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Metformin and the heart: Update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure
Abstract
Metformin has been in clinical use for the management of type 2 diabetes for more than 60 years and is supported by a vast database of clinical experience: this includes evidence for cardioprotection from randomised trials and real-world studies. Recently, the position of metformin as first choice glucose-lowering agent has been supplanted to some extent by the emergence of newer classes of antidiabetic therapy, namely the sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. These agents have benefitted through support from large cardiovascular outcomes trials with more modern trial designs than earlier studies conducted to assess metformin. Nevertheless, clinical research on metformin continues to further assess its many potentially advantageous effects. Here, we review the evidence for improved cardiovascular outcomes with metformin in the context of the current era of diabetes outcomes trials. Focus is directed towards the potentially cardioprotective actions of metformin in patients with type 2 diabetes and heart failure (HF), now recognised as the most common complication of diabetes.
... Воспаление, фиброз и разрежение микроциркуляторного русла миокарда многоплановость его метаболических эффектов вкупе с высоким уровнем безопасности привлекают внимание в свете потенциального воздействия препарата на множественные механизмы патогенеза ХСНсФВ (рис. 5) [49]. Так, ряд публикаций посвящен системным противовоспалительным эффектам бигуанида. ...
... Вследствие пандемии COVID-19 и рекомендаций регуляторных органов, осуществляющих надзор за исследованиями, с марта 2020 г. скрининг пациентов был временно приостановлен [63]. В продолжающемся рандомизированном двухфакторном плацебо-контролируемом исследовании DANHEART оценивается влияние метформина и сочетания гидралазина с изосорбида динитратом на клинические исходы у 1500 пациентов с СД2 и ХСНнФВ [49]. Доза метформина составляет 2000 мг в сутки (1000 мг в сутки при расчетной скорости клубочковой фильтрации 35-60 мл/мин/1,73 м 2 ) в течение 4 лет. ...
... К сожалению, вопросы подхода к его назначению при сочетании данных патологий с позиций кардиометаболической протекции остаются открытыми и малоизученными, хотя сегодня имеются доказательства защиты сердечно-сосудистой системы при использовании метформина, продемонстрированные в рандомизированных клинических наблюдательных и экспериментальных исследованиях, суммированных нами выше. Более того, метформин пытается удержать лидерские позиции у пациентов с СД2, текущее исследование SMARTEST (NCT03982381) -его первое непосредственное сравнением с ингибитором SGLT2 по влиянию на сердечно-сосудистые исходы, финал которого будет известен в 2024 г. [49]. ...
Insulin resistance, which is a fundamental pathogenetic factor of prediabetes, is closely associated with abdominal obesity on the one hand and the development of cardiovascular diseases, heart failure (HF), on the other. The pathogenetic role of insulin resistance is multifaceted and consists in the acceleration of atherosclerosis, the formation of left ventricular myocardial hypertrophy, including through mechanisms that do not depend on blood pressure, as well as the development of its diastolic dysfunction. The latter is the starting point for starting HF with preserved ejection fraction (HFpEF).
Compared with patients with HF with reduced ejection fraction, the presence of HFpEF determines a higher frequency of hospitalizations not due to decompensation of heart failure, but due to concomitant diseases, such as destabilization of the course of arterial hypertension, decompensation of type 2 diabetes mellitus, curation of which, in general, has a greater impact in terms of improving prognosis. Thus, in patients with prediabetes and HFpEF, the correction of insulin resistance as the underlying cause and trigger of cardiometabolic disorders can potentially improve not only insulin-glucose homeostasis, but also the parameters of myocardial diastolic function. This literature review is devoted to the accumulated experience of using metformin as a «strategic» antidiabetic drug in HFpEF and considering potential new points of its application as a protector of the cardiovascular system.
... As it does not induce hypoglycemia, it could be safely administered to normoglycemic subjects. Improved cardiovascular outcomes have been documented in patients with diabetes mellitus type II [39] and are suggested to be related to improved glycemia, beneficial effects on endothelial function, hemostasis, i.e., inhibition of platelet aggregation and blood viscosity, reduced levels of coagulation factors VII, XIII, von Willebrand factor, and enhanced fibrinolysis [39][40][41]. ...
... As it does not induce hypoglycemia, it could be safely administered to normoglycemic subjects. Improved cardiovascular outcomes have been documented in patients with diabetes mellitus type II [39] and are suggested to be related to improved glycemia, beneficial effects on endothelial function, hemostasis, i.e., inhibition of platelet aggregation and blood viscosity, reduced levels of coagulation factors VII, XIII, von Willebrand factor, and enhanced fibrinolysis [39][40][41]. ...
The involvement of the knee joint is the most common localization of the pathological process in osteoarthritis (OA), which is associated with obesity in over 50% of the patients and is mediated by mechanical, inflammatory, and metabolic mechanisms. Obesity and the associated conditions (hyperglycemia, dyslipidemia, and hypertension) have been found to be risk factors for the development of knee OA, which has led to the emerging concept of the existence of a distinct phenotype, i.e., metabolic knee OA. Combined assessment of markers derived from dysfunctional adipose tissue, markers of bone and cartilage metabolism, as well as high-sensitivity inflammatory markers and imaging, might reveal prognostic signs for metabolic knee OA. Interestingly, it has been suggested that drugs used for the treatment of other components of the metabolic syndrome may also affect the clinical course and retard the progression of metabolic-associated knee OA. In this regard, significant amounts of new data are accumulating about the role of metformin—a drug, commonly used in clinical practice with suggested multiple pleiotropic effects. The aim of the current review is to analyze the current views about the potential pleiotropic effects of metformin in OA. Upon the analysis of the different effects of metformin, major mechanisms that might be involved in OA are the influence of inflammation, oxidative stress, autophagy, adipokine levels, and microbiome modulation. There is an increasing amount of evidence from in vitro studies, animal models, and clinical trials that metformin can slow OA progression by modulating inflammatory and metabolic factors that are summarized in the current up-to-date review. Considering the contemporary concept about the existence of metabolic type knee OA, in which the accompanying obesity and systemic low-grade inflammation are suggested to influence disease course, metformin could be considered as a useful and safe component of the personalized therapeutic approach in knee OA patients with accompanying type II diabetes or obesity.
... A further review from Sachinidis et al. specifically examined cardiovascular outcome trials for incretin-based medications emphasizing the positive cardiovascular benefits of the GLP-1RAs [64]. Beyond the novel anti-diabetic agents, interest continues on the pleiotropic effects of older agents including metformin [65,66]. In this regard, Scherbthaner et al. reviewed the cardioprotective effects of metformin, particularly as relates to heart failure, while pointing out that due to the "age" of this drug it has not benefitted from the extensive cardiovascular outcome trials that have been afforded to the SGLT-2 inhibitors and GLP-1RAs [66]. ...
... Beyond the novel anti-diabetic agents, interest continues on the pleiotropic effects of older agents including metformin [65,66]. In this regard, Scherbthaner et al. reviewed the cardioprotective effects of metformin, particularly as relates to heart failure, while pointing out that due to the "age" of this drug it has not benefitted from the extensive cardiovascular outcome trials that have been afforded to the SGLT-2 inhibitors and GLP-1RAs [66]. Similarly, the role of insulin as a vasoactive factor was reviewed by Natali and Nesti emphasizing the presence of functional insulin receptors on endothelial and smooth muscle cells [67]. ...
... Additionally, there are still limited data from large-scale randomized controlled trials specifically evaluating the effects of metformin on heart failure outcomes. Many studies have been observational, raising concerns about confounding factors and biases [57]. ...
The increasing prevalence of both type 2 diabetes mellitus and heart failure has underscored the urgent need for optimized therapeutic strategies that address the complex interplay between these conditions. Dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as a popular class of glucose-lowering agents due to their favorable glycemic effects, safety profile, and potential cardiovascular benefits. However, the impact of DPP-4 inhibitors on heart failure outcomes in patients with diabetes remains contentious, with conflicting evidence from clinical trials and observational studies. This review critically examines current evidence on the use of DPP-4 inhibitors in patients with coexisting diabetes and heart failure, focusing on pharmacodynamics, safety, and efficacy outcomes. We explore the physiological mechanisms by which DPP-4 inhibitors may influence heart failure risk, including modulation of inflammation, oxidative stress, and myocardial fibrosis. Clinical trials such as SAVOR-TIMI 53, EXAMINE, and TECOS are evaluated to provide a comprehensive analysis of DPP-4 inhibitors’ effects on hospitalization for heart failure, mortality, and cardiovascular events in diabetic patients. While some trials suggest an increased risk of HF hospitalizations with specific DPP-4 inhibitors (e.g., saxagliptin), others report neutral effects, raising questions about the class effects versus individual drug characteristics within this group. Additionally, we address discrepancies in outcomes related to patient demographics, HF phenotype, and comorbid conditions that may influence DPP-4 inhibitors’ risk–benefit profile. Comparative insights into alternative glucose-lowering therapies such as SGLT2 inhibitors and GLP-1 receptor agonists are also provided, highlighting potential implications for treatment selection in this high-risk population. In summary, this review synthesizes available evidence on DPP-4 inhibitors’ impact in diabetic patients with heart failure, aiming to guide clinicians in making informed therapeutic decisions. While DPP-4 inhibitors remain a viable option in diabetes management, caution is warranted in patients with advanced heart failure, and future research is essential to refine patient-specific guidelines.
... Clinical studies have demonstrated that metformin significantly reduces mortality over a 10-year period, primarily by decreasing myocardial infarction events [84]. Additionally, meta-analyses confirm that metformin treatment is associated with reduced mortality and provides safety comparable to other glucose-lowering agents in both HFrEF and HFpEF diabetic patients [85][86][87][88]. ...
