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The Cochrane Database of Systematic... Jun 2020Worldwide, there is an increasing incidence of type 2 diabetes mellitus (T2DM). Metformin is still the recommended first-line glucose-lowering drug for people with T2DM.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Worldwide, there is an increasing incidence of type 2 diabetes mellitus (T2DM). Metformin is still the recommended first-line glucose-lowering drug for people with T2DM. Despite this, the effects of metformin on patient-important outcomes are still not clarified.
OBJECTIVES
To assess the effects of metformin monotherapy in adults with T2DM.
SEARCH METHODS
We based our search on a systematic report from the Agency for Healthcare Research and Quality, and topped-up the search in CENTRAL, MEDLINE, Embase, WHO ICTRP, and ClinicalTrials.gov. Additionally, we searched the reference lists of included trials and systematic reviews, as well as health technology assessment reports and medical agencies. The date of the last search for all databases was 2 December 2019, except Embase (searched up 28 April 2017).
SELECTION CRITERIA
We included randomised controlled trials (RCTs) with at least one year's duration comparing metformin monotherapy with no intervention, behaviour changing interventions or other glucose-lowering drugs in adults with T2DM.
DATA COLLECTION AND ANALYSIS
Two review authors read all abstracts and full-text articles/records, assessed risk of bias, and extracted outcome data independently. We resolved discrepancies by involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the overall certainty of the evidence by using the GRADE instrument.
MAIN RESULTS
We included 18 RCTs with multiple study arms (N = 10,680). The percentage of participants finishing the trials was approximately 58% in all groups. Treatment duration ranged from one to 10.7 years. We judged no trials to be at low risk of bias on all 'Risk of bias' domains. The main outcomes of interest were all-cause mortality, serious adverse events (SAEs), health-related quality of life (HRQoL), cardiovascular mortality (CVM), non-fatal myocardial infarction (NFMI), non-fatal stroke (NFS), and end-stage renal disease (ESRD). Two trials compared metformin (N = 370) with insulin (N = 454). Neither trial reported on all-cause mortality, SAE, CVM, NFMI, NFS or ESRD. One trial provided information on HRQoL but did not show a substantial difference between the interventions. Seven trials compared metformin with sulphonylureas. Four trials reported on all-cause mortality: in three trials no participant died, and in the remaining trial 31/1454 participants (2.1%) in the metformin group died compared with 31/1441 participants (2.2%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on SAE: in two trials no SAE occurred (186 participants); in the other trial 331/1454 participants (22.8%) in the metformin group experienced a SAE compared with 308/1441 participants (21.4%) in the sulphonylurea group (very low-certainty evidence). Two trials reported on CVM: in one trial no CVM was observed and in the other trial 4/1441 participants (0.3%) in the metformin group died of cardiovascular reasons compared with 8/1447 participants (0.6%) in the sulphonylurea group (very low-certainty evidence). Three trials reported on NFMI: in two trials no NFMI occurred, and in the other trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 15/1441 participants (1.0%) in the sulphonylurea group (very low-certainty evidence). One trial reported no NFS occurred (very low-certainty evidence). No trial reported on HRQoL or ESRD. Seven trials compared metformin with thiazolidinediones (very low-certainty evidence for all outcomes). Five trials reported on all-cause mortality: in two trials no participant died; the overall RR was 0.88, 95% CI 0.55 to 1.39; P = 0.57; 5 trials; 4402 participants). Four trials reported on SAE, the RR was 0,95, 95% CI 0.84 to 1.09; P = 0.49; 3208 participants. Four trials reported on CVM, the RR was 0.71, 95% CI 0.21 to 2.39; P = 0.58; 3211 participants. Three trial reported on NFMI: in two trials no NFMI occurred and in one trial 21/1454 participants (1.4%) in the metformin group experienced a NFMI compared with 25/1456 participants (1.7%) in the thiazolidinedione group. One trial reported no NFS occurred. No trial reported on HRQoL or ESRD. Three trials compared metformin with dipeptidyl peptidase-4 inhibitors (one trial each with saxagliptin, sitagliptin, vildagliptin with altogether 1977 participants). There was no substantial difference between the interventions for all-cause mortality, SAE, CVM, NFMI and NFS (very low-certainty evidence for all outcomes). One trial compared metformin with a glucagon-like peptide-1 analogue (very low-certainty evidence for all reported outcomes). There was no substantial difference between the interventions for all-cause mortality, CVM, NFMI and NFS. One or more SAEs were reported in 16/268 (6.0%) of the participants allocated to metformin compared with 35/539 (6.5%) of the participants allocated to a glucagon-like peptide-1 analogue. HRQoL or ESRD were not reported. One trial compared metformin with meglitinide and two trials compared metformin with no intervention. No deaths or SAEs occurred (very low-certainty evidence) no other patient-important outcomes were reported. No trial compared metformin with placebo or a behaviour changing interventions. Four ongoing trials with 5824 participants are likely to report one or more of our outcomes of interest and are estimated to be completed between 2018 and 2024. Furthermore, 24 trials with 2369 participants are awaiting assessment.
