Effect of metformin on all-cause mortality and major adverse cardiovascular events: An updated meta-analysis of randomized controlled trials

Monami, Matteo; Candido, Riccardo; Pintaudi, Basilio; Targher, Giovanni; Mannucci, Edoardo; Monache, Lina Delle; Gallo, Marco; Giaccari, Andrea; Masini, Maria Luisa; Mazzone, Fulvia; Medea, Gerardo; Trento, Marina; Turchetti, Giuseppe

doi:10.1016/j.numecd.2020.11.031

Cited by 34 publications

(28 citation statements)

References 20 publications

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“…Some meta‐analyses questions the CV effects of metformin 70 and suggest that the positive GLP‐1RA CV outcomes are independent of background metformin therapy 71‐73 . In comparison, other meta‐analyses conclude that metformin has CV benefits 74,75 . However, no CVOT has been conducted with GLP‐1RA (or SGLT‐2i) as first‐line therapies, and most organizations/societies recommend using metformin as first‐line therapy in patients with T2D and established or high‐risk of ASCVD 9,76‐79 .…”

Section: The Place For Glp‐1ras In the Standard Of Medical Care In Patients With T2dmentioning

confidence: 99%

Understanding the place for GLP‐1RA therapy: Translating guidelines for treatment of type 2 diabetes into everyday clinical practice and patient selection

Andreasen

Andersen

Knop

et al. 2021

Diabetes Obesity Metabolism

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Since the first glucagon‐like peptide 1 (GLP‐1) receptor agonist (GLP‐1RA) was approved in 2005 (exenatide twice daily) for type 2 diabetes (T2D), the class has developed with newer compounds having more pronounced effects on glycaemic control and body weight. Also, administration regimes have become more convenient with once weekly injections, and recently an oral administration has become available. Large‐scale randomized controlled cardiovascular (CV) outcome trials (CVOTs) have shown that GLP‐1RA therapy can reduce the risk of CV disease (CVD) in high‐risk individuals with T2D. In addition, GLP‐1RAs may have renal benefits driven by new‐onset macroalbuminuria, although no effect on hard renal endpoints has been found. Subsequently, the place for GLP‐1RA therapy has changed over recent years, with most societies endorsing GLP‐1RA therapy in patients with established or high risk of CVD independently of glycaemia. Initiation of GLP‐1RA therapy can be complex due to differences in efficacy, side effects and safety profiles as well as administration forms within the class. Implementing guideline recommendations into ideal patient selection may be challenging both in specialty and non‐specialty settings. To ensure adequate and proactive use of modern glucose‐lowering medications in the treatment of T2D, it is essential to recognize patients with high risk or documented CVD. The present review provides an overview of the efficacy and benefits of the currently available GLP‐1RA compounds. Furthermore, we review the results from recent large‐scale CVOTs in a clinical context and suggest improving the implementation of GLP‐1RA therapy across specialties to improve overall patient selection.

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Section: The Place For Glp‐1ras In the Standard Of Medical Care In Patients With T2dmentioning

confidence: 99%

Understanding the place for GLP‐1RA therapy: Translating guidelines for treatment of type 2 diabetes into everyday clinical practice and patient selection

Andreasen

Andersen

Knop

et al. 2021

Diabetes Obesity Metabolism

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“…SIRT1 also amplifies the activity of Nrf2 while suppressing the activity of NF-kappaB-accounting for the antioxidant and antiinflammatory effects of SIRT1 activators [166][167][168]. SIRT1-mediated enhancement of the activities of KLF2 and of endothelial nitric oxide synthase in vascular endothelium can be expected to promote vascular health [169][170][171][172]. In the liver, SIRT1 activity decreases de novo lipogenesis by suppressing the activity of the transcription factor SREBP-1c, while AMPK up-regulates free fatty acid oxidation via inhibition of acetyl-CoA carboxylase-effects that are useful for management of non-alcoholic fatty liver disease [173,174].…”