Heart failure (HF) represents a multifaceted clinical syndrome characterized by the heart’s inability to pump blood efficiently to meet the body’s metabolic demands. Despite advances in medical management, HF remains a major cause of morbidity and mortality worldwide. In recent years, considerable attention has been directed toward understanding the molecular mechanisms underlying HF pathogenesis, with a particular focus on the role of AMP-activated protein kinase (AMPK) and protein O-GlcNAcylation. This review comprehensively examines the current understanding of AMPK and O-GlcNAcylation signalling pathways in HF, emphasizing their interplay and dysregulation. We delve into the intricate molecular mechanisms by which AMPK and O-GlcNAcylation contribute to cardiac energetics, metabolism, and remodelling, highlighting recent preclinical and clinical studies that have explored novel therapeutic interventions targeting these pathways.
... Often overlooked are metformin's effects on hemostasis and thrombolysis, particularly in decreasing platelet aggregation, altering fibrin polymerization, and reducing plasminogen activator inhibitor-1 (PAI-1) [92]. Despite this catalog of beneficial effects on the vascular system, most studies with metformin have noted little effect on blood pressure, beyond small reductions consistent with decreased adiposity, and also an antitumor effect [93,94]. Several studies continue to examine the cardiovascular effects of metformin, and several prospective studies with cardiovascular endpoints are ongoing, notably SGLT2 Inhibitor or Metformin as Standard Treatment of Early Stage Type 2 Diabetes (SMARTEST) (NCT03982381) [95,96], Metformin and Prevention of Cardiovascular Events in Patients With Acute Myocardial Infarction and Prediabetes (MIMET) (NCT05182970) [97,98], DANHEART (H-HeFT and Met-HeFT) (NCT03514108) [99,100], and Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular OuTcomes (VA-IMPACT) (NCT02915198) [101]. ...
The insulin–heart axis plays a pivotal role in the pathophysiology of cardiovascular disease (CVD) in insulin-resistant states, including type 2 diabetes mellitus. Insulin resistance disrupts glucose and lipid metabolism, leading to systemic inflammation, oxidative stress, and atherogenesis, which contribute to heart failure (HF) and other CVDs. This review was conducted by systematically searching PubMed, Scopus, and Web of Science databases for peer-reviewed studies published in the past decade, focusing on therapeutic interventions targeting the insulin–heart axis. Studies were selected based on their relevance to insulin resistance, cardiovascular outcomes, and the efficacy of pharmacologic treatments. Key findings from the review highlight the efficacy of lifestyle modifications, such as dietary changes and physical activity, which remain the cornerstone of managing insulin resistance and improving cardiovascular outcomes. Moreover, pharmacologic interventions, such as metformin, sodium–glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors, have shown efficacy in reducing cardiovascular risk by addressing metabolic dysfunction, reducing inflammation, and improving endothelial function. Furthermore, emerging treatments, such as angiotensin receptor–neprilysin inhibitors, and mechanical interventions like ventricular assist devices offer new avenues for managing HF in insulin-resistant patients. The potential of these therapies to improve left ventricular ejection fraction and reverse pathological cardiac remodeling highlights the importance of early intervention. However, challenges remain in optimizing treatment regimens and understanding the long-term cardiovascular effects of these agents. Future research should focus on personalized approaches that integrate lifestyle and pharmacologic therapies to effectively target the insulin–heart axis and mitigate the burden of cardiovascular complications in insulin-resistant populations.
... Although metformin is often used for HF with type 2 diabetes, its cardiovascular effects remain only partially understood (5). Similarly, the detailed mechanisms of action of metformin are unclear. ...
This randomized trial tested the effect of metformin on glycemic control and cardiac function in patients with heart failure (HF) and type 2 diabetes while evaluating intestinal effects on selected gut microbiome products reflected by trimethylamine-N-oxide (TMAO) and gut-derived incretins. Metformin treatment improved glycemic control and postprandial metabolism and enhanced postprandial glucagon-like peptide 1 (GLP-1) secretion but did not influence cardiac function or the TMAO levels. Metabolic effects of metformin in HF may be mediated by an improvement in intestinal endocrine function and enhanced secretion of the gut-derived incretin GLP-1.
... Multiple experimental studies and epidemiological data have shown that metformin has great potential in the prevention and treatment of age-related diseases. Long term use can reduce many pathological risks associated with aging, including cardiovascular diseases, neurodegenerative diseases, and cancers (Porter et al., 2019;Schernthaner et al., 2022). Currently, research on the anti-aging effects of metformin is receiving increasing attention, and its impact on aging MSCs has also been extensively studied (Table 3). ...
Mesenchymal stem cells (MSCs) are a type of pluripotent adult stem cell with strong self-renewal and multi-differentiation abilities. Their excellent biological traits, minimal immunogenicity, and abundant availability have made them the perfect seed cells for treating a wide range of diseases. After more than 60 years of clinical practice, metformin is currently one of the most commonly used hypoglycaemic drugs for type 2 diabetes in clinical practice. In addition, metformin has shown great potential in the treatment of various systemic diseases except for type 2 diabetes in recent years, and the mechanisms are involved with antioxidant stress, anti-inflammatory, and induced autophagy, etc. This article reviews the effects and the underlying mechanisms of metformin on the biological properties, including proliferation, multi-differentiation, and aging, of MSCs in vitro and in vivo with the aim of providing theoretical support for in-depth scientific research and clinical applications in MSCs-mediated disease treatment.
... Summary of antidiabetic drug classes on heart failure[51][52][53][54][55][56][57][58].Second-or third-line medication. If digoxin is used to treat HF, avoid or discontinue acarbose.SGLT2i, sodium-glucose transporter 2 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonists; DPP-4i, dipeptidyl peptidase-4 inhibitor; GKA, glucokinase activator; TZDs, thiazolidinedions; HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; DM, diabetes mellitus; HF, heart failure; CHD, coronary heart disease; NYHA, New York Heart Association; RCTs, randomized controlled studies. ...
Heart failure (HF) is a complex clinical syndrome caused by structural or functional dysfunction of the ventricular filling or blood supply. Diabetes mellitus (DM) is an independent predictor of mortality for HF. The increase in prevalence, co-morbidity and hospitalization rates of both DM and HF has further fueled the possibility of overlapping disease pathology between the two. For decades, antidiabetic drugs that are known to definitively increase the risk of HF are the thiazolidinediones (TZDs) and saxagliptin in the dipeptidyl peptidase-4 (DPP-4) inhibitor, and insulin, which causes sodium and water retention, and whether metformin is effective or safe for HF is not clear. Notably, sodium-glucose transporter 2 (SGLT2) inhibitors and partial glucagon-like peptide-1 receptor agonists (GLP-1 RA) all achieved positive results for HF endpoints, with SGLT2 inhibitors in particular significantly reducing the composite endpoint of cardiovascular mortality and hospitalization for heart failure (HHF). Further understanding of the mutual pathophysiological mechanisms between HF and DM may facilitate the detection of novel therapeutic targets to improve the clinical outcome. This review focuses on the association between HF and DM, emphasizing the efficacy and safety of antidiabetic drugs and HF treatment. In addition, recent therapeutic advances in HF and the important mechanisms by which SGLT2 inhibitors/mineralocorticoid receptor antagonist (MRA)/vericiguat contribute to the benefits of HF are summarized.
... The previously mentioned compounds promote signaling via kinases; however, some inhibitors of CaMKL family members are already being tested in clinical trials. Notably, several CHK1 inhibitors (Prexasertib (LY2606368), SCH 900776, BBI-355 (trial identifier: NCT05827614), and PEP07 (trial identifier: NCT05659732 and NCT05983523)) are in phase 1/2 of a clinical trial studying oncotherapy [165][166][167]. Moreover, the SIK2/3 inhibitor GRN-300 is in phase 1 studies and focuses on gynecological cancers [168]. ...
Circulating low-density lipoprotein (LDL) levels are a major risk factor for cardiovascular diseases (CVD), and even though current treatment strategies focusing on lowering lipid levels are effective, CVD remains the primary cause of death worldwide. Atherosclerosis is the major cause of CVD and is a chronic inflammatory condition in which various cell types and protein kinases play a crucial role. However, the underlying mechanisms of atherosclerosis are not entirely understood yet. Notably, protein kinases are highly druggable targets and represent, therefore, a novel way to target atherosclerosis. In this review, the potential role of the calcium/calmodulin-dependent protein kinase-like (CaMKL) family and its role in atherosclerosis will be discussed. This family consists of 12 subfamilies, among which are the well-described and conserved liver kinase B1 (LKB1) and 5′ adenosine monophosphate-activated protein kinase (AMPK) subfamilies. Interestingly, LKB1 plays a key role and is considered a master kinase within the CaMKL family. It has been shown that LKB1 signaling leads to atheroprotective effects, while, for example, members of the microtubule affinity-regulating kinase (MARK) subfamily have been described to aggravate atherosclerosis development. These observations highlight the importance of studying kinases and their signaling pathways in atherosclerosis, bringing us a step closer to unraveling the underlying mechanisms of atherosclerosis.