AUTHORS' CONCLUSIONS
There is no clear evidence whether metformin monotherapy compared with no intervention, behaviour changing interventions or other glucose-lowering drugs influences patient-important outcomes.
Topics: Adult; Carbamates; Cardiovascular Diseases; Cause of Death; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Metformin; Myocardial Infarction; Piperidines; Quality of Life; Randomized Controlled Trials as Topic; Stroke; Sulfonylurea Compounds
PubMed: 32501595
DOI: 10.1002/14651858.CD012906.pub2 -
Journal of Family Medicine and Primary... Mar 2022Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) rarely cause euglycemic diabetic ketoacidosis (euDKA) in diabetic patients. The aim was to identify...
BACKGROUND
Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) rarely cause euglycemic diabetic ketoacidosis (euDKA) in diabetic patients. The aim was to identify demographic, clinical, and predisposing factors for euDKA from published case reports.
METHODS
A systematic review of published case reports of euDKA in patients receiving SGLT2 inhibitors and meta-analysis of clinical trials to quantify the risk ratio (RR) of DKA in patients receiving SGLT2 inhibitors. PubMed and EMBASE databases were searched for the case reports of and clinical trials from January 2010 to August 2020. Studies published in English language were included and other languages were excluded. Data related to patients' demography, clinical presentation, drug and dose of SGLT2 inhibitors, and concomitant medication were extracted. Incidence of diabetic ketoacidosis (DKA) extracted from clinical trials. Data related to demographic, clinical, and other parameters presented as ratios and proportions and incidence of DKA in RR using Review Manager 5.3.
RESULTS
Forty-seven of 160 reports with an aggregate of 77 patients were included in the analysis. The majority of the patients were females (67.53%), with T2DM and with gastrointestinal symptoms (58%). Surgery was the most common precipitating factor (/ = 15/77). Canagliflozin (/ = 34/77) was the commonest SGLT2 inhibitor reported along with metformin as the concomitant medication (63.6%). The pooled RR of DKA was 3.70 (95%CI 2.58, 5.29) and I = 0%.
CONCLUSION
euDKA is commonly seen in middle-aged female, T2DM patients taking SGLT2 inhibitors along with metformin. The risk of DKA in patients receiving SGLT2 inhibitors increases by 3.7 times than the other medication.
PubMed: 35495849
DOI: 10.4103/jfmpc.jfmpc_644_21 -
Respirology (Carlton, Vic.) Nov 2023Long COVID, or post-acute COVID-19 sequelae, is experienced by an estimated one in eight adults following acute COVID-19. Long COVID is a new and complex chronic health... (Review)
Review
Long COVID, or post-acute COVID-19 sequelae, is experienced by an estimated one in eight adults following acute COVID-19. Long COVID is a new and complex chronic health condition that typically includes multiple symptoms that cross organ systems and fluctuate over time; a one-size-fits-all approach is, therefore, not likely to be appropriate nor relevant for long COVID treatment. 'Treatable Traits' is a personalized medicine approach, purpose-built to address the complexity and heterogeneity of complex chronic conditions. This comprehensive review aimed to understand how a treatable traits approach could be applied to long COVID, by first identifying the most prevalent long COVID treatable traits and then the available evidence for strategies to target these traits. An umbrella review of 22 systematic reviews identified 34 symptoms and complications common with long COVID, grouped into eight long COVID treatable trait clusters: neurological, chest, psychological, pain, fatigue, sleep impairment, functional impairment and other. A systematic review of randomized control trials identified 18 studies that explored different intervention approaches for long COVID prevention (k = 4) or management (k = 14). While a single study reported metformin as effective for long COVID prevention, the findings need to be replicated and consensus is required around how to define long COVID as a clinical trial endpoint. For long COVID management, current evidence supports exercise training or respiratory muscle training for long COVID treatable traits in the chest and functional limitation clusters. While there are studies exploring interventions targeting other long COVID treatable traits, further high-quality RCTs are needed, particularly targeting treatable traits in the clusters of fatigue, psychological, pain and sleep impairment.