Section: Discussionmentioning

confidence: 99%

Nutraceutical and Dietary Strategies for Up-Regulating Macroautophagy

McCarty

2022

IJMS

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Macroautophagy is a “cell cleansing” process that rids cells of protein aggregates and damaged organelles that may contribute to disease pathogenesis and the dysfunctions associated with aging. Measures which boost longevity and health span in rodents typically up-regulate macroautophagy, and it has often been suggested that safe strategies which can promote this process in humans may contribute to healthful aging. The kinase ULK1 serves as a trigger for autophagy initiation, and the transcription factors TFEB, FOXO1, ATF4 and CHOP promote expression of a number of proteins which mediate macroautophagy. Nutraceutical or dietary measures which stimulate AMPK, SIRT1, eIF5A, and that diminish the activities of AKT and mTORC1, can be expected to boost the activities of these pro-autophagic factors. The activity of AMPK can be stimulated with the phytochemical berberine. SIRT1 activation may be achieved with a range of agents, including ferulic acid, melatonin, urolithin A, N1-methylnicotinamide, nicotinamide riboside, and glucosamine; correction of ubiquinone deficiency may also be useful in this regard, as may dietary strategies such as time-restricted feeding or intermittent fasting. In the context of an age-related decrease in cellular polyamine levels, provision of exogenous spermidine can boost the hypusination reaction required for the appropriate post-translational modification of eIF5A. Low-protein plant-based diets could be expected to increase ATF4 and CHOP expression, while diminishing IGF-I-mediated activation of AKT and mTORC1. Hence, practical strategies for protecting health by up-regulating macroautophagy may be feasible.

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“…A recent summary of the available cardiovascular evidence regarding metformin was provided by the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists [ 64 ]. They published an updated meta-analysis in 2021 in which they only selected the UKPDS and the SPREAD-DIMCAD for their endpoint on major cardiovascular effects with a combined odds ratio of 0.52 (95% CI 0.37, 0.73) favoring metformin and a non-significant trend for reduced all-cause mortality (odds ratio (OR) 0.80 (95% CI 0.60, 1.07)).…”

Section: Cardiovascular Effectsmentioning

confidence: 99%

Metformin: A Narrative Review of Its Potential Benefits for Cardiovascular Disease, Cancer and Dementia

2022

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The biguanide metformin has been used as first-line therapy in type 2 diabetes mellitus (T2DM) treatment for several decades. In addition to its glucose-lowering properties and its prevention of weight gain, the landmark UK Prospective Diabetes Study (UKPDS) demonstrated cardioprotective properties in obese T2DM patients. Coupled with a favorable side effect profile and low cost, metformin has become the cornerstone in the treatment of T2DM worldwide. In addition, metformin is increasingly being investigated for its potential anticancer and neuroprotective properties both in T2DM patients and non-diabetic individuals. In the meantime, new drugs with powerful cardioprotective properties have been introduced and compete with metformin for its place in the treatment of T2DM. In this review we will discuss actual insights in the various working mechanisms of metformin and the evidence for its beneficial effects on (the prevention of) cardiovascular disease, cancer and dementia. In addition to observational evidence, emphasis is placed on randomized trials and recent meta-analyses to obtain an up-to-date overview of the use of metformin in clinical practice.

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Effect of metformin on all-cause mortality and major adverse cardiovascular events: An updated meta-analysis of randomized controlled trials

Cited by 34 publications

References 20 publications

Understanding the place for GLP‐1RA therapy: Translating guidelines for treatment of type 2 diabetes into everyday clinical practice and patient selection

Understanding the place for GLP‐1RA therapy: Translating guidelines for treatment of type 2 diabetes into everyday clinical practice and patient selection

Nutraceutical and Dietary Strategies for Up-Regulating Macroautophagy

Metformin: A Narrative Review of Its Potential Benefits for Cardiovascular Disease, Cancer and Dementia

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