Gastrointestinal adverse events of metformin treatment in patients with type 2 diabetes mellitus:A systematic review, meta-analysis and meta-regression of randomized controlled trials

INTRODUCTION: Metformin is the first choice drug in the treatment of type 2 diabetes mellitus but its administration may be linked to gastrointestinal adverse events limiting its use. OBJECTIVES: The objective of this systematic review and meta-analysis was to assess the risk of gastrointestinal adverse events related to metformin use in patients with type 2 diabetes treated with metformin. METHODS: PUB MED/CINAHL/Web of Science/Scopus were searched from database inception until 08.11.2020 for articles in English and randomized controlled trials related to patients with type 2 diabetes treated with metformin were included. RESULTS: From 5315 publications, we identified 199 potentially eligible full-text articles. Finally, 71 randomized controlled trials were included in the meta-analysis. In these studies, metformin use was associated with higher risk of abdominal pain, diarrhea and nausea comparing to control. The risks of abdominal pain and nausea were highest comparing to placebo. Bloating risk was only elevated when metformin treatment was compared to DPP4i. CONCLUSIONS: The risk of gastrointestinal adverse events such as abdominal pain, nausea and diarrhea is higher in type 2 diabetes patients treated with metformin compared to other antidiabetic drugs. There is a higher risk of bloating and diarrhea with metformin immediate-release than with metformin extended release formulation. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021289975, identifier CRD42021289975

Low Quantitative Blush Evaluator score predicts larger infarct size and reduced left ventricular systolic function in patients with STEMI regardless of diabetes status

Type 2 diabetes mellitus (T2DM) and diminished myocardial perfusion increase the risk of heart failure (HF) and/or all-cause mortality during 6-year follow up following primary percutaneous coronary intervention (pPCI) for ST elevation myocardial infarction (STEMI). The aim of the present study was to evaluate the impact of myocardial perfusion on infarct size and left ventricular ejection fraction (LVEF) in patients with T2DM and STEMI treated with pPCI. This is an ancillary analysis of an observational cohort study of T2DM patients with STEMI. We enrolled 406 patients with STEMI, including 104 with T2DM. Myocardial perfusion was assessed with the Quantitative Myocardial Blush Evaluator (QUBE) and infarct size with the creatine kinase myocardial band (CK-MB) maximal activity and troponin area under the curve. LVEF was measured with biplane echocardiography using Simpson's method at admission and hospital discharge. Analysis of covariance was used for modeling the association between myocardial perfusion, infarct size and left ventricular systolic function. Patients with T2DM and diminished perfusion (QUBE below median) had the highest CK-MB maximal activity (252.7 ± 307.2 IU/L, P < 0.01) along with the lowest LVEF (40.6 ± 10.0, P < 0.001). Older age (p = 0.001), QuBE below median (p = 0.026), and maximal CK-MB activity (p < 0.001) were independent predictors of LVEF. Diminished myocardial perfusion assessed by QuBE predicts significantly larger enzymatic infarct size and lower LVEF among patients with STEMI treated with pPCI, regardless of diabetes status

The influence of SGLT2 inhibitors on oxidative stress in heart failure and chronic kidney disease in patients with type 2 diabetes

There is increasing interest in sodium-glucose cotransporter 2 inhibitors (SGLT2i) as not only a new oral glucose-lowering drug class but also one with cardio- and nephroprotective potential. Understanding the underlying mechanisms is therefore of great interest, and postulated benefits have included increased natriuresis, lower blood pressure, increased haematocrit, enhanced cardiac fatty acid utilization, reduced low-grade inflammation, and decreased oxidative stress. In particular, redox homeostasis seems to be crucial in the pathogenesis of heart and kidney disease in diabetes, and there is accumulating evidence that SGLT2i have beneficial effects in this perspective. In this review, we aimed to summarize the potential mechanisms of the influence of SGLT2i on oxidative stress parameters in animal and human studies, with a special focus on heart failure and chronic kidney disease in diabetes mellitus

Machine learning profiles of cardiovascular risk in patients with diabetes mellitus: the Silesia Diabetes-Heart Project