... In a series of studies such as the prevention of rheumatoid arthritis, metformin has been shown to not only lower blood glucose, but also reduce body weight and indirectly inhibit inflammation by altering the intestinal flora, thus reducing the risk of developing a number of diseases [20][21][22][23][24]. Available studies have demonstrated that metformin acts not only through AMP-activated protein kinase, but also through mitochondrial complex 1, growth differentiation factor 15, and glucagon-like peptide 1/glucagon [25][26][27][28]. At the same time, many basic studies have demonstrated that metformin can play a cardiovascular protective role by reducing endothelial dysfunction and reducing oxidative stress to improve inflammation [29]. Unfortunately, however, metformin is still not classified as a cardiovascular drug [30][31][32][33][34]. ...
Background:
The cardiovascular effects of metformin continue to be a subject of debate within the medical community.
Methods:
The Mendelian randomization (MR) study used data from genome-wide association studies (GWAS) to explore the causal association with six diseases that are associated with bimatoprost treatment and myocardial infarction, chronic heart failure, atrial fibrillation, hypertrophic and dilated cardiomyopathy, and valvular disease. Genome-wide significant single nucleotide polymorphisms (SNPs), that are associated with metformin use were selected as the instrumental variables. To determine the causal relationship between metformin use and various cardiovascular diseases, MR analysis was conducted, employing methods such as Instrumental Variable Weighting (IVW).
Results:
The IVW analysis demonstrated a positive association between metformin treatment and the risk of myocardial infarction (OR = 22.67, 95% CI 3.22-34.01; P = 0.002). Conversely, metformin treatment exhibited a negative association with the risk of developing valvular disease (OR = 0.98, 95% CI 0.95-1.00; P = 0.046) and hypertrophic cardiomyopathy (OR = 0.01, 95% CI 0.00-0.22; P = 0.016). Multiple test correction found that metformin treatment was causally associated with the risk of both hypertrophic cardiomyopathy (PFDR = 0.048) and myocardial infarction (PFDR = 0.012). The analysis revealed limited heterogeneity in the individual results, absence of pleiotropy evidence, and indications of stability in the findings.
Conclusion:
The MR study discovered from a genetic standpoint that metformin may lower the risk of hypertrophic cardiomyopathy and valvular heart disease, yet it could elevate the risk of myocardial infarction.
... In summary, metformin is a safe drug that could be used in non-diabetic patients; while it shows glucose lowering effects in hyperglycemic states, metformin does not cause hypoglycemia or any other metabolic derangement in normoglycemic individuals. Therefore, metformin has been safely used for a number of reasons in patients without diabetes, e.g. as an anti-inflammatory, anti-cancer, cardiovascular protective, and even anti-dementia agent [73][74][75]. As discussed above, in vitro, experimental, and clinical studies underline the protective effects of metformin on the bone integrity, regardless of the glycemic state. ...
Adrenal insufficiency (AI) is a serious disorder characterized by the adrenal glucocorticoid deficiency. Regardless of the etiology, AI patients need long-term replacement therapy for glucocorticoids and, in some cases, for mineralocorticoids. The replacement therapy cannot completely mirror the physiological secretion patterns, and therefore, glucocorticoid excess is a common sequela in AI patients. Moreover, due to the absence of the reliable clinical markers to monitor the adequacy of the replacement therapy, clinicians often over-treat the AI patients to avoid adrenal crisis. Long-term glucocorticoid use is associated with the loss of bone density and osteoporosis, increasing the risk of fractures. Moreover, glucocorticoid-induced hyperglycemia and type 2 diabetes mellitus further aggravates the bone disorders. In the recent years, ameliorating effects of metformin on glucocorticoid-induced bone disorders, as well as hyperglycemia, have been reported by a multitude of studies; and here, we reviewed and discussed the most recent findings regarding the positive effects of metformin on alleviating the bone disorders, and their implications in the AI patients.
... [61] body weight, can help reduce the chance of developing T2DM [5,17,303]. Though there are medications capable of curing T2DM, including metformin [232], sulfonylurea [113], and insulin [143] are the currently available scientifically proven synthetic anti-diabetic medications. Also, α-glucosidase inhibitors [131], thiazolidinediones [275], glucagon-like peptide-1 receptor agonists [205], pramlintide [101], and dipeptidyl peptidase-4 inhibitors [56] are some of the newer medications with little evidence supporting their use. ...
Currently, the incidence of metabolic disorders is increasing, setting a challenge to global health. With major advancement in the diagnostic tools and clinical procedures, much has been known in the etiology of metabolic disorders and their corresponding pathophysiologies. In addition, the use of in vitro and in vivo experimental models prior to clinical studies has promoted numerous biomedical breakthroughs, including in the discovery and development of drug candidates to treat metabolic disorders. Indeed, chemicals isolated from natural products have been extensively studied as prospective drug candidates to manage diabetes, obesity, heart-related diseases, and cancer, partly due to their antioxidant and anti-inflammatory properties. Continuous efforts have been made in parallel to improve their bioactivity and bioavailability using selected drug delivery approaches. Here, we provide insights on recent progress in the role of inflammatory-mediated responses on the initiation of metabolic disorders, with particular reference to diabetes mellitus, obesity, heart-related diseases, and cancer. In addition, we discussed the prospective role of natural products in the management of diabetes, obesity, heart-related diseases, and cancers and provide lists of potential biological targets for high throughput screening in drug discovery and development. Lastly, we discussed findings observed in the preclinical and clinical studies prior to identifying suitable approaches on the phytochemical drug delivery systems that are potential to be used in the treatment of metabolic disorders.
... Treatment with metformin and sodium-glucose cotransporter 2 inhibitor (SGLT2i) is found to reduce the risk of AF in diabetic patients.79,80 Besides modulating the electrophysiology of the atrium, these agents also confer pleiotropic metabolic protection.81,82 Modulation of autonomic balance may underlie the metabolic and antiarrhythmic efficacy. ...
... Years of research have shown that metformin, a firstline treatment for type 2 diabetes mellitus (T2DM), may be able to treat or prevent other complications in people with diabetes (Griffin et al. 2017;Jia et al. 2021;Schernthaner et al. 2022). Perhaps metformin could be the expected savior. ...
Metformin has been used clinically for more than 60 years. As time goes by, more and more miraculous effects of metformin beyond the clinic have been discovered and discussed. In addition to the clinically approved hypoglycemic effect, it also has a positive metabolic regulation effect on the human body that cannot be ignored. Such as anti-cancer, anti-aging, brain repair, cardiovascular protection, gastrointestinal regulation, hair growth and inhibition of thyroid nodules, and other nonclinical effects. Metformin affects almost the entire body in the situation taking it over a long period, and the preventive effects of metformin in addition to treating diabetes are also beginning to be recommended in some guidelines. This review is mainly composed of four parts: the development history of metformin, the progress of clinical efficacy, the nonclinical efficacy of metformin, and the consideration and prospect of its application.
... MF protects only normal cells without preventing damage to cancer cells ) and also shows synergism with some chemotherapeutic agents (Honjo et al. 2014;Koritzinsky 2015). Beyond its hypoglycemic antidiabetic activity, MF reveals pleiotropic effects (Pietrocola and Kroemer 2017), causing a decrease in morbidity and mortality rates from cardiovascular diseases (Han et al. 2019;Schernthaner et al. 2022) and reduction in the risk of developing various oncological diseases (Pernicova and Korbonits 2014;Cheng et al. 2022). MF exhibits geroprotective and anticarcinogenic effects (Martin-Castillo et al. 2010;Chen et al. 2012;Campbell et al. 2017), can inhibit cellular ROS production and stimulate DNA damage responses (DeFronzo and Goodman 1995), thus reducing cancer risk. ...
The antidiabetic drug metformin (MF) exhibits redox-modulating effects in various pathologies associated with oxidative stress and mitigates ionizing radiation-induced toxicity, but the underlying mechanisms remain to be elucidated. Thus, we studied some radiomitigatory effects of MF and explored the possible mechanisms behind them. Highly sensitive luminescence methods and non-competitive enzyme-linked immunosorbent assay (ELISA) were used in in vitro studies, and in vivo the damage to bone marrow cells and its repair were assessed by the micronucleus test. In a solution, MF at concentrations exceeding 0.1 µM effectively intercepts •OH upon X-ray-irradiation, but does not react directly with H2O2. MF accelerates the decomposition of H2O2 catalyzed by copper ions. MF does not affect the radiation-induced formation of H2O2 in the solution of bovine gamma-globulin (BGG), but has a modulating effect on the generation of H2O2 in the solution of bovine serum albumin (BSA). MF at 0.05–1 mM decreases the radiation-induced formation of 8-oxoguanine in a DNA solution depending on the concentration of MF with a maximum at 0.25 mM. MF at doses of 3 mg/kg body weight (bw) and 30 mg/kg bw administered to mice after irradiation, but not before irradiation, reduces the frequency of micronucleus formation in polychromatophilic erythrocytes of mouse red bone marrow. Our work has shown that the radiomitigatory properties of MF are mediated by antioxidant mechanisms of action, possibly including its ability to chelate polyvalent metal ions.
Graphical abstract
... For example, the DPP employed a target dose of metformin of 1750 mg/day for diabetes prevention 83 and the median dose of metformin, the most common first pharmacologic antidiabetic therapy, in the UKPDS was 2550 mg/day. 1 Randomised trials and many observational studies indicate cardiovascular benefit with metformin at all stages of type 2 diabetes (reviewed elsewhere). 101,102 These are important considerations, because in the clinical experience of the authors, metformin is often under dosed, especially in prediabetes. A range of tablet strengths facilitates titration of metformin, and in the authors' experience, use of a 750 mg metformin tablet facilitates achievement of a dose of 1500 mg for prediabetes, and the 1000 mg XR tablet facilitates achievement of the maximum dosage of 2000 mg/day. ...
