Metformin and health outcomes: An umbrella review of systematic reviews with meta-analyses.

BACKGROUND: The objective was to capture the breadth of outcomes that have been associated with metformin use and to systematically assess the quality, strength and credibility of these associations using the umbrella review methodology. METHODS: Four major databases were searched until 31 May 2020. Meta-analyses of observational studies and meta-analyses of randomized controlled trials (RCTs) (including active and placebo control arms) were included. RESULTS: From 175 eligible publications, we identified 427 different meta-analyses, including 167 meta-analyses of observational studies, 147 meta-analyses of RCTs for metformin vs placebo/no treatment and 113 meta-analyses of RCTs for metformin vs active medications. There was no association classified as convincing or highly suggestive from meta-analyses of observational studies, but some suggestive/weak associations of metformin use with a lower mortality risk of CVD and cancer. In meta-analyses of RCTs, metformin was associated with a lower incidence of diabetes in people with prediabetes or no diabetes at baseline; lower ovarian hyperstimulation syndrome incidence (in women in controlled ovarian stimulation); higher success for clinical pregnancy rate in poly-cystic ovary syndrome (PCOS); and significant reduction in body mass index in people with type 1 diabetes mellitus, in women who have obesity/overweight with PCOS and in obese/overweight women. Of 175 publications, 166 scored as low or critically low quality per AMSTAR 2 criteria. CONCLUSIONS: Observational evidence on metformin seems largely unreliable. Randomized evidence shows benefits for preventing diabetes and in some gynaecological and obstetrical settings. However, almost all meta-analyses are of low or critically low quality according to AMSTAR 2 criteria.

Effect of low-dose aspirin on health outcomes: An umbrella review of systematic reviews and meta-analyses.

AIMS: This study aimed to use an umbrella review methodology to capture the range of outcomes that were associated with low-dose aspirin and to systematically assess the credibility of this evidence. METHODS: Aspirin is associated with several health outcomes, but the overall benefit/risk balance related to aspirin use is unclear. We searched three major databases up to 15 August 2019 for meta-analyses of observational studies and randomized controlled trials (RCTs) including low-dose aspirin compared to placebo or other treatments. Based on random-effects summary effect sizes, 95% prediction intervals, heterogeneity, small-study effects and excess significance, significant meta-analyses of observational studies were classified from convincing (class I) to weak (class IV). For meta-analyses of RCTs, outcomes with random effects P-value < .005 and a moderate/high GRADE assessment, were classified as strong evidence. From 6802 hits, 67 meta-analyses (156 outcomes) were eligible. RESULTS: Observational data showed highly suggestive evidence for aspirin use and increased risk of upper gastrointestinal bleeding (RR = 2.28, 95% CI: 1.97-2.64). In RCTs of low-dose aspirin, we observed strong evidence for lower risk of CVD in people without CVD (RR = 0.83; 95% CI: 0.79-0.87) and in general population (RR = 0.83; 95% CI: 0.79-0.89), higher risk of major gastrointestinal (RR = 1.47; 95% CI: 1.26-1.72) and intracranial bleeding (RR = 1.34; 95% CI: 1.18-1.53), and of major bleedings in people without CVD (RR = 1.62; 95% CI: 1.26-2.08). CONCLUSION: Compared to other active medications, low-dose aspirin had strong evidence for lower risk of bleeding, but also lower comparative efficacy. Low-dose aspirin significantly lowers CVD risk and increases risk of bleeding. Evidence for multiple other health outcomes is limited.

Magnesium and health outcomes: an umbrella review of systematic reviews and meta-analyses of observational and intervention studies.