Topics: Adult; Humans; Post-Acute COVID-19 Syndrome; COVID-19; Chronic Disease; Fatigue; Pain
PubMed: 37715729
DOI: 10.1111/resp.14596 -
The Cochrane Database of Systematic... Dec 2019The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether metformin can prevent or delay... (Meta-Analysis)
Meta-Analysis
Metformin for prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus.
BACKGROUND
The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether metformin can prevent or delay T2DM and its complications in people with increased risk of developing T2DM is unknown.
OBJECTIVES
To assess the effects of metformin for the prevention or delay of T2DM and its associated complications in persons at increased risk for the T2DM.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Scopus, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was March 2019.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) with a duration of one year or more comparing metformin with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or standard care in people with impaired glucose tolerance, impaired fasting glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or combinations of these.
DATA COLLECTION AND ANALYSIS
Two review authors read all abstracts and full-text articles and records, assessed risk of bias and extracted outcome data independently. We used a random-effects model to perform meta-analysis and calculated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the certainty of the evidence using GRADE.
MAIN RESULTS
We included 20 RCTs randomising 6774 participants. One trial contributed 48% of all participants. The duration of intervention in the trials varied from one to five years. We judged none of the trials to be at low risk of bias in all 'Risk of bias' domains. Our main outcome measures were all-cause mortality, incidence of T2DM, serious adverse events (SAEs), cardiovascular mortality, non-fatal myocardial infarction or stroke, health-related quality of life and socioeconomic effects.The following comparisons mostly reported only a fraction of our main outcome set. Fifteen RCTs compared metformin with diet and exercise with or without placebo: all-cause mortality was 7/1353 versus 7/1480 (RR 1.11, 95% CI 0.41 to 3.01; P = 0.83; 2833 participants, 5 trials; very low-quality evidence); incidence of T2DM was 324/1751 versus 529/1881 participants (RR 0.50, 95% CI 0.38 to 0.65; P < 0.001; 3632 participants, 12 trials; moderate-quality evidence); the reporting of SAEs was insufficient and diverse and meta-analysis could not be performed (reported numbers were 4/118 versus 2/191; 309 participants; 4 trials; very low-quality evidence); cardiovascular mortality was 1/1073 versus 4/1082 (2416 participants; 2 trials; very low-quality evidence). One trial reported no clear difference in health-related quality of life after 3.2 years of follow-up (very low-quality evidence). Two trials estimated the direct medical costs (DMC) per participant for metformin varying from $220 to $1177 versus $61 to $184 in the comparator group (2416 participants; 2 trials; low-quality evidence). Eight RCTs compared metformin with intensive diet and exercise: all-cause mortality was 7/1278 versus 4/1272 (RR 1.61, 95% CI 0.50 to 5.23; P = 0.43; 2550 participants, 4 trials; very low-quality evidence); incidence of T2DM was 304/1455 versus 251/1505 (RR 0.80, 95% CI 0.47 to 1.37; P = 0.42; 2960 participants, 7 trials; moderate-quality evidence); the reporting of SAEs was sparse and meta-analysis could not be performed (one trial reported 1/44 in the metformin group versus 0/36 in the intensive exercise and diet group with SAEs). One trial reported that 1/1073 participants in the metformin group compared with 2/1079 participants in the comparator group died from cardiovascular causes. One trial reported that no participant died due to cardiovascular causes (very low-quality evidence). Two trials estimated the DMC per participant for metformin varying from $220 to $1177 versus $225 to $3628 in the comparator group (2400 participants; 2 trials; very low-quality evidence). Three RCTs compared metformin with acarbose: all-cause mortality was 1/44 versus 0/45 (89 participants; 1 trial; very low-quality evidence); incidence of T2DM was 12/147 versus 7/148 (RR 1.72, 95% CI 0.72 to 4.14; P = 0.22; 295 participants; 3 trials; low-quality evidence); SAEs were 1/51 versus 2/50 (101 participants; 1 trial; very low-quality evidence). Three RCTs compared metformin with thiazolidinediones: incidence of T2DM was 9/161 versus 9/159 (RR 0.99, 95% CI 0.41 to 2.40; P = 0.98; 320 participants; 3 trials; low-quality evidence). SAEs were 3/45 versus 0/41 (86 participants; 1 trial; very low-quality evidence). Three RCTs compared metformin plus intensive diet and exercise with identical intensive diet and exercise: all-cause mortality was 1/121 versus 1/120 participants (450 participants; 2 trials; very low-quality evidence); incidence of T2DM was 48/166 versus 53/166 (RR 0.55, 95% CI 0.10 to 2.92; P = 0.49; 332 participants; 2 trials; very low-quality evidence). One trial estimated the DMC of metformin plus intensive diet and exercise to be $270 per participant compared with $225 in the comparator group (94 participants; 1 trial; very-low quality evidence). One trial in 45 participants compared metformin with a sulphonylurea. The trial reported no patient-important outcomes. For all comparisons there were no data on non-fatal myocardial infarction, non-fatal stroke or microvascular complications. We identified 11 ongoing trials which potentially could provide data of interest for this review. These trials will add a total of 17,853 participants in future updates of this review.