The onset of type 2 diabetes increases the risk of vascular complications and death. We know now that that this risk begins long before the diabetes diagnosis. Prediabetes and type 2 diabetes are not separate entities in practice and exist within a continuum of dysglycaemia and vascular risk that increases in severity over time. This excess risk requires early intervention with lifestyle therapy supported with pharmacologic antidiabetic therapy, intensified promptly where necessary throughout the duration of the diabetes continuum. Metformin is an evidence-based treatment for preventing prediabetes and improves cardiovascular outcomes in people with type 2 diabetes from diagnosis onwards. Newer agents (SGLT2 inhibitors and GLP-1 agonists) are appropriate for people presenting with type 2 diabetes and significant cardiovascular comorbidity. Additional therapies should be used without delay to achieve patients’ individualised HbA1c goals and to minimise cardiovascular risk.
... It is important to understand the pathophysiology of lactic acidosis and the contexts in which it arises, as there is evidence that fear of this adverse outcome has led to under use of metformin in patients with conditions, such as chronic kidney disease, hepatic dysfunction and heart failure. 20 Moreover, a range of potential therapeutic actions of metformin in addition to its antihyperglycaemic actions in recent years, including possibly beneficial actions on the cardiovascular system (on the vascular endothelium 21 and the failing heart) 22,23 , an anti-inflammatory action of potential relevance to rheumatic immunological diseases 24 , anti-cancer activity 25 , and potential for the treatment of morbidities associated with aging 26 . The possibility of extensions to the therapeutic indications for metformin beyond prediabetes and diabetes in the future adds to the need to study this rare, but serious side-effect. ...
Objective
Metformin-associated lactic acidosis (MaLA) occurs rarely and is thus difficult to study. We analysed 4241 individual case safety reports of lactic acidosis (LA) that implicated metformin as a suspected drug reported to the pharmacovigilance database of Merck KGaA, Darmstadt, Germany. The primary objective was to review reports for quality and completeness of data to support diagnoses of MaLA. We also explored the correlations between reported biomarkers, and associations between biomarkers and outcomes.
Research Design and Methods
Records were analysed for completeness in supporting diagnoses of LA or metformin-associated LA (MaLA), against commonly used diagnostic criteria. Correlations between indices of exposure to metformin and biomarkers of LA and mortality were investigated.
Results
Missing data was common, especially for plasma metformin. Clinical/biomarker evidence supported a diagnosis of LA in only 33% of cases (LA subpopulation) and of MaLA in only 9% (MaLA subpopulation). The metformin plasma level correlated weakly with plasma lactate (positive) and pH (negative). About one-fifth (21.9%) of cases reported a fatal outcome. Metformin exposure (plasma level or dose) was not associated with increased mortality risk (there was a suggestion of decreased risk at higher levels of exposure to metformin). Plasma lactate was the only variable associated with increased risk of mortality. Examination of concomitant risk factors for MaLA identified renal dysfunction (including of iatrogenic origin) as a potential driver of mortality in this population.
Conclusion
Despite the high frequency of missing data, this is the largest analysis of cases of MaLA supported by measurements of circulating metformin, and lactate, and pH, to date. Plasma lactate, and not metformin dose or plasma level, appeared to be the main driver of mortality in the setting of LA or MaLA. Further research with more complete case reports is required.
... Others, however, have commented on the potential beneficial effects of metfomin in countering the development of the serious sequalae of diabetes such as heart failure and arguing for appropriate CV outcome trials to provide evidence of whether, for instance, there are superior benefits to metformin versus SGLT2 inhibitors for the prevention of heart failure secondary to diabetes [152]. Schernhaner et al. (2022) have summarized the current evidence and status of on-going clinical trials to assess the benefits of metformin versus other anti-diabetic drugs and cardiovascular outcomes [153]. For instance, the RCT, SGLT2 Inhibitor or Metformin as Standard Treatment of Early Stage Type 2 Diabetes (SMARTEST) study (NCTO3982381) due for completion in late 2025, compares the CV benefits of metformin versus dapagliflozin in 4300 patients with T2D. ...
Metformin was first used to treat type 2 diabetes in the late 1950s and in 2022 remains the first-choice drug used daily by approximately 150 million people. An accumulation of positive pre-clinical and clinical data has stimulated interest in re-purposing metformin to treat a variety of diseases including COVID-19. In polycystic ovary syndrome metformin improves insulin sensitivity. In type 1 diabetes metformin may help reduce the insulin dose. Meta-analysis and data from pre-clinical and clinical studies link metformin to a reduction in the incidence of cancer. Clinical trials, including MILES (Metformin In Longevity Study), and TAME (Targeting Aging with Metformin), have been designed to determine if metformin can offset aging and extend lifespan. Pre-clinical and clinical data suggest that metformin, via suppression of pro-inflammatory pathways, protection of mitochondria and vascular function, and direct actions on neuronal stem cells, may protect against neurodegenerative diseases. Metformin has also been studied for its anti-bacterial, −viral, −malaria efficacy. Collectively, these data raise the question: Is metformin a drug for all diseases? It remains unclear as to whether all of these putative beneficial effects are secondary to its actions as an anti-hyperglycemic and insulin-sensitizing drug, or result from other cellular actions, including inhibition of mTOR (mammalian target for rapamycin), or direct anti-viral actions. Clarification is also sought as to whether data from ex vivo studies based on the use of high concentrations of metformin can be translated into clinical benefits, or whether they reflect a ‘Paracelsus’ effect. The environmental impact of metformin, a drug with no known metabolites, is another emerging issue that has been linked to endocrine disruption in fish, and extensive use in T2D has also raised concerns over effects on human reproduction. The objectives for this review are to: 1) evaluate the putative mechanism(s) of action of metformin; 2) analyze the controversial evidence for metformin's effectiveness in the treatment of diseases other than type 2 diabetes; 3) assess the reproducibility of the data, and finally 4) reach an informed conclusion as to whether metformin is a drug for all diseases and reasons. We conclude that the primary clinical benefits of metformin result from its insulin-sensitizing and antihyperglycaemic effects that secondarily contribute to a reduced risk of a number of diseases and thereby enhancing healthspan. However, benefits like improving vascular endothelial function that are independent of effects on glucose homeostasis add to metformin's therapeutic actions.
Zusammenfassung
Wie aus zahlreichen umfangreichen Studien hervorgeht, haben SGLT-2-Inhibitoren nicht nur positive Effekte auf den Glukosestoffwechsel, sondern darüber hinaus eine ausgeprägte protektive Wirkung auf Herz und Nieren. Damit kommt dieser Wirkstoffklasse eine wichtige Rolle in der Primär- und Sekundärprävention diabetes-assoziierter Komorbiditäten zu. Leitlinien sprechen auf Basis der Evidenz für SGLT-2-Inhibitoren eine Empfehlung für deren frühen Einsatz bei Menschen mit Typ-2-Diabetes und gleichzeitigem hohen Risiko für kardiovaskuläre und/oder renale Ereignisse aus. Verordnungszahlen zeigen jedoch, dass diese Empfehlungen aktuell nicht umgesetzt werden und deutlich mehr Menschen mit Typ-2-Diabetes von einer organprotektiven Therapie profitieren könnten. Daher soll in dieser Übersichtsarbeit der Stellenwert der SGLT-2-Inhibitoren im Vergleich zu anderen oralen Therapieansätzen für die Behandlung des Typ-2-Diabetes dargestellt werden.
Metformin, a biguanide derived from Galega officinalis, was first synthesized by Werner and Bell in 1922. Metformin was approved for the treatment of diabetes by the US Food and Drug Administration in 1994. It has since become the most widely used oral antidiabetic agent. The exact mechanisms by which metformin exerts its clinical effects remain the subject of ongoing research. Metformin interacts with multiple molecular pathways, and the downstream effects of which affect weight, cardiovascular health, and longevity. Metformin reduces hunger by mitigating insulin resistance in the hypothalamic pro-opiomelanocortin neurons. It enhances satiety by stimulating the enteral release of glucagon-like peptide 1. It also induces favorable changes to enteric microbiota, enhancing metabolism. These effects cumulatively contribute to metformin-induced weight loss. Metformin use has shown associations with improved cardiovascular outcomes including reduced all-cause mortality, lower rates of myocardial infarctions, and improved heart failure outcomes. Many of these actions are mediated through the direct activation of adenosine monophosphate-activated kinase (AMPK), which, in turn, enhances cellular energy production and endothelial nitric oxide synthase-mediated vascular relaxation. It antagonizes proinflammatory cytokines, reducing cardiac fibrosis and remodeling. The metformin-AMPK pathway may also explain the potential utility of metformin in mitigating aging. Acting through AMPK, it inhibits the mammalian target of rapamycin, leading to increased autophagy and cell growth. The metformin-AMPK-sirtuin pathway may also contribute to longevity. In this review, we will discuss the use of metformin in weight loss, cardiovascular health, and longevity, highlighting the historic background, molecular mechanisms, and current evidence.
Metformin (dimethyl‐biguanide) can claim its origins in the use of Galega officinalis as a plant treatment for symptoms ascribed to diabetes. Since the first clinical use of metformin as a glucose‐lowering agent in 1957, this medicine has emerged as a first‐line pharmacological option to support lifestyle interventions in the management of type 2 diabetes (T2D). It acts through multiple cellular pathways, principally in the gut, liver and muscle, to counter insulin resistance and lower blood glucose without weight gain or risk of overt hypoglycaemia. Other effects include improvements in lipid metabolism, decreased inflammation and lower long‐term cardiovascular risk. Metformin is conveniently combined with other diabetes medications, can be prescribed in prediabetes to reduce the risk of progression to T2D, and is used in some regions to assist glycaemic control in pregnancy. Consistent with its diversity of actions, established safety profile and cost‐effectiveness, metformin is being assessed for further possible clinical applications. The use of metformin requires adequate renal function for drug elimination, and may cause initial gastrointestinal side effects, which can be moderated by taking with meals or using an extended‐release formulation. Thus, metformin serves as a valuable therapeutic resource for use throughout the natural history of T2D.
