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Efficacy and safety of a sodium-glucose co-transporter-2 inhibitor versus placebo as an add-on therapy for people with type 2 diabetes inadequately treated with metformin and a dipeptidyl peptidase-4 inhibitor: a systematic review and meta-analysis of randomised controlled trials.
De Buitléir, C, O' Connor, E, Satti, MM, Shaw, J, Liew, A
Diabetic medicine : a journal of the British Diabetic Association. 2021;(2):e14409
Abstract
AIMS: To conduct a systematic review and meta-analysis to assess the efficacy, safety and tolerability of sodium-glucose co-transporter-2 inhibitors vs placebo as add-on therapy after metformin and dipeptidyl peptidase-4 inhibitor dual therapy in type 2 diabetes. METHODS This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO registration number: CRD42018099398). A search was conducted via PubMed, www.clinicaltrials.gov and Cochrane Central Register of Controlled Trials of relevant randomised controlled trials up until 14 August 2020 that compared sodium-glucose co-transporter-2 inhibitors vs placebo as add-on therapy after metformin and dipeptidyl peptidase-4 inhibitor therapy. A random-effects model was used. RESULTS Six randomised controlled trials (1661 participants) met the inclusion criteria. Compared with placebo, sodium-glucose co-transporter-2 inhibitor treatment, as add-on to metformin and dipeptidyl peptidase-4 inhibitor therapy, was associated with a significant reduction in HbA1c level [mean difference -8 mmol/mol, 95% CI -10, -6 (-0.7%, 95% CI -0.9, -0.6); P < 0.00001], in fasting plasma glucose level [mean difference -1.70 mmol/l, 95% CI -1.91, -1.49; P < 0.00001], in weight (mean difference -1.76 kg, 95% CI -2.04, -1.48; P < 0.00001) and in blood pressure (systolic blood pressure: mean difference -3.6 mmHg, 95% CI -4.8, -2.4; P < 0.00001; diastolic blood pressure: mean difference -1.5 mmHg; 95% CI -2.4, -0.6; P = 0.002). Genital mycotic infections (odds ratio 7.37, 95% CI 3.06, 17.76; P < 0.00001) were more common with sodium-glucose co-transporter-2 inhibitors, but there was no significant statistical difference in urinary tract infections (odds ratio 1.16, 95% CI 0.63, 2.13; P = 0.64), in hypoglycaemia (odds ratio 1.36, 95% CI 0.61, 3.04; P = 0.45), or in discontinuation rates due to adverse events (odds ratio 1.52, 95% CI 0.78, 2.97; P = 0.22) between the two groups. CONCLUSIONS In comparison with placebo, add-on therapy with a sodium-glucose co-transporter-2 inhibitor is significantly more efficacious in lowering HbA1c , fasting plasma glucose and weight in people with type 2 diabetes following inadequate glycaemic control with metformin and a dipeptidyl peptidase-4 inhibitor. The rate of discontinuation due to adverse events was similar despite higher risk of genital mycotic infections.
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Risk of Skin Cancer Associated with Metformin Use: A Meta-Analysis of Randomized Controlled Trials and Observational Studies.
Chang, MS, Hartman, RI, Xue, J, Giovannucci, EL, Nan, H, Yang, K
Cancer prevention research (Philadelphia, Pa.). 2021;(1):77-84
Abstract
Previous studies demonstrate mixed evidence regarding the association between metformin and skin cancer risk. To synthesize prior evidence and evaluate the association between metformin and skin cancer risk in patients with diabetes/prediabetes, we conducted a meta-analysis. A systematic literature search was performed up to March 23, 2020 to identify randomized controlled trials (RCT) and observational studies of metformin that reported any event of squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma. In a meta-analysis of 6 trials involving 8,541 patients (Peto method), compared with controls, metformin was not significantly associated with decreased risk of melanoma [OR, 0.82; 95% confidence interval (CI), 0.27-2.43], BCC (OR, 0.75; 95% CI, 0.36-1.57), SCC (OR, 0.98; 95% CI, 0.06-15.60), total nonmelanoma skin cancer (NMSC; OR, 0.69; 95% CI, 0.38-1.24), or total skin cancer (OR, 0.71; 95% CI, 0.42-1.20). This nonsignificant association pattern was consistent with the random-effects meta-analysis of 4 cohort studies with 354,746 patients (melanoma: RR, 0.91; 95% CI, 0.62-1.33; NMSC RR, 0.65; 95% CI, 0.35-1.18; total skin cancer: RR, 0.83; 95% CI, 0.59-1.16). In conclusion, meta-analyses of both RCT and cohort studies showed no statistically significant association between metformin and skin cancer risks, although suggestive evidence of modestly reduced risks of skin cancer among metformin users was observed. Further studies are needed. PREVENTION RELEVANCE Meta-analyses of RCT and cohort studies showed no significant association between metformin and skin cancer, although suggestive evidence of modestly reduced skin cancer risks among metformin users was observed. These findings suggest metformin use should not influence current medical decision making for diabetes patients at risk of developing skin cancer.