AUTHORS' CONCLUSIONS
Metformin compared with placebo or diet and exercise reduced or delayed the risk of T2DM in people at increased risk for the development of T2DM (moderate-quality evidence). However, metformin compared to intensive diet and exercise did not reduce or delay the risk of T2DM (moderate-quality evidence). Likewise, the combination of metformin and intensive diet and exercise compared to intensive diet and exercise only neither showed an advantage or disadvantage regarding the development of T2DM (very low-quality evidence). Data on patient-important outcomes such as mortality, macrovascular and microvascular diabetic complications and health-related quality of life were sparse or missing.
Topics: Diabetes Mellitus, Type 2; Glucose Intolerance; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Prediabetic State; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 31794067
DOI: 10.1002/14651858.CD008558.pub2 -
The Cochrane Database of Systematic... Aug 2020Metformin has been proposed as possibly a safer and more effective long-term treatment than the oral contraceptive pill (OCP) in women with polycystic ovary syndrome... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Metformin has been proposed as possibly a safer and more effective long-term treatment than the oral contraceptive pill (OCP) in women with polycystic ovary syndrome (PCOS). It is important to directly compare the efficacy and safety of metformin versus OCP in the long-term treatment of women with PCOS. This is an update of a Cochrane Review comparing insulin sensitising agents with the OCP and only includes studies on metformin.
OBJECTIVES
To assess the effectiveness and safety of metformin versus the OCP (alone or in combination) in improving clinical, hormonal, and metabolic features of PCOS.
SEARCH METHODS
In August 2019 we searched the Cochrane Gynaecology and Fertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and CINAHL, the trial registers, handsearched references of the identified articles, and contacted experts in the field to identify additional studies.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of the use of metformin versus the OCP (alone or in combination) for women with PCOS.
DATA COLLECTION AND ANALYSIS
We used standard methods recommended by Cochrane. The primary review outcomes were the clinical parameters of hirsutism and adverse events, both severe (requiring stopping of medication), and minor. In the presence of substantial heterogeneity (I statistic > 50), which could be explained by pre-specified subgroup analyses on the basis of BMI, we reported the subgroups separately.
MAIN RESULTS
This is a substantive update. We identified 38 additional studies. We included 44 RCTs (2253 women), which comprised 39 RCTs on adult women (2047 women) and five RCTs on adolescent women (206 women). Evidence quality ranged from very low to low. The main limitations were risk of bias, imprecision and inconsistency. Metformin versus the OCP In adult women, we are uncertain of the effect of metformin compared to the OCP on hirsutism in subgroup body mass index (BMI) < 25 kg/m (mean difference (MD) 0.38, 95% confidence interval (CI) -0.44 to 1.19, 3 RCTs, n = 134, I = 50%, very low-quality evidence) and subgroup BMI > 30 kg/m (MD -0.38, 95% CI -1.93 to 1.17; 2 RCTs, n = 85, I = 34%, low-quality evidence). Metformin may be less effective in improving hirsutism compared to the OCP in the subgroup BMI 25 kg/m to 30 kg/m (MD 1.92, 95% CI 1.21 to 2.64, 5 RCTs, n = 254, I = 0%, low-quality evidence). Metformin may increase severe gastro-intestinal adverse events rate compared to the OCP (Peto odds ratio (OR) 6.42, 95% CI 2.98 to 13.84, 11 RCTs, n = 602, I = 0%, low-quality evidence). Metformin may decrease the incidence of severe other adverse events compared to the OCP (Peto OR 0.20, 95% CI 0.09 to 0.44, 8 RCTs, n = 363, I = 0%, low-quality evidence). There were no trials reporting on minor adverse events. In adolescents, we are uncertain whether there is a difference between Metformin and the OCP, on hirsutism and adverse events. Metformin versus metformin combined with the OCP In adult women, metformin