AimsAs cardiovascular disease (CVD) is a leading cause of death for patients with diabetes mellitus (DM), we aimed to find important factors that predict cardiovascular (CV) risk using a machine learning (ML) approach.Methods and resultsWe performed a single center, observational study in a cohort of 238 DM patients (mean age ± SD 52.15 ± 17.27 years, 54% female) as a part of the Silesia Diabetes-Heart Project. Having gathered patients' medical history, demographic data, laboratory test results, results from the Michigan Neuropathy Screening Instrument (assessing diabetic peripheral neuropathy) and Ewing's battery examination (determining the presence of cardiovascular autonomic neuropathy), we managed use a ML approach to predict the occurrence of overt CVD on the basis of five most discriminative predictors with the area under the receiver operating characteristic curve of 0.86 (95% CI 0.80-0.91). Those features included the presence of past or current foot ulceration, age, the treatment with beta-blocker (BB) and angiotensin converting enzyme inhibitor (ACEi). On the basis of the aforementioned parameters, unsupervised clustering identified different CV risk groups. The highest CV risk was determined for the eldest patients treated in large extent with ACEi but not BB and having current foot ulceration, and for slightly younger individuals treated extensively with both above-mentioned drugs, with relatively small percentage of diabetic ulceration.ConclusionsUsing a ML approach in a prospective cohort of patients with DM, we identified important factors that predicted CV risk. If a patient was treated with ACEi or BB, is older and has/had a foot ulcer, this strongly predicts that he/she is at high risk of having overt CVD

Metabolically "extremely unhealthy" obese and non-obese people with diabetes and the risk of cardiovascular adverse events: the Silesia Diabetes - Heart Project.

BackgroundThere is a growing burden of non-obese people with diabetes mellitus (DM). However, their cardiovascular risk (CV), especially in the presence of cardiovascular-kidney-metabolic (CKM) comorbidities is poorly characterised. The aim of this study was to analyse the risk of major CV adverse events in people with DM according to the presence of obesity and comorbidities (hypertension, chronic kidney disease, and dyslipidaemia).MethodsWe analysed persons who were enrolled in the prospective Silesia Diabetes Heart Project (NCT05626413). Individuals were divided into 6 categories according to the presence of different clinical risk factors (obesity and CKM comorbidities): (i) Group 1: non-obese with 0 CKM comorbidities; (ii) Group 2: non-obese with 1-2 CKM comorbidities; (iii) Group 3: non-obese with 3 CKM comorbidities (non-obese "extremely unhealthy"); (iv) Group 4: obese with 0 CKM comorbidities; (v) Group 5: obese with 1-2 CKM comorbidities; and (vi) Group 6: obese with 3 CKM comorbidities (obese "extremely unhealthy"). The primary outcome was a composite of CV death, myocardial infarction (MI), new onset of heart failure (HF), and ischemic stroke.Results2105 people with DM were included [median age 60 (IQR 45-70), 48.8% females]. Both Group 1 and Group 6 were associated with a higher risk of events of the primary composite outcome (aHR 4.50, 95% CI 1.20-16.88; and aHR 3.78, 95% CI 1.06-13.47, respectively). On interaction analysis, in "extremely unhealthy" persons the impact of CKM comorbidities in determining the risk of adverse events was consistent in obese and non-obese ones (Pint=0.824), but more pronounced in individuals aged int= 0.028).ConclusionBoth non-obese and obese people with DM and 3 associated CKM comorbidities represent an "extremely unhealthy" phenotype which are at the highest risk of CV adverse events. These results highlight the importance of risk stratification of people with DM for risk factor management utilising an interdisciplinary approach

Prognostic Impact and Prevalence of Cachexia in Patients With Heart Failure: A Systematic Review and Meta-Analysis.

BackgroundCachexia, defined as the combination of weight loss, weakness, fatigue, anorexia and abnormal biochemical markers based on Evans' criteria, is known to exacerbate the prognosis of heart failure (HF) patients. This systematic review and meta-analysis investigates the prognostic impact and prevalence of cachexia, as defined by Evans' criteria, in patients with HF.MethodsPubMed, Cochrane Library, Scopus and Web of Science were searched from inception until December 2023, including HF patients for whom the Evans' criteria were applied to explore the prevalence and prognostic impact of cachexia. This study employed a meta-analyses using the random-effects model and inverse-variance method that was adhered to the revised 2020 PRISMA guidelines for systematic reviews and meta-analyses (CRD42023446443).ResultsSix prospective or retrospective studies of 2252 patients with HF were included, whereby all-cause mortality was significantly greater in patients with cachexia with low heterogeneity among studies (HR: 1.60, 95% CI 1.31-1.95, p 2 = 0%). For the studies that used full, uniformly defined Evans' criteria, among 1844 patients, mortality remained greater in patients with cachexia (HR: 1.58, 95% CI 1.27-1.97, p 2 = 0%). In a subgroup analysis among 1714 of HF with reduced ejection fraction, the results were consistent (HR: 1.57, 95% CI 1.28-1.92, p 2 = 0%). Additionally, 10 studies comprising 2862 patients indicated a 31% risk of cachexia in HF (95% CI 21-43%, I2 = 94%).ConclusionsCachexia is an independent predictor for increased all-cause mortality among patients with HF with a notable prevalence of 31%. Interventions aiding in improving fatigue, anorexia and exercise capacity could help improve the quality of life of this clinical population

Metabolically 'extremely unhealthy' obese and non-obese patients with diabetes and the risk of cardiovascular events: a French nationwide cohort study.