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The effects of myo-inositol vs. metformin on the ovarian function in the polycystic ovary syndrome: a systematic review and meta-analysis.
Azizi Kutenaei, M, Hosseini Teshnizi, S, Ghaemmaghami, P, Eini, F, Roozbeh, N
European review for medical and pharmacological sciences. 2021;(7):3105-3115
Abstract
OBJECTIVE Recent studies have revealed that myo-inositol could be more influential in patients with polycystic ovary syndrome (PCOS). This study was aimed to determine and compare the effects of myo-inositol and metformin on hormonal and metabolic profiles and fertility outcomes. MATERIALS AND METHODS A comprehensive search was carried out among the English-language databases, including PubMed, Scopus, Cochrane Library, Google Scholar, and Web of Science, and the articles published from April 2010 to February 2019 were tracked down. The fixed and random-effects meta-analysis was used to estimate the pooled effect size. The meta-analysis was performed in Stata Version 14.0. RESULTS Nine studies with 331 patients treated with metformin and 307 patients treated with myo-inositol groups were included in the analysis. The research groups did not diverge significantly in terms of the basic characteristics, such as age and Body Mass Index (BMI). In the myo-inositol group, the levels of Luteinizing Hormone (LH) [12.55% (95% I: 11.41-13.68%)], S. testosterone [44.38% (95% CI: 38.09-50.67%)] and prolactin [7.97% (95% CI: 6.58- 9.37%)] were significantly higher than those recorded, i.e., LH [7.97% (95% CI: 6.58- 9.37%)], S. testosterone [8.48% (95% CI: 3.14-13.83%)] and prolactin [7.14% (95% CI: 1.50-14.79%)] for the metformin group (p<0.001). CONCLUSIONS Due to the dearth of related research and the high heterogeneity of the Randomized Clinical Trials (RCTs) included in other studies, the present systematic review could not establish any differences between metformin and myo-inositol concerning the hormonal profile and the ovarian function. However, the findings indicated that myo-inositol could improve fertility outcomes by modulating hyperandrogenism. Randomized trials are required to understand the mechanistic actions of myo-inositol in comparison with those of metformin regarding oocyte and embryo quality, fertilization, pregnancy, and live birth rates.
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Association of Metformin Use with Asthma Exacerbation in Patients with Concurrent Asthma and Diabetes: A Systematic Review and Meta-Analysis of Observational Studies.