may be less effective in improving hirsutism compared to Metformin combined with the OCP (MD 1.36, 95% CI 0.62 to 2.11, 3 RCTs, n = 135, I= 9%, low-quality evidence). We are uncertain if there was a difference between metformin and metformin combined with the OCP for severe gastro-intestinal adverse events (OR 0.74, 95% CI 0.21 to 2.53, 3 RCTs, n = 171, I = 0%, low-quality evidence), or for severe other adverse events (OR 0.56, 95% CI 0.11 to 2.82, 2 RCTs, n = 109, I = 44%, low-quality evidence). There were no trials reporting on minor adverse events. In adolescents, there were no trials for this comparison. The OCP versus metformin combined with the OCP In adult women, the OCP may be less effective in improving hirsutism compared to metformin combined with the OCP (MD 0.54, 95% CI 0.20 to 0.89, 6 RCTs, n = 389, I= 1%, low-quality evidence). The OCP may decrease the incidence of severe gastro-intestinal adverse events compared to metformin combined with the OCP (OR 0.20, 95% CI 0.06 to 0.72, 5 RCTs, n = 228, I = 0%, low-quality evidence). We are uncertain if there is a difference between the OCP and metformin combined with the OCP for severe other adverse events (OR 1.61, 95% CI 0.49 to 5.37, 4 RCTs, n = 159, I = 12%, low-quality evidence). The OCP may decrease the incidence of minor (gastro-intestinal) adverse events compared to metformin combined with the OCP (OR 0.06, 95% CI 0.01 to 0.44, 2 RCTs, n = 98, I = 0%, low-quality evidence). In adolescents, we are uncertain whether there is a difference between the OCP, compared to metformin combined with the OCP, on hirsutism or adverse events.
AUTHORS' CONCLUSIONS
In adult women with PCOS, metformin may be less effective in improving hirsutism compared to the OCP in the subgroup BMI 25 kg/m to 30 kg/m but we are uncertain if there was a difference between metformin and the OCP in subgroups BMI < 25 kg/m and BMI > 30kg/m. Compared to the OCP, metformin may increase the incidence of severe gastro-intestinal adverse events and decrease the incidence of severe other adverse events with no trials reporting on minor adverse events. Either metformin alone or the OCP alone may be less effective in improving hirsutism compared to metformin combined with the OCP. We are uncertain whether there is a difference between the OCP alone and metformin alone compared to metformin combined with the OCP for severe or minor adverse events except for the OCP versus metformin combined with the OCP where the OCP may decrease the incidence of severe and minor gastro-intestinal adverse events. In adolescent women with PCOS, we are uncertain whether there is a difference between any of the comparisons for hirsutism and adverse events due to either no evidence or very low-quality evidence. Further large well-designed RCTs that stratify for BMI are needed to evaluate metformin versus the OCP and combinations in women with PCOS, in particular adolescent women.
Topics: Acne Vulgaris; Adolescent; Adult; Body Mass Index; Cardiovascular Diseases; Contraceptives, Oral, Combined; Drug Therapy, Combination; Endometrial Neoplasms; Female; Hirsutism; Humans; Hypoglycemic Agents; Menstruation Disturbances; Metformin; Polycystic Ovary Syndrome; Randomized Controlled Trials as Topic; Young Adult
PubMed: 32794179
DOI: 10.1002/14651858.CD005552.pub3 -
Molecular Metabolism Nov 2023The gut microbiota is increasingly recognized as a crucial factor in human health and disease. Metformin, a commonly prescribed medication for type 2 diabetes, has been... (Review)
Review
BACKGROUND
The gut microbiota is increasingly recognized as a crucial factor in human health and disease. Metformin, a commonly prescribed medication for type 2 diabetes, has been studied for its potential impact on the gut microbiota in preclinical models. However, the effects of metformin on the gut microbiota in humans remain uncertain.
SCOPE OF REVIEW
We conducted a systematic review of clinical trials and observational studies to assess the existing knowledge on the impact of metformin on the gut microbiota in humans. The review focused on changes in bacterial composition and diversity following metformin treatment.
