OF THE KEY FINDINGS
Cannabinoids appear to be a promising group of drugs for the treatment of cannabis withdrawal symptoms. These medications may help decrease the rate of relapse in the treatment of cannabis dependence due to withdrawal symptoms occurring within the first few weeks of treatment.
SYSTEMATIC REVIEW REGISTRATION
The protocol for this review has been registered in the PROSPERO International prospective register of systematic reviews (PROSPERO 2014:CRD42014014118).
Topics: Algorithms; Cannabinoid Receptor Agonists; Databases, Bibliographic; Humans; Marijuana Abuse; Substance Withdrawal Syndrome
PubMed: 30361897
DOI: 10.1007/s40263-018-0577-6 -
Caspian Journal of Internal Medicine 2016Chronic obstructive pulmonary disease (COPD) is usually considered one of the leading causes of death worldwide, so finding proper therapeutic strategies for this... (Review)
Review
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is usually considered one of the leading causes of death worldwide, so finding proper therapeutic strategies for this disease is of high importance. In this meta-analysis, we reviewed the existing literature on the efficacy and safety of conventional long acting beta agonists (LABAs) in COPD patients.
METHODS
We searched MEDLINE and Google scholar to identify relevant articles. We limited data to double-blinded randomized controlled trials (RCTs). Data of 14, 832 COPD subjects including 7540 patients under a β2 agonist (cases) and 7292 taking placebo (controls) retrieved from 20 randomized controlled trials and were enrolled into this meta-analysis. Evaluated outcomes included overall mortality, exacerbations and tolerance to the drug.
RESULTS
The analysis of survival showed no significant difference between those taking LABAs or placebo (relative risk (RR): 0.945, 95% confidence interval (CI): 0.821-1.088, P=0.432). Exacerbation rate, however, was significantly lower among the cases than among the controls (RR: 0.859, 95%CI: 0.800-0.922, p<0.001). Similar observation was detected in analyzing the rate of drug withdrawal in patients of the two groups with patients under placebo having significantly higher rate of drug discontinuation due to adverse events or disease symptoms (RR:0.821, 95% CI: 0.774-0.871; p<0.007).
CONCLUSION
In conclusion, we found that the use of conventional LABA therapy in COPD patients is associated with a lower exacerbation rate of the disease as well as higher tolerance to the drug, but no survival advantage is expectable. Substitution of LABAs with new agents is recommended.
PubMed: 27386055
DOI: No ID Found -
Pharmacotherapy Dec 2022To evaluate the cardiovascular outcomes of glucagon-like peptide-1 receptor agonists (GLP1-RA) in patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD). (Meta-Analysis)
Meta-Analysis Review
AIM
To evaluate the cardiovascular outcomes of glucagon-like peptide-1 receptor agonists (GLP1-RA) in patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD).
MATERIALS AND METHODS
We searched PubMed, Ovid MEDLINE, CINAHL, and Web of Science databases for randomized controlled trials reporting event rates for a composite cardiovascular outcome of cardiovascular death, myocardial infarction, and stroke in patients with T2DM and CKD receiving GLP1-RA or placebo. Studies were restricted to those reporting specific event rates for patients with CKD separately from the overall population. We conducted a meta-analysis using a random-effects model. This meta-analysis was registered on PROSPERO (CRD42022320157).
RESULTS
A total of four studies comprising 7130 patients was included in our analysis. Four different GLP1-RA were assessed in a population with CKD defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m . Treatment with GLP1-RA was not associated with a significant reduction in the composite cardiovascular end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke (odds ratio (OR) 0.80; 95% confidence interval (CI), 0.59-1.07; p = 0.13) among patients with T2DM and CKD. Individual components of the composite cardiovascular end point were assessed in two trials and did not show evidence of an effect of GLP1-RA in reducing cardiovascular end points.
CONCLUSIONS
Pooled analysis of clinical trials reporting separate cardiovascular events rates in patients with T2DM and CKD did not find GLP1-RA to be associated with a reduction in composite cardiovascular event rates. Select GLP1-RA may offer cardiovascular event reduction in patients with T2DM and CKD, but this does not appear to be a class effect. Use of GLP1-RA with demonstrated cardiovascular benefits should be preferred in patients with CKD and T2DM to further reduce cardiovascular risk.
Topics: Humans; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Myocardial Infarction; Renal Insufficiency, Chronic; Stroke
PubMed: 36271706
DOI: 10.1002/phar.2737 -
Endocrine Jan 2018Dopamine agonists (DAs) are recommended as first-line treatment for patients with hyperprolactinemia. Generally, it is accepted that patients with hyperprolactinemia do... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Dopamine agonists (DAs) are recommended as first-line treatment for patients with hyperprolactinemia. Generally, it is accepted that patients with hyperprolactinemia do not need lifelong medication, but the optimal timing for DA withdrawal has not been determined. The aim of this systematic review and meta-analysis is to assess the impact of DA withdrawal on the clinical outcomes of patients with hyperprolactinemia, and to explore possible factors affecting successful DA withdrawal.