Wen, L, Zhong, W, Chai, Y, Zhong, Q, Gao, J, Guan, L, Zhang Mengzhi, , Huaiquan, L, Haiyang, Y, Qingxue, W, et al
Canadian respiratory journal. 2020;:9705604
Abstract
BACKGROUND Asthma and diabetes are both diseases that affect a wide range of people worldwide. As a common treatment for diabetes, metformin has also been reported to be effective in improving asthma outcomes. We conducted a combined analysis to examine the efficacy of metformin in reducing asthma exacerbation in patients with concurrent asthma and diabetes. METHODS We searched the PubMed, Embase, and CENTRAL databases for articles published prior to April 2020 to find observational studies of individuals with concurrent asthma and diabetes that compared the risk of asthma exacerbation between metformin users and nonusers. Two researchers separately screened the studies, extracted data, and evaluated the risk of bias. The primary outcome was the adjusted risk of asthma exacerbation. The secondary outcomes were the adjusted risk of asthma-related hospitalization and emergency room visits. Review Manager was used for data analysis and plotting. I 2 and χ 2 tests were used to estimate heterogeneity. A random effects or fixed effects model was used depending on the heterogeneity. Odds ratios were calculated for dichotomous variables. RESULTS We included two studies with a total of 25252 patients. The pooled effect size showed that metformin was inversely associated with a risk of asthma exacerbation (OR = 0.65, 95% CI 0.28-1.48; χ 2 = 5.42, P=0.02; I 2 = 82%), asthma-related emergency department visits (OR = 0.81, 95% CI 0.74-0.89; χ 2 = 0.36, P=0.55; I 2 = 0%), and hospitalizations (OR = 0.43, 95% CI 0.14-1.29; χ 2 = 4.01, P=0.05; I 2 = 75%). CONCLUSION This meta-analysis suggested that metformin decreased the risk of asthma-related emergency room visits for patients with concurrent asthma and diabetes. Metformin reduced the risk of asthma-related hospitalization and exacerbation but was not statistically significant. More randomized trials involving larger samples should be considered, and the mechanisms of these effects need to be fully elucidated.
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[Relative frequency of urinary tract infections in patients affected by diabetes mellitus type 2 treated with metformin and SGLT2 inhibitor. Network meta-analysis].
Merész, G, Szabó, S, Dóczy, V, Hölgyesi, Á, Szakács, Z
Orvosi hetilap. 2020;(13):491-501
Abstract
Introduction and aim: The of this research was to conduct a network meta-analysis based on a systematic literature search to compare the relative frequency of urinary tract infections using sodium-glucose cotransporter-2 (SGLT2) inhibitors combined with metformin in the therapy of type 2 diabetes. Method: MEDLINE and EMBASE databases were searched to identify publications of randomized, controlled trials investigating SGLT2 inhibitors combined with metformin in the therapy of type 2 diabetes and providing information on the frequency of urinary tract infections. Results: 10 165 unique citations were screened to identify 10 publications to be included in the network meta-analysis. The network meta-analysis showed reduced risk of urinary tract infections for low-dose ertugliflozin compared to other SGLT2 inhibitors (ertugliflozin 5 mg vs. empagliflozin 10 mg: RR: 0.606, 95% CrI: 0.264-1.415; ertugliflozin 5 mg vs. dapagliflozin 10 mg: RR = 0.853, 95% CrI: 0.301-2.285). For high-dose comparisons, empagliflozin 25 mg showed reduced risk of urinary tract infections compared to both ertugliflozin 15 mg (RR = 0.745, 95% CrI 0.330-1.610) and dapagliflozin 10 mg (RR = 0.680, 95% CrI: 0.337-1.289). The difference between active substances and their doses was not statistically significant for the relative frequency of urinary tract infections. The meta-regression revealed a statistically significant association between baseline fasting plasma glucose level and relative frequency of urinary tract infections (β = 0.785, 95% CrI: 0.062-1.587). Conclusion: There was no statistically significant difference between SGLT2 inhibitors investigated in this study in terms of the relative frequency of urinary tract infections. This research demonstrates the applicability of network meta-analyses when assessing the relative effectiveness and safety of interventions. Orv Hetil. 2020; 161(13): 491-501.
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Comparison of the efficacy between NAC and metformin in treating PCOS patients: a meta-analysis.
Song, Y, Wang, H, Huang, H, Zhu, Z
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2020;(3):204-210
Abstract
Our aim is to evaluate the clinical effectiveness and safety by comparing N-acetyl-cysteine (NAC) with metformin administrated by polycystic ovary syndrome (PCOS) patients. Systematic review and meta-analysis of randomized clinical trials (RCTs). MEDLINE, EMBASE, Web of Science and China National Knowledge Infrastructure were searched for studies. 10 studies were considered eligible for inclusion. NAC significantly reduced BMI and total testosterone, there was no significant difference in pregnancy rate, serum LH level, fasting insulin, and LH/FSH ratio. In conclusions, NAC may be considered as an alternative supplement to metformin, but large-scale randomized controlled trials are needed to assess the efficacy and safety of NAC in PCOS patients.