MAJOR CONCLUSIONS
Thirteen studies were included in the analysis. The results revealed alterations in the abundance of bacterial genera from various phyla, suggesting that metformin may selectively influence certain groups of bacteria in the gut microbiota. However, the effects on gut microbiota diversity were inconsistent across populations, with conflicting findings on changes in alpha and beta diversity measures. Overall, the use of metformin was associated with changes in the abundance of specific bacterial genera within the gut microbiota of human populations. However, the effects on gut microbiota diversity were not consistent, highlighting the need for further research to understand the underlying mechanisms and clinical significance of these changes.
Topics: Humans; Metformin; Diabetes Mellitus, Type 2; Gastrointestinal Microbiome; Bacteria
PubMed: 37696355
DOI: 10.1016/j.molmet.2023.101805 -
Diabetes Care Jul 2023Observational and preclinical data suggest metformin may prevent severe coronavirus disease 2019 (COVID-19) outcomes. (Review)
Review
BACKGROUND
Observational and preclinical data suggest metformin may prevent severe coronavirus disease 2019 (COVID-19) outcomes.
PURPOSE
We conducted a systematic review of randomized, placebo-controlled clinical trials of metformin treatment for COVID-19 to determine whether metformin affects clinical or laboratory outcomes in individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and present a structured summary of preclinical data.
STUDY SELECTION
Two independent reviewers searched PubMed, Scopus, Cochrane COVID-19 Study Register, and ClinicalTrials.gov on 1 February 2023 with no date restrictions for trials where investigators randomized adults with COVID-19 to metformin versus control and assessed clinical and/or laboratory outcomes of interest. The Cochrane Risk of Bias 2 tool was used to assess bias.
DATA EXTRACTION
Two reviewers extracted data pertaining to prespecified outcomes of each interest from each included trial.
DATA SYNTHESIS
The synthesis plan was developed a priori and was guided by Synthesis Without Meta-analysis (SWiM) guidelines. Summary tables and narrative synthesis were used (PROSPERO, 2022, CRD42022349896). Three randomized trials met inclusion criteria. In two of the trials investigators found that metformin improved clinical outcomes (prevented need for oxygen and prevented need for acute health care use), and in the third trial a larger portion of adults with diabetes were enrolled but results did show a direction of benefit similar to that of the other trials in the per-protocol group. In the largest trial, subjects were enrolled during the delta and omicron waves and vaccinated individuals were included. The certainty of evidence that metformin prevents health care use due to COVID-19 was moderate per Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Many preclinical studies have shown metformin to be effective against SARS-CoV-2.
LIMITATIONS
Limitations include inclusion of only three trials and heterogeneity between trials.
CONCLUSIONS
Future trials will help define the role of metformin in COVID-19 treatment guidelines.
Topics: Adult; Humans; COVID-19; SARS-CoV-2; Metformin; COVID-19 Drug Treatment; Bias
PubMed: 37339345
DOI: 10.2337/dc22-2539 -
Acta Bio-medica : Atenei Parmensis Aug 2023the COVID-19 infection, caused by severe Coronavirus 2 syndrome (Sars-Cov-2), immediately appeared to be the most tragic global pandemic event of the twentieth century.... (Meta-Analysis)
Meta-Analysis
the COVID-19 infection, caused by severe Coronavirus 2 syndrome (Sars-Cov-2), immediately appeared to be the most tragic global pandemic event of the twentieth century. Right from the start of the pandemic, diabetic patients treated with metformin experienced a reduction in mortality and complications from COVID-19 compared to those with different treatments or no treatment. Objective The main objective of the study was to observe the effects of metformin in hospitalized subjects infected with COVID-19. Specifically, the outcomes of hospitalization in Intensive Care Units or death were examined. Materials and Methods A specific research PICOS was developed and the Pubmed, Embase and Scopus databases were consulted down to April 30, 2022. To estimate the extent of the metformin effect and risk of severity in SARS-CoV-2 infection, the Odd Ratio (OR) with 95% Confidence Interval (CI) published by the authors of the selected systematic reviews was used. Results from five systematic reviews 36 studies were selected. The final meta-analysis showed that thanks to treatment with metformin, DM2 patients affected by COVID-19 had protection against risk of disease severity, complications (ES 0.80; 95% CI) and mortality (ES 0.69; 95% CI). Conclusions More in-depth studies on the use of metformin, compared to other molecules, may be required to understand the real protective potential of the drug against negative outcomes caused by COVID-19 infection in DM2 patients.