Background
In recent years, several studies have explored the effect of metformin on myocardial infarction (MI), but whether metformin has an improvement effect in patients with MI is controversial. This study was aimed to investigate the causal relationship between metformin and MI using Mendelian randomization (MR) analysis.
Methods
The genome-wide significant (P<5×10⁻⁸) single-nucleotide polymorphisms (SNPs) in patients with metformin and patients with MI were screened from the Open genome-wide association study (GWAS) project as instrumental variables (IVs). The study outcomes mainly included MI, old MI, acute MI, acute transmural MI of inferior wall, and acute transmural MI of anterior wall. The inverse variance weighted (IVW) method was applied to assess the main causal effect, and weighted median, simple mode, weighted mode methods, and MR-Egger regression were auxiliary applied for supplementary proof. The causal relationship between metformin and MI was assessed using odds ratios (OR) and 95% confidence intervals (95% CI). A leave-one-out method was used to explore the effect of individual SNPs on the results of IVW analyses, and a funnel plot was used to analyze the potential bias of the study results, thus ensuring the robustness of the results.
Results
In total, 16, 84, 39, 26, and 34 SNPs were selected as IVs to assess the genetic association between metformin and outcomes of MI, old MI, acute MI, acute transmural MI of inferior wall, and acute transmural MI of anterior wall, respectively. Treatment with metformin does not affect the risk of acute transmural MI of anterior wall at the genetic level (P>0.05; OR for inverse variance weighted was 1.010). In the cases of MI, old MI, acute MI, and acute transmural MI of inferior wall, metformin may even be a risk factor for patients (P<0.05; ORs for inverse variance weighted were 1.078, 1.026, 1.022 and 1.018 respectively). There was no horizontal pleiotropy or heterogeneity among IVs. The results were stable when removing the SNPs one by one.
Conclusion
Metformin is not protective against the risk of myocardial infarction in patients and may even be a risk factor for MI, old MI, acute MI, and acute transmural MI of inferior wall.
Objective
Despite the strong association between gout and pre-diabetes, the role of metformin in gout among individuals with pre-diabetes remains uncertain. We compared the incidence rates of gout in adults with pre-diabetes starting metformin with those not using antidiabetic treatments.
Methods
We conducted a new-user, propensity score-matched cohort study using electronic health records from an academic health system (2007–2022). Pre-diabetes was defined based on haemoglobin A1c levels. Metformin users were identified and followed from the first metformin prescription date. Non-users of antidiabetic medications were matched to metformin users based on propensity score and the start of follow-up. The primary outcome was incident gout. Cox proportional hazards models estimated the HR for metformin. Linear regression analyses assessed the association between metformin use and changes in serum urate (SU) or C-reactive protein (CRP).
Results
We identified 25 064 individuals with pre-diabetes and propensity score-matched 1154 metformin initiators to 13 877 non-users. Baseline characteristics were well balanced (all standardised mean differences <0.1). The median follow-up was 3.9 years. The incidence rate of gout per 1000 person-years was lower in metformin users 7.1 (95% CI 5.1 to 10) compared with non-users 9.5 (95% CI 8.8 to 10.2). Metformin initiation was associated with a reduced relative risk of gout (HR 0.68, 95% CI 0.48 to 0.96). No relationship was found between metformin and changes in SU or CRP.
Conclusions
Metformin use was associated with a reduced risk of gout among adults with pre-diabetes, suggesting that metformin may be important in lowering gout risk in individuals with pre-diabetes.
Heart diseases, such as coronary heart disease and heart failure, often occur together with diabetes mellitus, chronic obstructive pulmonary disease and depression; however, dementia and malignant diseases also contribute to mortality and hospitalization. This results in the problem of often unavoidable polypharmacy, which can have an unfavorable effect on the clinical course. It is therefore important to avoid unfavorable interactions as far as possible and to prioritize medications that have a positive effect on both the underlying and concomitant disease. The article gives examples of concomitant diseases and their medications as well as recommendations for avoiding unfavorable comedications.
Among its many cardiovascular benefits, exercise training improves heart function and protects the heart against age-related decline, pathological stress, and injury. Here, we focus on cardiac benefits with an emphasis on more recent updates to our understanding. While the cardiomyocyte continues to play a central role as both a target and effector of exercise’s benefits, there is a growing recognition of the important roles of other, noncardiomyocyte lineages and pathways, including some that lie outside the heart itself. We review what is known about mediators of exercise’s benefits—both those intrinsic to the heart (at the level of cardiomyocytes, fibroblasts, or vascular cells) and those that are systemic (including metabolism, inflammation, the microbiome, and aging)—highlighting what is known about the molecular mechanisms responsible.
The current umbrella review aimed to evaluate the effect of metformin on all-cause mortality (ACM), cardiovascular mortality, and cardiovascular disease (CVD) incidence in DM patients.
PubMed, Scopus, Cochrane, Google Scholar, and Web of Science databases were searched with special keywords. Related studies were included after screening by two independent investigators based on title and full texts. The AMSTAR2 checklist was used to assess the quality of studies, and Cochran tests were used to assess the heterogeneity between studies. Overall, seventeen systematic reviews and meta-analysis studies were included. The results revealed that the risk of ACM in patients who received metformin was lower than in patients who did not receive metformin. (OR: 0.80, 95% CI:0.744,0.855); also, the risk of CVD mortality in metformin patients was lower than in the other two groups (placebo and other anti-diabetic drugs) (OR: 0.771, 95% CI:0.688,0.853, P:0.001). The risk of CVD in metformin users was also lower than in the other two groups (OR: 0.828, 95% CI:0.781,0.785).
This comprehensive review showed that the risk of ACM, death due to CVD, and incidents of CVD in DM who use metformin was lower than the patients who received a placebo only or other diabetic drugs, which can guide clinicians in medical decision-making.
Introduction:
For a long time, metformin has been the first-line treatment for glycaemic control in type 2 diabetes, however, the results of recent cardiovascular outcome trials of sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists have caused many to question metformin's position in the guidelines. Although there are several plausible mechanisms by which metformin might have beneficial cardiovascular effects, for example its anti-inflammatory effects and metabolic properties, and numerous observational data suggesting improved cardiovascular outcomes with metformin use, the main randomised clinical trial data for metformin was published over 20 years ago. Nevertheless, the overwhelming majority of participants in contemporary type 2 diabetes trials were prescribed metformin.
Areas covered:
In this review we will summarise the potential mechanisms of cardiovascular benefit with metformin, before discussing clinical data in individuals with or without diabetes.
Expert opinion:
Metformin may have some cardiovascular benefit in patients with and without diabetes, however the majority of clinical trials were small and are before the use SGLT2 inhibitors and GLP1-RAs. Larger contemporary randomised trials with metformin evaluating its cardiovascular benefit are warranted.
Hepatocellular carcinoma (HCC) is one of the leading causes of death, which deserves further study to reveal the underlying molecular mechanisms. Studies have shown that miR-9 in associated with poor prognosis in HCC patients. However, the mechanisms of transcriptional activation regulation of miR-9 and its role in the malignant progression of HCC have been rarely investigated. Some transcriptional coactivators can form phase-separated condensates at super-enhancers that compartmentalize and concentrate the transcription apparatus to drive robust gene expression. Here, we demonstrate that Twist1 and YY1 could form a transcriptional complex with p300, creating local high-concentration phase-separated interaction hubs at the super-enhancers of miR-9 and activate its expression to promote the malignant progression of HCC by stimulating the migration and invasion of hepatocellular carcinoma cells. Twist1-YY1-p300 phase-separated condensates were disrupted by metformin (Met) and thus reduce miR-9 expression, thereby inhibiting the malignant progression of HCC. Our study demonstrates that the Twist1 transcriptional factor complex involved in the malignant progression of HCC can form phase separation condensates at super-enhancers of miR-9 to promote the expression of oncogenes in HCC cells. It provides a potential target for the therapy of HCC and offers insights into the mechanism of Met in HCC inhibition.
Introduction:
Cell therapy with mesenchymal stem cells (MSCs) and biomaterials holds great potential for the treatment of diabetic ulceration; however, the underlying mechanism as well as its compatibility with the first-line anti-diabetic drug, metformin (MTF), has not been well elucidated.
Methods:
MSCs derived from the umbilical cord were labeled with fluorescent proteins, followed by transplantation in a fibrin scaffold (MSCs/FG) onto the STZ-induced diabetic wound in a C57BL6/J mouse model. MTF was administered by oral gavage at a dose of 250 mg/kg/day. The wound healing rate, epithelization, angiogenesis, and underlying mechanism were evaluated in MSCs/FG- and MTF-treated diabetic wounds. Moreover, the dose-dependent effects of MTF and involvement of the Akt/mTOR pathway were analyzed in keratinocyte and fibroblast cultures.