BackgroundNon-obese patients with diabetes mellitus (DM) are becoming more prevalent, but their cardiovascular risk (CV) especially when accompanied with cardio-renal-metabolic co-morbidities (hypertension, chronic kidney disease, hyperlipidemia) is not well characterised. The aim of the study was to assess the CV risk among patients with DM in relation to obesity and cardio-renal-metabolic co-morbidities.Materials and methodsThis was a cohort study of all patients with DM without a history of major adverse cardiovascular event who were hospitalized for any reason in France in 2013 with at least 5 years of follow-up. They were categorized by the presence of obesity vs no obesity, as well as three cardio-renal-metabolic co-morbidities: hypertension, chronic kidney disease, hyperlipidemia. 'Extremely unhealthy' patients with DM were defined as those having all 3 co-morbidities.ResultsThere were 196,112 patients (mean age 65.7 (SD 13.7) years; 54.3% males) included into the analysis. During a mean follow-up of 4.69 ± 1.79 years, when adjusted for multiple covariates, the non-obese and 'extremely unhealthy' obese patients had the highest risk of CV death [aHR 1.40 (95% CI, 1.22-1.61) and 1.48 (95% CI, 1.25-1.75), respectively]. The 'extremely unhealthy' obese had the highest risk of MACE-HF [aHR 1.84 (95% CI, 1.72-1.97)] and new-onset AF [aHR 1.64 (95% CI, 1.47-1.83)].ConclusionBoth non-obese and obese patients with DM with associated cardio-renal-metabolic co-morbidities are an 'extremely unhealthy' phenotype with the highest risk of CV death and CV events

Natriuretic peptides and C-reactive protein in in heart failure and malnutrition: a systematic review and meta-analysis.

BackgroundHeart failure (HF) and malnutrition exhibit overlapping risk factors, characterized by increased levels of natriuretic peptides and an inflammatory profile. The aim of this study was to compare the differences in plasma brain natriuretic peptide (BNP), N-terminal-pro B-type natriuretic peptide (NT-proBNP), and C-reactive protein (CRP) in patients with HF and malnutrition versus normal nutrition.MethodsFrom inception until July 2023, the databases, PubMed, Scopus, Web of Science, and Cochrane Library were searched. To examine the association among malnutrition [controlling nutritional status (CONUT) score ≥2; Geriatric Nutritional Risk Index (GNRI) score ResultsA significant association of GNRI with increased levels of BNP were demonstrated [mean difference (MD): 204.99, 95% confidence interval (CI) (101.02, 308.96, I2 = 88%, P 2 = 92%, P = 0.05)]. GNRI [MD: 1885.14, 95% CI (1428.76-2341.52, I2 = 0%, P 2 = 0%, P 2 = 87%, P = 0.01)] whereas significantly higher levels of CRP were observed in those with higher CONUT [MD: 0.40, 95% CI (0.08-0.72, I2 = 88%, P = 0.01)]. Employing meta-regression, age was deemed a potential moderator between CRP and GNRI.ConclusionsNormal nutrition scores in patients with HF are linked to lower BNP, NT-proBNP, and CRP levels compared with malnourished counterparts. Despite the significant link between CRP and malnutrition, their relationship may be influenced in older groups considering the sensitivity of GNRI due to ageing factors

Association between natriuretic peptides and C-reactive protein with frailty in heart failure: a systematic review and meta-analysis.

BackgroundHeart failure (HF) and frailty are accompanied by a bidirectional relationship, sharing common risk factors including elevated levels of natriuretic peptides and inflammation. The aim of this study was to compare biomarkers associated with poor clinical outcomes, that is, plasma brain natriuretic peptide (BNP), N-terminal-pro B-type natriuretic peptide (NT-proBNP), and C-reactive protein (CRP) in patients with HF and frailty vs. patients with HF without frailty.MethodsFrom inception until July 2023, PubMed, Scopus, Web of Science, and Cochrane Library a systematic literature search was conducted. To evaluate whether frailty is linked with greater levels of BNP, NT-proBNP, and CRP, a meta-analysis using a random-effects model was used to calculate the pooled effects (CRD42023446607).ResultsFifty-three studies were included in this systematic review and meta-analysis. Patients with HF and frailty displayed significantly higher levels of BNP (k = 11; SMD: 0.53, 95%CI 0.30-0.76, I2 = 86%, P 2 = 72%, P 2 = 62%, P ConclusionsFrailty in HF is linked to increased concentrations of BNP, NT-proBNP, and CRP, which have been epidemiologically associated with adverse outcomes. The increased risk of NYHA III/IV classification further emphasizes the clinical impact of frailty in this population