METHODS
The databases of PubMed, Cochrane and EMBASE were searched up to May 2016.
RESULTS
The proportion of patients with persisting normoprolactinemia after DA withdrawal reached 36.6% in a random effects model (95% CI, 29.4-44.2%; I-squared: 82.5%). Data of stratified analysis showed that the success rate of drug withdrawal was high in patients using cabergoline (CAB) as the only treatment (41.2%; 95% CI 32.3-50.4%) and those using CAB over 24 months (48.7%; 95% CI 38.9-58.5%), especially in patients with idiopathic hyperprolactinemia (73.2%; 95% CI 55.6-87.7%). In addition, patients who received a low maintenance dose of CAB, and had a significant reduction in tumor size (over 50%) before withdrawal, were more likely to achieve success (51.5 and 49.4%, respectively).
CONCLUSION
The success rate of DA withdrawal has increased in recent years. Further, the success rate of CAB withdrawal was higher than that of bromocriptine, especially in patients with a duration of treatment longer than 24 months. Conclusively, the probability of success was higher in patients who received low-dose CAB maintenance treatment and those who achieved a significant reduction in tumor size before withdrawal.
Topics: Dopamine Agonists; Drug Administration Schedule; Humans; Hyperprolactinemia; Pituitary Neoplasms; Prolactinoma; Time Factors; Withholding Treatment
PubMed: 29043560
DOI: 10.1007/s12020-017-1444-9 -
BMC Cardiovascular Disorders Jun 2023In recent years, the incidence of diabetes mellitus has been increasing annually, and cardiovascular complications secondary to diabetes mellitus have become the leading... (Meta-Analysis)
Meta-Analysis
BACKGROUND
In recent years, the incidence of diabetes mellitus has been increasing annually, and cardiovascular complications secondary to diabetes mellitus have become the leading cause of death in diabetic patients. Considering the high incidence of type 2 diabetes (T2DM) combined with cardiovascular disease (CVD), some new hypoglycemic agents with cardiovascular protective effects have attracted extensive attention. However, the specific role of these regimens in ventricular remodeling remains unknown. The purpose of this network meta-analysis was to compare the effects of sodium glucose cotransporter type 2 inhibitor (SGLT-2i), glucagon-like peptide 1 receptor agonist (GLP-1RA) and dipeptidyl peptidase-4 inhibitor (DPP-4i) on ventricular remodeling in patients with T2DM and/or CVD.
METHODS
Articles published prior to 24 August 2022 were retrieved in four electronic databases: the Cochrane Library, Embase, PubMed, and Web of Science. This meta-analysis included randomized controlled trials (RCTs) and a small number of cohort studies. The differences in mean changes of left ventricular ultrasonic parameters between the treatment and control groups were compared.
RESULTS
A total of 31 RCTs and 4 cohort studies involving 4322 patients were analyzed. GLP-1RA was more significantly associated with improvement in left ventricular end-systolic diameter (LVESD) [MD = -0.38 mm, 95% CI (-0.66, -0.10)] and LV mass index (LVMI) [MD = -1.07 g/m, 95% CI (-1.71, -0.42)], but significantly decreased e' [MD = -0.43 cm/s 95% CI (-0.81, -0.04)]. DPP-4i was more strongly associated with improvement in e' [MD = 3.82 cm/s, 95% CI (2.92,4.7)] and E/e'[MD = -5.97 95% CI (-10.35, -1.59)], but significantly inhibited LV ejection fraction (LVEF) [MD = -0.89% 95% CI (-1.76, -0.03)]. SGLT-2i significantly improved LVMI [MD = -0.28 g/m, 95% CI (-0.43, -0.12)] and LV end-diastolic diameter (LVEDD) [MD = -0.72 ml, 95% CI (-1.30, -0.14)] in the overall population, as well as E/e' and SBP in T2DM patients combined with CVD, without showing any negative effect on left ventricular function.
CONCLUSION
The results of the network meta-analysis provided high certainty to suggest that SGLT-2i may be more effective in cardiac remodeling compared to GLP-1RA and DPP-4i. While GLP-1RA and DPP-4i may have a tendency to improve cardiac systolic and diastolic function respectively. SGLT-2i is the most recommended drug for reversing ventricular remodeling in this meta-analysis.
Topics: Humans; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Network Meta-Analysis; Protease Inhibitors; Ventricular Remodeling
PubMed: 37296380
DOI: 10.1186/s12872-023-03324-6