Results:
MSCs/FG significantly promoted angiogenesis in diabetic wound healing without signs of differentiation or integration. The recruitment of fibroblasts and keratinocytes by MSCs/FG promotes migration and vascular endothelial growth factor (VEGF) expression in an Akt/mTOR-dependent manner. MTF, which is generally considered a mTOR inhibitor, displayed dose-dependent effects on MSC-unregulated Akt/mTOR and VEGF expression. Oral administration of MTF at an anti-diabetic dosage synergistically acted with MSCs/FG to promote Akt/mTOR activation, VEGF expression, and subsequent angiogenesis in diabetic wounds; however, it reduced the survival of MSCs.
Conclusions:
Our study identifies that MTF coordinates with mesenchymal cells to promote Akt/mTOR activation and VEGF-mediated angiogenesis during diabetic wound healing. These findings offer new insights into MSCs engraftment in FG scaffolds for diabetic wound healing and provide support for the promotion of MSCs therapy in patients prescribed with MTF.
The pharmacotherapy of type 2 diabetes mellitus (T2DM) has markedly evolved in the last two decades. Classical antidiabetic agents (sulphonylureas, metformin, insulin) are now in competition with new glucose-lowering medications. Alpha-glucosidase inhibitors and thiazolidinediones (glitazones) were not able to replace older agents, because of insufficient efficacy and/or poor tolerability/safety. In contrast, incretin-based therapies, both dipeptidyl peptidase-4 inhibitors (DPP-4is or gliptins, oral agents) and glucagon-like peptide-1 receptor agonists (GLP-1RAs, subcutaneous injections) are a major breakthrough in the management of T2DM. Because they are not associated with hypoglycaemia and weight gain, DPP-4is tend to replace sulphonylureas as add-on to metformin while GLP-1RAs tend to replace basal insulin therapy after failure of oral therapies. Furthermore, placebo-controlled cardiovascular outcome trials demonstrated neutrality for DPP-4is, but cardiovascular protection for GLP-1RAs in patients with T2DM at high cardiovascular risk. More recently sodium-glucose cotransporter 2 inhibitors (SGLT2is or gliflozins, oral agents) also showed cardiovascular protection, especially a reduction in hospitalisation for heart failure, as well as a renal protection in patients with and without T2DM, at high cardiovascular risk, with established heart failure and/or with chronic kidney disease. Thus, GLP-1RAs and SGLT2is are now considered as preferred drugs in T2DM patients with or at high risk of atherosclerotic cardiovascular disease whereas SGLT2is are more specifically recommended in patients with or at risk of heart failure and renal (albuminuric) disease. The management of T2DM is moving from a glucocentric approach to a broader strategy focusing on all risk factors, including overweight/obesity, and to an organ-disease targeted personalized approach.
Type 2 diabetes is associated with a higher risk of cardiac arrhythmias, especially in presence of cardiovascular disease and/or heart failure. Even if atrial fibrillation/flutter episodes are the most frequent and well-studied, ventricular arrhythmias (VA: tachycardia/fibrillation) are more severe and can lead to sudden cardiac arrest/death (SCA/SCD). The effects of glucose-lowering agents on the risk of VA/SCD remain poorly understood. Findings may be derived from experimental animal studies, randomised controlled trials/cardiovascular outcome trials and observational retrospective studies. A higher risk was attributed to hypoglycaemia when induced by insulin or even more critically by sulphonylureas. Insulin-secreting agents seem to be associated with a higher risk of cardiac arrhythmias compared with insulin sensitizers (metformin, thiazolidinediones), yet the risk linked to sulphonylureas remains controverted. Incretin-based therapies (DPP-4 inhibitors and GLP-1 receptor agonists) overall appear to be neutral regarding the risk of cardiac arrhythmias, despite some heterogeneous results. SGLT2 inhibitors appear to reduce the risk of SCA/SCD and possibly VA, yet only a non-significant trend was noticed in most reports. Overall, hazard ratios with SGLT2 inhibitors versus other therapies were lower for SCD (presumably of diverse causes) than for well demonstrated VA episodes. Underlying mechanisms remain uncertain and numerous pleiotropic effects may be involved. Prospective controlled trials and experimental studies specifically devoted to the effects of SGLT2 inhibitors on cardiac arrhythmias are needed to confirm their positive effects in diabetic patients and in individuals with heart failure irrespective of diabetes and, if possible, to carefully dissect the underlying protective mechanisms.
Introduction
There is a bi-directional link between type 2 diabetes mellitus (T2DM) and heart failure (HF) and their co-existence markedly increases an individual’s morbidity and mortality. Therefore, it is of major importance to diagnose early (and, even better, prevent) HF in T2DM patients, as well as adequately treat T2DM patients with HF.
Areas covered
The present narrative review discusses the effects of different antidiabetic drugs [metformin, pioglitazone, sulphonylureas (SUs), dipeptidyl peptidase 4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter 2 inhibitors (SGLT2i) and insulin] on HF incidence, hospitalization and outcomes. Current guidelines of diabetes and cardiology societies on this issue are also commented on.
Expert opinion
Metformin (+lifestyle interventions) is the first-line treatment for all T2DM patients and SGLT2i are the preferred drugs (class I, level of evidence A) in patients with T2DM and HF. Pioglitazone is contraindicated in HF, whereas SUs, DPP4i, GLP-1 RAs and insulin are considered as neutral. However, SUs may cause hypoglycemia and weight gain, saxagliptin (a DPP4i) must be avoided in this setting and GLP-1 RAs seem not to affect HF risk. There is an urgent need of increasing guidelines implementation regarding SGLT2i use in clinical practice, to sufficiently tackle the HF burden in T2DM.
Type 2 diabetes (T2D) is a widely prevalent disease with substantial economic and social impact for which multiple conventional and novel pharmacotherapies are currently available; however, the landscape of T2D treatment is constantly changing as new therapies emerge and the understanding of currently available agents deepens. This review aims to provide an updated summary of the pharmacotherapeutic approach to T2D. Each class of agents is presented by mechanism of action, details of administration, side effect profile, cost, and use in certain populations including heart failure, non-alcoholic fatty liver disease, obesity, chronic kidney disease, and older individuals. We also review targets of novel therapeutic T2D agent development. Finally, we outline an up-to-date treatment approach that starts with identification of an individualized goal for glycemic control then selection, initiation, and further intensification of a personalized therapeutic plan for T2D.
Background
Risk factors for heart failure with preserved ejection fraction (HFpEF) include hypertension, age, sex, and obesity. Emerging evidence suggests that the gut microbiota independently contributes to each one of these risk factors, potentially mediated via gut microbial‐derived metabolites such as short‐chain fatty acids. In this study, we determined whether the gut microbiota were associated with HFpEF and its risk factors.
Methods and Results
We recruited 26 patients with HFpEF and 67 control participants from 2 independent communities. Patients with HFpEF were diagnosed by exercise right heart catheterization. We assessed the gut microbiome by bacterial 16S rRNA sequencing and food intake by the food frequency questionnaire. There was a significant difference in α‐diversity (eg, number of microbes) and β‐diversity (eg, type and abundance of microbes) between both cohorts of controls and patients with HFpEF ( P =0.001). We did not find an association between β‐diversity and specific demographic or hemodynamic parameters or risk factors for HFpEF. The Firmicutes to Bacteroidetes ratio, a commonly used marker of gut dysbiosis, was lower, but not significantly so ( P =0.093), in the patients with HFpEF. Compared with controls, the gut microbiome of patients with HFpEF was depleted of bacteria that are short‐chain fatty acid producers. Consistent with this, participants with HFpEF consumed less dietary fiber (17.6±7.7 versus 23.2±8.8 g/day; P =0.016).
Conclusions
We demonstrate key changes in the gut microbiota in patients with HFpEF, including the depletion of bacteria that generate metabolites known to be important for cardiovascular homeostasis. Further studies are required to validate the role of these gut microbiota and metabolites in the pathophysiology of HFpEF.
The endothelium is the single-cell monolayer that lines the entire vasculature. The endothelium has a barrier function to separate blood from organs and tissues but also has an increasingly appreciated role in anti-coagulation, vascular senescence, endocrine secretion, suppression of inflammation and beyond. In modern times, endothelial cells have been identified as the source of major endocrine and vaso-regulatory factors principally the dissolved lipophilic vosodilating gas, nitric oxide and the potent vascular constricting G protein receptor agonists, the peptide endothelin. The role of the endothelium can be conveniently conceptualized. Continued investigations of the mechanism of endothelial dysfunction will lead to novel therapies for cardiovascular disease. In this review, we discuss the impact of endothelial dysfunction on cardiovascular disease and assess the clinical relevance of endothelial dysfunction.
Background
Metformin and sulfonylurea are commonly prescribed oral medications for type 2 diabetes mellitus. The association of metformin and sulfonylureas on heart failure outcomes in patients with reduced estimated glomerular filtration rate remains poorly understood.
Methods and Results
This retrospective cohort combined data from National Veterans Health Administration, Medicare, Medicaid, and the National Death Index. New users of metformin or sulfonylurea who reached an estimated glomerular filtration rate of 60 mL/min per 1.73 m ² or serum creatinine of 1.5 mg/dL and continued metformin or sulfonylurea were included. The primary outcome was hospitalization for heart failure. Echocardiogram reports were obtained to determine each patient's ejection fraction (EF) (reduced EF <40%; midrange EF 40%–49%; ≥50%). The primary analysis estimated the cause‐specific hazard ratios for metformin versus sulfonylurea and estimated the cumulative incidence functions for heart failure hospitalization and competing events. The weighted cohort included 24 685 metformin users and 24 805 sulfonylurea users with reduced kidney function (median age 70 years, estimated glomerular filtration rate 55.8 mL/min per 1.73 m ² ). The prevalence of underlying heart failure (12.1%) and cardiovascular disease (31.7%) was similar between groups. There were 16.9 (95% CI, 15.8–18.1) versus 20.7 (95% CI, 19.5–22.0) heart failure hospitalizations per 1000 person‐years for metformin and sulfonylurea users, respectively, yielding a cause‐specific hazard of 0.85 (95% CI, 0.78–0.93). Among heart failure hospitalizations, 44.5% did not have echocardiogram information available; 29.3% were categorized as reduced EF, 8.9% as midrange EF, and 17.2% as preserved EF. Heart failure hospitalization with reduced EF (hazard ratio, 0.79; 95% CI, 0.67–0.93) and unknown EF (hazard ratio, 0.84; 95% CI 0.74–96) were significantly lower in metformin versus sulfonylurea users.