Topics: Humans; COVID-19; SARS-CoV-2; Systematic Reviews as Topic; Databases, Factual; Metformin
PubMed: 37695186
DOI: 10.23750/abm.v94iS3.14405 -
The Cochrane Database of Systematic... Jun 2020The prevalence of gestational diabetes mellitus (GDM) is increasing, with approximately 15% of pregnant women affected worldwide, varying by country, ethnicity and...
BACKGROUND
The prevalence of gestational diabetes mellitus (GDM) is increasing, with approximately 15% of pregnant women affected worldwide, varying by country, ethnicity and diagnostic thresholds. There are associated short- and long-term health risks for women and their babies.
OBJECTIVES
We aimed to summarise the evidence from Cochrane systematic reviews on the effects of interventions for preventing GDM.
METHODS
We searched the Cochrane Database of Systematic Reviews (6 August 2019) with key words 'gestational diabetes' OR 'GDM' to identify reviews pre-specifying GDM as an outcome. We included reviews of interventions in women who were pregnant or planning a pregnancy, irrespective of their GDM risk status. Two overview authors independently assessed eligibility, extracted data and assessed quality of evidence using ROBIS and GRADE tools. We assigned interventions to categories with graphic icons to classify the effectiveness of interventions as: clear evidence of benefit or harm (GRADE moderate- or high-quality evidence with a confidence interval (CI) that did not cross the line of no effect); clear evidence of no effect or equivalence (GRADE moderate- or high-quality evidence with a narrow CI crossing the line of no effect); possible benefit or harm (low-quality evidence with a CI that did not cross the line of no effect or GRADE moderate- or high-quality evidence with a wide CI); or unknown benefit or harm (GRADE low-quality evidence with a wide CI or very low-quality evidence).
MAIN RESULTS
We included 11 Cochrane Reviews (71 trials, 23,154 women) with data on GDM. Nine additional reviews pre-specified GDM as an outcome, but did not identify GDM data in included trials. Ten of the 11 reviews were judged to be at low risk of bias and one review at unclear risk of bias. Interventions assessed included diet, exercise, a combination of diet and exercise, dietary supplements, pharmaceuticals, and management of other health problems in pregnancy. The quality of evidence ranged from high to very low. Diet Unknown benefit or harm: there was unknown benefit or harm of dietary advice versus standard care, on the risk of GDM: risk ratio (RR) 0.60, 95% CI 0.35 to 1.04; 5 trials; 1279 women; very low-quality evidence. There was unknown benefit or harm of a low glycaemic index diet versus a moderate-high glycaemic index diet on the risk of GDM: RR 0.91, 95% CI 0.63 to 1.31; 4 trials; 912 women; low-quality evidence. Exercise Unknown benefit or harm: there was unknown benefit or harm for exercise interventions versus standard antenatal care on the risk of GDM: RR 1.10, 95% CI 0.66 to 1.84; 3 trials; 826 women; low-quality evidence. Diet and exercise combined Possible benefit: combined diet and exercise interventions during pregnancy versus standard care possibly reduced the risk of GDM: RR 0.85, 95% CI 0.71 to 1.01; 19 trials; 6633 women; moderate-quality evidence. Dietary supplements Clear evidence of no effect: omega-3 fatty acid supplementation versus none in pregnancy had no effect on the risk of GDM: RR 1.02, 95% CI 0.83 to 1.26; 12 trials; 5235 women; high-quality evidence. Possible benefit: myo-inositol supplementation during pregnancy versus control possibly reduced the risk of GDM: RR 0.43, 95% CI 0.29 to 0.64; 3 trials; 502 women; low-quality evidence. Possible benefit: vitamin D supplementation versus placebo or control in pregnancy possibly reduced the risk of GDM: RR 0.51, 95% CI 0.27 to 0.97; 4 trials; 446 women; low-quality evidence. Unknown benefit or harm: there was unknown benefit or harm of probiotic with dietary intervention versus placebo with dietary intervention (RR 0.37, 95% CI 0.15 to 0.89; 1 trial; 114 women; very low-quality evidence), or probiotic with dietary intervention versus control (RR 0.38, 95% CI 0.16 to 0.92; 1 trial; 111 women; very low-quality evidence) on the risk of GDM. There was unknown benefit or harm of vitamin D + calcium supplementation versus placebo (RR 0.33, 95% CI 0.01 to 7.84; 1 trial; 54 women; very low-quality evidence) or vitamin D + calcium + other minerals versus calcium + other minerals (RR 0.42, 95% CI 0.10 to 1.73; 1 trial; 1298 women; very low-quality evidence) on the risk of GDM. Pharmaceutical Possible benefit: metformin versus placebo given to obese pregnant women possibly reduced the risk of GDM: RR 0.85, 95% CI 0.61 to 1.19; 3 trials; 892 women; moderate-quality evidence. Unknown benefit or harm:eight small trials with low- to very low-quality evidence showed unknown benefit or harm for heparin, aspirin, leukocyte immunisation or IgG given to women with a previous stillbirth on the risk of GDM. Management of other health issues Clear evidence of no effect: universal versus risk based screening of pregnant women for thyroid dysfunction had no effect on the risk of GDM: RR 0.93, 95% CI 0.70 to 1.25; 1 trial; 4516 women; moderate-quality evidence. Unknown benefit or harm: there was unknown benefit or harm of using fractional exhaled nitrogen oxide versus a clinical algorithm to adjust asthma therapy on the risk of GDM: RR 0.74, 95% CI 0.31 to 1.77; 1 trial; 210 women; low-quality evidence. There was unknown benefit or harm of pharmacist led multidisciplinary approach to management of maternal asthma versus standard care on the risk of GDM: RR 5.00, 95% CI 0.25 to 99.82; 1 trial; 58 women; low-quality evidence.