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Metformin Therapy Reduces Obesity Indices in Children and Adolescents: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
Sadeghi, A, Mousavi, SM, Mokhtari, T, Parohan, M, Milajerdi, A
Childhood obesity (Print). 2020;(3):174-191
Abstract
Purpose: Few studies have summarized findings for the effect of metformin on obesity indices. Therefore, we aimed to conduct a systematic review and meta-analysis on the effect of metformin on obesity indices among children and adolescents. Methods: Relevant articles published up to September 2018 were searched in SCOPUS, Medline, and Google Scholar using appropriate keywords. All clinical trials that examined the effect of metformin on obesity indices in children and adolescents were included. Results: Overall, 38 studies, including 2199 participants (39.75% male and 60.25% female), were included. The pooled results indicated that metformin significantly reduced BMI [weighted mean difference (WMD): -1.07 kg/m2; 95% confidence interval (CI): -1.43 to -0.72]. Same findings were found for waist circumference (WC) (WMD: -1.93 cm; 95% CI: -2.69 to -1.16). Metformin also reduced body weight in all participants (WMD: -2.51 kg; 95% CI: -3.14 to -1.89). Moreover, it reduced body fat mass in patients with overweight or obesity (WMD: -1.90%; 95% CI: -3.25 to -0.56) and chronic diseases (WMD: -1.41%; 95% CI: -2.23 to -0.58), but not among those with growth problems. Metformin therapy did not affect lean body mass (LBM) in patients with overweight or obesity and growth problems; however, it reduced LBM in patients with chronic diseases (WMD: -1.49 kg; 95% CI: -2.69 to -0.30). Conclusions: We found a significant reduction in BMI, body weight, WC, and fat mass following administration with metformin. However, the effect of metformin on LBM was not significant. Further studies are required to confirm these findings.
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Efficacy of Once-Weekly Semaglutide vs Empagliflozin Added to Metformin in Type 2 Diabetes: Patient-Level Meta-analysis.
Lingvay, I, Capehorn, MS, Catarig, AM, Johansen, P, Lawson, J, Sandberg, A, Shaw, R, Paine, A
The Journal of clinical endocrinology and metabolism. 2020;(12):e4593-604
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Abstract
CONTEXT No head-to-head trials have directly compared once-weekly (OW) semaglutide, a human glucagon-like peptide-1 analog, with empagliflozin, a sodium-glucose co-transporter-2 inhibitor, in type 2 diabetes (T2D). OBJECTIVE We indirectly compared the efficacy of OW semaglutide 1 mg vs once-daily (OD) empagliflozin 25 mg in patients with T2D inadequately controlled on metformin monotherapy, using individual patient data (IPD) and meta-regression methodology. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS IPD for patients with T2D receiving metformin monotherapy and randomized to OW semaglutide 1 mg (SUSTAIN 2, 3, 8 trials), or to OD empagliflozin 25 mg (PIONEER 2 trial) were included. Meta-regression analyses were adjusted for potential prognostic factors and effect modifiers. MAIN OUTCOME MEASURES The primary efficacy outcomes were change from baseline to end-of-treatment (~1 year) in HbA1c (%-point) and body weight (kg). Responder outcomes and other clinically relevant efficacy measures were analyzed. RESULTS Baseline characteristics were similar between OW semaglutide (n = 995) and empagliflozin (n = 410). Our analyses showed that OW semaglutide significantly reduced mean HbA1c and body weight vs empagliflozin (estimated treatment difference: -0.61%-point [95% confidence interval (CI): -0.72; -0.49] and -1.65 kg [95% CI: -2.22; -1.08], respectively; both P < 0.0001). Complementary analyses supported the robustness of these results. A significantly greater proportion of patients on OW semaglutide vs empagliflozin also achieved HbA1c targets and weight-loss responses. CONCLUSIONS This indirect comparison suggests that OW semaglutide 1 mg provides superior reductions in HbA1c and body weight vs OD empagliflozin 25 mg in patients with T2D when added to metformin monotherapy.
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The effect of metformin on biomarkers associated with breast cancer outcomes: a systematic review, meta-analysis, and dose-response of randomized clinical trials.