Conclusions
Among patients with type 2 diabetes mellitus who developed worsening kidney function, persistent metformin compared with sulfonylurea use was associated with reduced heart failure hospitalization.
Background: Metformin is the first-line antidiabetic medication for type 2 diabetes mellitus (T2DM). However, the association between metformin and outcomes in T2DM patients with heart failure with preserved ejection fraction (HFpEF) is still unknown. We aimed to explore the association between metformin and adverse outcome in T2DM patients with HFpEF.
Methods: A total of 372 T2DM patients with HFpEF hospitalized from January 1, 2013, to December 31, 2017, were included in this retrospective cohort study. There were 113 and 259 subjects in metformin and non-metformin group, respectively. Subjects were followed up for all-cause mortality, cardiovascular death, all-cause hospitalization, and heart failure hospitalization.
Results: The median follow-up period was 47 months. Eleven patients (2.49% per patient-year) in the metformin group and 56 patients (5.52% per patient-year) in the non-metformin group deceased during follow-up ( P = 0.031). However, a multivariable Cox regression failed to show that metformin was an independent factor of all-cause mortality [HR (95% CI) = 0.682 (0.346–1.345); P = 0.269]. A subgroup analysis revealed a significant association between metformin and all-cause mortality in patients with a higher hemoglobin A1c (HbA1c) level (HbA1c ≥7%) [HR (95% CI) = 0.339 (0.117–0.997); P = 0.045]. The 4-year estimated number needed to treat (NNT) with metformin compared with non-metformin for all-cause mortality was 12 in all populations and 8 in the HbA1c ≥7% subgroup.
Conclusions: Metformin was not independently associated with clinical outcomes in patients with T2DM and HFpEF, but was associated with lower all-cause mortality in the subgroup of patients with poor glycemic control. Prospective, randomized controlled trials are needed to further verify these findings.
PurposeThe glucose-lowering drug metformin has recently been shown to reduce myocardial oxygen consumption and increase myocardial efficiency in chronic heart failure (HF) patients without diabetes. However, it remains to be established whether these beneficial myocardial effects are associated with metformin-induced alterations in whole-body insulin sensitivity and substrate metabolism.Methods
Eighteen HF patients with reduced ejection fraction and without diabetes (median age, 65 (interquartile range 55–68); ejection fraction 39 ± 6%; HbA1c 5.5 to 6.4%) were randomized to receive metformin (n = 10) or placebo (n = 8) for 3 months. We studied the effects of metformin on whole-body insulin sensitivity using a two-step hyperinsulinemic euglycemic clamp incorporating isotope-labeled tracers of glucose, palmitate, and urea. Substrate metabolism and skeletal muscle mitochondrial respiratory capacity were determined by indirect calorimetry and high-resolution respirometry, and body composition was assessed by bioelectrical impedance analysis. The primary outcome measure was change in insulin sensitivity.ResultsCompared with placebo, metformin treatment lowered mean glycated hemoglobin levels (absolute mean difference, − 0.2%; 95% CI − 0.3 to 0.0; p = 0.03), reduced body weight (− 2.8 kg; 95% CI − 5.0 to − 0.6; p = 0.02), and increased fasting glucagon levels (3.2 pmol L−1; 95% CI 0.4 to 6.0; p = 0.03). No changes were observed in whole-body insulin sensitivity, endogenous glucose production, and peripheral glucose disposal or oxidation with metformin. Equally, resting energy expenditure, lipid and urea turnover, and skeletal muscle mitochondrial respiratory capacity remained unaltered.Conclusion
Increased myocardial efficiency during metformin treatment is not mediated through improvements in insulin action in HF patients without diabetes.Clinical Trial RegistrationURL: https://clinicaltrials.gov. Unique identifier: NCT02810132. Date of registration: June 22, 2016.
Background:
Observational series suggest a mortality benefit from metformin in the heart failure (HF) population. However, the benefit of metformin in HF with preserved ejection fraction (HFpEF) has yet to be explored. We performed a systematic review and meta-analysis to identify whether variation in EF impacts mortality outcomes in HF patients treated with metformin.
Methods:
MEDLINE and EMBASE were searched up to October 2019. Observational studies and randomised trials reporting mortality in HF patients and the proportion of patients with an EF > 50% at baseline were included. Other baseline variables were used to assess for heterogeneity in treatment outcomes between groups. Regression models were used to determine the interaction between metformin and subgroups on mortality.
Results:
Four studies reported the proportion of patients with a preserved EF and were analysed. Metformin reduced mortality in both preserved or reduced EF after adjustment with HF therapies such as angiotensin converting enzyme inhibitors (ACEi) and beta-blockers (β = - 0.2 [95% CI - 0.3 to - 0.1], p = 0.02). Significantly greater protective effects were seen with EF > 50% (p = 0.003). Metformin treatment with insulin, ACEi and beta-blocker therapy were also shown to have a reduction in mortality (insulin p = 0.002; ACEi p < 0.001; beta-blocker p = 0.017), whereas female gender was associated with worse outcomes (p < 0.001).
Conclusions:
Metformin treatment is associated with a reduction in mortality in patients with HFpEF.
Early treatment may prevent or delay the onset of type 2 diabetes mellitus (T2DM) in individuals who are at high risk. Lifestyle interventions and the hypoglycemic drug metformin have been shown to reduce T2DM incidence. The effectiveness of such interventions may be enhanced by targeting environmental factors such as the intestinal microbiota, which has been proven to predict the response to lifestyle interventions and play a part in mediating the glucose-lowering effects of metformin. Shifts in the intestinal microbiota “towards a more balanced state” may promote glucose homeostasis by regulating short-chain fatty acids’ production. This study aimed to investigate the safety and effect of a multi-strain probiotic on glycemic, inflammatory, and permeability markers in adults with prediabetes and early T2DM and to assess whether the probiotic can enhance metformin’s effect on glycaemia. A randomised controlled pilot study was conducted in 60 adults with a BMI ≥ 25 kg/m2 and with prediabetes or T2DM (within the previous 12 months). The participants were randomised to a multi-strain probiotic (L. plantarum, L. bulgaricus, L. gasseri, B. breve, B. animalis sbsp. lactis, B. bifidum, S. thermophilus, and S. boulardii) or placebo for 12 weeks. Analyses of the primary outcome (fasting plasma glucose) and secondary outcomes, including, but not limited to, circulating lipopolysaccharide, zonulin, and short chain fatty acids and a metagenomic analysis of the fecal microbiome were performed at baseline and 12 weeks post-intervention. The results showed no significant differences in the primary and secondary outcome measures between the probiotic and placebo group. An analysis of a subgroup of participants taking metformin showed a decrease in fasting plasma glucose, HbA1c, insulin resistance, and zonulin; an increase in plasma butyrate concentrations; and an enrichment of microbial butyrate-producing pathways in the probiotic group but not in the placebo group. Probiotics may act as an adjunctive to metformin by increasing the production of butyrate, which may consequently enhance glucose management.
PurposeTo evaluate the effects of metformin on serum lipid profiles in nondiabetic adults through a comprehensive meta-analysis.Methods
In the present meta-analysis, randomized and controlled trials were collected by searching PubMed, Embase, and Cochrane Libraries from inception to April 2019. Compared with placebos, the effects of metformin treatment on lipid profiles in nondiabetic adults were evaluated.ResultsForty-seven studies from 45 articles including 5731 participants were enrolled. Pooled results showed that metformin had significant effects on total cholesterol (mean change −6.57 mg/dl; 95% CI −9.66, −3.47; P = 0.000) and LDL-c (mean change −4.69 mg/dl; 95% CI −7.38, −2.00; P = 0.001), but insignificant effects on HDL-c (mean change −4.33 mg/dl; 95% CI −9.62, 0.96; P = 0.109) and triglyceride (mean change −0.85 mg/dl; 95% CI −0.36, 2.06; P = 0.169). Significant heterogeneities were found for all lipid profiles (HDL-c = 85.5%; LDL-c = 59.9%; total cholesterol = 75.3% and triglyceride = 67.1%). Different from the pooled data, in a subgroup analysis, the effect of metformin on triglyceride in patients with polycystic ovarian syndrome (PCOS) was significant with a mean reduction of 8.15 mg/dl. In addition, sensitivity analysis showed that the pooled effects of metformin on serum lipid profiles were stable. Publication bias derived from funnel plots or Begg’s tests (P = 0.933, 0.860, 0.904, and 0.567 for HDL-c, LDL-c, total cholesterol, and triglyceride, respectively) was not significant.Conclusion
This meta-analysis revealed that metformin could reduce total cholesterol and LDL-c in nondiabetic adults. In addition, metformin might exert a triglyceride-lowering effect in nondiabetics with PCOS status.