PURPOSE: To map and grade all health outcomes associated with magnesium (Mg) intake and supplementation using an umbrella review. METHODS: Umbrella review of systematic reviews with meta-analyses of observational studies and randomized controlled trials (RCTs) using placebo/no intervention as control group. We assessed meta-analyses of observational studies based on random-effect summary effect sizes and their p values, 95% prediction intervals, heterogeneity, small-study effects and excess significance. For meta-analyses of RCTs, outcomes with a random-effect p value < 0.005 and a high-GRADE assessment were classified as strong evidence. RESULTS: From 2048 abstracts, 16 meta-analyses and 55 independent outcomes were included (36 in RCTs and 19 in observational studies). In RCTs of Mg versus placebo/no active treatment, 12 over 36 outcomes reported significant results (p < 0.05). A strong evidence for decreased need for hospitalization in pregnancy and for decreased risk of frequency and intensity of migraine relapses in people with migraine was observed using the GRADE assessment. In observational studies, 9/19 outcomes were significant (p < 0.05). However, only one outcome presented highly suggestive evidence (lower incidence of type 2 diabetes in people with higher Mg intake at baseline) and one suggestive (lower incidence of stroke associated with higher Mg intake at baseline). CONCLUSION: Strong evidence according to the GRADE suggests that Mg supplementation can decrease the risk of hospitalization in pregnant women and reduce the intensity/frequency of migraine. Higher Mg intake is associated with a decreased risk of type 2 diabetes and stroke with highly suggestive and suggestive evidence, respectively, in observational studies.

The risk stratification in atrial fibrillation.

Atrial fibrillation (AF) is the most common rhythm disorder and represents a major public health problem because it carries an increased risk of arterial thromboembolism and ischemic stroke. Because the absolute benefit of antithrombotic therapy depends on the underlying risk of stroke, an accurate stratification of patients' risk is needed to choose the appropriate antithrombotic strategy. Over the years, several stroke risk stratification models (RSMs) were developed based on the 'classic' risk factors for stroke such as increasing age, hypertension, diabetes mellitus, and left ventricular dysfunction. Among all RSMs, the CHADS(2) score is the most popular and used one thanks to its simplicity and endorsement in several widely promulgated practice guidelines. Despite its validation in large datasets and specific population of AF patients, it has many limitations, especially due to the non-inclusion of several proven risk factors for stroke and to the classification of a large number of patients in the intermediate risk category, so creating ambiguity over the most appropriate antithrombotic therapy. Thus, the CHA(2)DS(2)-VASc score was introduced and was demonstrated to perform better than the CHADS(2), even in a "real world" population of elderly AF patients. Recently, in view of the availability of new oral anticoagulant drugs, that can overcome the limitations of warfarin and allow a more personalized therapy, many efforts are being made to identify other possibilities to assess the thromboembolic risk in AF patients. It has been demonstrated that an increase in C-reactive protein and interleukin-6 and the presence of G20210A factor II gene polymorphism and hyper-homocysteinemia are independent risk factors for ischemic complications in AF patients. Even the presence of chronic renal disease and the daily AF burden, registered with implantable monitors, are associated with an increase risk of stroke. Finally, the assessment of thromboembolic risk should go hand in hand with the consideration of the risk of bleeding. For this purpose, it has been recently developed a practical bleeding risk score, the HAS-BLED, which was included in the last ESC guidelines for the risk stratification of AF patients before starting anticoagulant therapy.

Helicobacter pylori: usefulness of an empirical fourth-line rifabutin-based regimen.

Helicobacter pylori represents the major cause of gastric cancer, gastric lymphoma and peptic ulcer diseases. In some cases, the infection persists even after three rounds of treatment. The evaluated article reports on the efficacy of an empirical multicenter, prospective fourth­line rescue study with rifabutin in patients with three consecutive eradication failures. A total of 100 patients (31% peptic ulcer and 69% functional dyspepsia) were included to receive a fourth­line with rifabutin (150 mg twice daily [b.i.d.]), amoxicillin (1 g b.i.d.) and a proton­pump inhibitor (standard dose b.i.d.) for 10 days. The end point was H. pylori eradication, determined by (13)C-urea breath test 4-8 weeks after therapy. H. pylori eradication was achieved in approximately 50% of patients. Adverse events (mainly metallic taste, nausea and diarrhea) were reported in 30 patients. Thus, a fourth-line rifabutin-based rescue therapy constitutes a valid strategy after multiple previous H. pylori eradication failures with key antibiotics, such as clarithromycin, metronidazole, tetracycline and levofloxacin.