AUTHORS' CONCLUSIONS
No interventions to prevent GDM in 11 systematic reviews were of clear benefit or harm. A combination of exercise and diet, supplementation with myo-inositol, supplementation with vitamin D and metformin were of possible benefit in reducing the risk of GDM, but further high-quality evidence is needed. Omega-3-fatty acid supplementation and universal screening for thyroid dysfunction did not alter the risk of GDM. There was insufficient high-quality evidence to establish the effect on the risk of GDM of diet or exercise alone, probiotics, vitamin D with calcium or other vitamins and minerals, interventions in pregnancy after a previous stillbirth, and different asthma management strategies in pregnancy. There is a lack of trials investigating the effect of interventions prior to or between pregnancies on risk of GDM.
Topics: Diabetes, Gestational; Diet, Diabetic; Dietary Supplements; Exercise; Fatty Acids, Omega-3; Female; Humans; Hypoglycemic Agents; Inositol; Metformin; Pregnancy; Probiotics; Systematic Reviews as Topic; Vitamin B Complex; Vitamin D; Vitamins
PubMed: 32526091
DOI: 10.1002/14651858.CD012394.pub3 -
The Journal of Clinical Endocrinology... May 2024Insulin resistance is common in women with polycystic ovary syndrome (PCOS). Inositol may have insulin sensitizing effects; however, its efficacy in the management of... (Meta-Analysis)
Meta-Analysis
CONTEXT
Insulin resistance is common in women with polycystic ovary syndrome (PCOS). Inositol may have insulin sensitizing effects; however, its efficacy in the management of PCOS remains indeterminate.
OBJECTIVE
To inform the 2023 international evidence-based guidelines in PCOS, this systematic review and meta-analysis evaluated the efficacy of inositol, alone or in combination with other therapies, in the management of PCOS.
DATA SOURCES
Medline, PsycInfo, EMBASE, All EBM, and CINAHL from inception until August 2022.
STUDY SELECTION
Thirty trials (n = 2230; 1093 intervention, 1137 control), with 19 pooled in meta-analyses were included.
DATA EXTRACTION
Data were extracted for hormonal, metabolic, lipids, psychological, anthropometric, reproductive outcomes, and adverse effects by 1 reviewer, independently verified by a second.
DATA SYNTHESIS
Thirteen comparisons were assessed, with 3 in meta-analyses. Evidence suggests benefits for myo-inositol or D-chiro-inositol (DCI) for some metabolic measures and potential benefits from DCI for ovulation, but inositol may have no effect on other outcomes. Metformin may improve waist-hip ratio and hirsutism compared to inositol, but there is likely no difference for reproductive outcomes, and the evidence is very uncertain for body mass indexI. Myo-inositol likely causes fewer gastrointestinal adverse events compared with metformin; however, these are typically mild and self-limited.
CONCLUSION
The evidence supporting the use of inositol in the management of PCOS is limited and inconclusive. Clinicians and their patients should consider the uncertainty of the evidence together with individual values and preferences when engaging in shared decision-making regarding the use of inositol for PCOS.
Topics: Polycystic Ovary Syndrome; Humans; Inositol; Female; Practice Guidelines as Topic; Insulin Resistance; Evidence-Based Medicine
PubMed: 38163998
DOI: 10.1210/clinem/dgad762