Rahmani, J, Manzari, N, Thompson, J, Gudi, SK, Chhabra, M, Naik, G, Mousavi, SM, Varkaneh, HK, Clark, C, Zhang, Y
Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 2020;(1):37-49
Abstract
PURPOSE Breast cancer is a leading cause of cancer mortality in developed countries. We performed a meta-analysis of randomized clinical trials to investigate the effect of metformin on biomarkers associated with breast cancer outcomes and to explore the dose-response relationship. METHODS A systematic search was performed from onset of the database to January 2019 in MEDLINE/PubMed, SCOPUS, and Cochrane library to identify randomized clinical trials investigating the impact of metformin on insulin, glucose, CRP, leptin, body mass indices (BMI), cholesterol, Ki-67, and Homeostatic Model Assessment for Insulin-Resistance (HOMA-IR). Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence intervals (CI) using a random-effects models. RESULTS Nine studies providing 1,363 participants were included in the meta-analysis. Pooled results showed a significant reduction in insulin (WMD: - 0.99 U/ml, 95% CI - 1.66, - 0.33), glucose (WMD: - 1.78 ml/dl, 95% CI - 2.96, - 0.60), CRP (WMD: - 0.60 mg/l, 95% CI - 0.88, - 0.33), HOMA-IR (WMD: - 0.45, 95% CI - 0.77, - 0.11), leptin (WMD: - 2.44 ng/ml, 95% CI - 3.28, - 1.61), BMI (WMD: - 0.55 kg/m2, 95% CI - 1.00, - 0.11), and Ki-67 (WMD: - 4.06, 95% CI - 7.59, - 0.54). Results of the subgroup analyses showed that insulin, glucose, and BMI decreased more significantly when the duration of administering metformin intervention was above 4 weeks. We did not observe non-linear changes in the dose-response relationship between metformin and biomarkers as outcomes. CONCLUSIONS Breast cancer patients receiving metformin as treatment for diabetes showed significant reduction in levels of insulin, fasting glucose, CRP, HOMA, leptin, BMI, and Ki-67.
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Vascular and metabolic effects of metformin added to insulin therapy in patients with type 1 diabetes: A systematic review and meta-analysis.
Liu, YS, Chen, CN, Chen, ZG, Peng, Y, Lin, XP, Xu, LL
Diabetes/metabolism research and reviews. 2020;(6):e3334
Abstract
BACKGROUND The incidence of type 1 diabetes mellitus (T1DM) is increasing among youth worldwide, translating to an increased risk ofearly-onset cardiovascular disease (CVD). Mounting studies have shown that metformin may reduce maximal carotidintima-media thickness (cIMT), improve insulin resistance and metabolic control in subjects with T1DM, and thus, may extend cardioprotective benefits. This systematic review and meta-analysis was performed to assess the efficacy and safety of metformin added to insulin therapy on reducing CVD risks and improving metabolism in T1DM. METHODS PubMed, EMBASE, and the Cochrane Library were systematically searched for randomized controlled trials (RCTs) that compared metformin and insulin combination (duration ≥3 months) to insulin treatment alone in T1DM. Data were expressed as weighted/standardized mean differences (MDs/SMDs) for continuous outcomes and risk ratios (RRs) for dichotomous outcomes, along with 95% confidence intervals (CIs). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to evaluate the overall certainty of the evidence. RESULTS Nineteen RCTs (n = 1540) met the eligibility criteria. Metformin treatment significantly reduced carotid artery intima-media thickness (MD -0.06 mm [95% CI -0.88, -0.28], P < .001). Though no significant difference was found in insulin sensitivity (SMD 2.21 [95% CI -1.88, 6.29], P = .29), the total daily insulin dosage (SMD -0.81 [95% CI -1.25, -0.36], P < .001) along with traditional CVD risk factors showed improvement by better glycaemic control, partial lipid profiles, diastolic blood pressure, and limited weight gain, with neutral effect on diabetic ketoacidosis, lactic acidosis, and hypoglycaemia. However, metformin therapy increased the incidence of gastrointestinal adverse events. CONCLUSIONS Metformin with insulin has the potential to retard the progression of atherosclerosis and provides better metabolic control in patients with T1DM, and thus, providing a potential therapeutic strategy for patients with T1DM on reducing CVD risks.