The American Diabetes Association and the European Association for the Study of Diabetes have briefly updated their 2018 recommendations on management of hyperglycaemia, based on important research findings from large cardiovascular outcomes trials published in 2019. Important changes include: (1) the decision to treat high-risk individuals with a glucagon-like-peptide 1 (GLP-1) receptor agonist or sodium–glucose cotransporter 2 (SGLT2) inhibitor to reduce major adverse cardiovascular events (MACE), hospitalisation for heart failure (hHF), cardiovascular death or chronic kidney disease (CKD) progression should be considered independently of baseline HbA1c or individualised HbA1c target; (2) GLP-1 receptor agonists can also be considered in patients with type 2 diabetes without established cardiovascular disease (CVD) but with the presence of specific indicators of high risk; and (3) SGLT2 inhibitors are recommended in patients with type 2 diabetes and heart failure, particularly those with heart failure with reduced ejection fraction, to reduce hHF, MACE and CVD death, as well as in patients with type 2 diabetes with CKD (eGFR 30 to ≤60 ml min−1 [1.73 m]−2 or urinary albumin-to-creatinine ratio >30 mg/g, particularly >300 mg/g) to prevent the progression of CKD, hHF, MACE and cardiovascular death.
Background:
The use of metformin after acute myocardial infarction (AMI) has been associated with reduced mortality in people with type 2 diabetes mellitus (T2DM). However, it is not known if it is acutely cardioprotective in patients taking metformin at the time of AMI. We compared patient outcomes according to metformin status at the time of admission for fatal and non-fatal AMI in a large cohort of patients in England.
Methods:
This study used linked data from primary care, hospital admissions and death registry from 4.7 million inhabitants in England, as part of the CALIBER resource. The primary endpoint was a composite of acute myocardial infarction requiring hospitalisation, stroke and cardiovascular death. The secondary endpoints were heart failure (HF) hospitalisation and all-cause mortality.
Results:
4,030 patients with T2DM and incident AMI recorded between January 1998 and October 2010 were included. At AMI admission, 63.9% of patients were receiving metformin and 36.1% another oral hypoglycaemic drug. Median follow-up was 343 (IQR: 1-1436) days. Adjusted analyses showed an increased hazard of the composite endpoint in metformin users compared to non-users (HR 1.09 [1.01-1.19]), but not of the secondary endpoints. The higher risk of the composite endpoint in metformin users was only observed in people taking metformin at AMI admission, whereas metformin use post-AMI was associated with a reduction in risk of all-cause mortality (0.76 [0.62-0.93], P = 0.009).
Conclusions:
Our study suggests that metformin use at the time of first AMI is associated with increased risk of cardiovascular disease and death in patients with T2DM, while its use post-AMI might be beneficial. Further investigation in well-designed randomised controlled trials is indicated, especially in view of emerging evidence of cardioprotection from sodium-glucose co-transporter-2 (SGLT2) inhibitors.
Background
A beneficial effect of metformin on heart failure requires confirmation.
Methods and Results
Patients with new‐onset type 2 diabetes mellitus during 1999 to 2005 were enrolled from Taiwan's National Health Insurance database and followed up from January 1, 2006, until December 31, 2011. Main analyses were conducted in an unmatched cohort (172 542 metformin ever users and 43 744 never users) and a propensity score matched‐pair cohort (matched cohort I, 41 714 ever users and 41 714 never users). Hazard ratios were estimated by Cox hazard regression incorporated with the inverse probability of treatment weighting using the propensity score in the unmatched cohort and by naïve method in the matched cohort I. Results showed that the respective incidence rates of heart failure hospitalization in ever users and never users were 304.25 and 864.31 per 100 000 person‐years in the unmatched cohort (hazard ratio, 0.350; 95% CI, 0.329–0.373) and were 469.66 and 817.01 per 100 000 person‐years in the matched cohort I (hazard ratio, 0.571; 95% CI, 0.526–0.620). A dose‐response pattern was consistently observed while estimating hazard ratios for the tertiles of cumulative duration of metformin therapy. Findings were supported by another propensity score–matched cohort created after excluding 10 potential instrumental variables in the estimation of propensity score (matched cohort II ). An approximately 40% lower risk was consistently observed among ever users in different models derived from the matched cohorts I and II , but models from the matched cohort II were less subject to model misspecification.
Conclusions
Metformin use is associated with a lower risk of heart failure hospitalization.
Background:
Metformin is the most widely prescribed drug to lower glucose and has a definitive effect on the cardiovascular system. The goal of this systematic review and meta-analysis is to assess the effects of metformin on mortality and cardiac function among patients with coronary artery disease (CAD).
Methods:
Relevant studies reported before October 2018 was retrieved from databases including PubMed, EMBASE, Cochrane Library and Web of Science. Hazard ratio (HR) was calculated to evaluate the all-cause mortality, cardiovascular mortality and incidence of cardiovascular events (CV events), to figure out the level of left ventricular ejection fraction (LVEF), creatine kinase MB (CK-MB), type B natriuretic peptide (BNP) and to compare the average level of low density lipoprotein (LDL).
Results:
In this meta-analysis were included 40 studies comprising 1,066,408 patients. The cardiovascular mortality, all-cause mortality and incidence of CV events were lowered to adjusted HR (aHR) = 0.81, aHR = 0.67 and aHR = 0. 83 respectively after the patients with CAD were given metformin. Subgroup analysis showed that metformin reduced all-cause mortality in myocardial infarction (MI) (aHR = 0.79) and heart failure (HF) patients (aHR = 0.84), the incidence of CV events in HF (aHR = 0.83) and type II diabetes mellitus (T2DM) patients (aHR = 0.83), but had no significant effect on MI (aHR = 0.87) and non-T2DM patients (aHR = 0.92). Metformin is superior to sulphonylurea (aHR = 0.81) in effects on lowering the incidence of CV events and in effects on patients who don't use medication. The CK-MB level in the metformin group was lower than that in the control group standard mean difference (SMD) = - 0.11). There was no significant evidence that metformin altered LVEF (MD = 2.91), BNP (MD = - 0.02) and LDL (MD = - 0.08).
Conclusion:
Metformin reduces cardiovascular mortality, all-cause mortality and CV events in CAD patients. For MI patients and CAD patients without T2DM, metformin has no significant effect of reducing the incidence of CV events. Metformin has a better effect of reducing the incidence of CV events than sulfonylureas.
Background:
We previously reported that a median of 5.6 years of intensive as compared with standard glucose lowering in 1791 military veterans with type 2 diabetes resulted in a risk of major cardiovascular events that was significantly lower (by 17%) after a total of 10 years of combined intervention and observational follow-up. We now report the full 15-year follow-up.
Methods:
We observationally followed enrolled participants (complete cohort) after the conclusion of the original clinical trial by using central databases to identify cardiovascular events, hospitalizations, and deaths. Participants were asked whether they would be willing to provide additional data by means of surveys and chart reviews (survey cohort). The prespecified primary outcome was a composite of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, and death from cardiovascular causes. Death from any cause was a prespecified secondary outcome.
Results:
There were 1655 participants in the complete cohort and 1391 in the survey cohort. During the trial (which originally enrolled 1791 participants), the separation of the glycated hemoglobin curves between the intensive-therapy group (892 participants) and the standard-therapy group (899 participants) averaged 1.5 percentage points, and this difference declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a period of 15 years of follow-up (active treatment plus post-trial observation), the risks of major cardiovascular events or death were not lower in the intensive-therapy group than in the standard-therapy group (hazard ratio for primary outcome, 0.91; 95% confidence interval [CI], 0.78 to 1.06; P = 0.23; hazard ratio for death, 1.02; 95% CI, 0.88 to 1.18). The risk of major cardiovascular disease outcomes was reduced, however, during an extended interval of separation of the glycated hemoglobin curves (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but this benefit did not continue after equalization of the glycated hemoglobin levels (hazard ratio, 1.26; 95% CI, 0.90 to 1.75).
Conclusions:
Participants with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had a lower risk of cardiovascular events than those who received standard therapy only during the prolonged period in which the glycated hemoglobin curves were separated. There was no evidence of a legacy effect or a mortality benefit with intensive glucose control. (Funded by the VA Cooperative Studies Program; VADT ClinicalTrials.gov number, NCT00032487.).
Metformin is a drug from the biguanide family that is used for decades as the first-line therapeutic choice for the treatment of type 2 diabetes. Despite its worldwide democratization, owing to its clinical efficacy, high safety profile and cheap cost, the exact mechanism(s) of action of this anti-hyperglycemic molecule with pleiotropic properties still remains to be fully elucidated. The concept that metformin would exert some of its actions though modulation of the mitochondrial bioenergetics was initially forged in the 50s but undeniably revived at the beginning of the twenty-first century when it was shown to induce a weak but specific inhibition of the mitochondrial respiratory-chain complex 1. Furthermore, metformin has been reported to reduce generation of reactive oxygen species at the complex 1 and to prevent mitochondrial-mediated apoptosis, suggesting that it can protect against oxidative stress-induced cell death. Nevertheless, despite some recent progress and the demonstration of its key role in the inhibition of hepatic gluconeogenesis, the exact nature of the mitochondrial interaction between the drug and the complex 1 is still poorly characterized. Recent studies reported that metformin may also have anti-neoplastic properties by inhibiting cancer cell growth and proliferation, at least partly through its mitochondrial action. As such, many trials are currently conducted for exploring the repositioning of metformin as a potential drug for cancer therapy. In this mini-review, we discuss both historical and more recent findings on the central role played by the interaction between metformin and the mitochondria in its cellular mechanism of action.
Management guidelines continue to identify metformin as initial pharmacologic antidiabetic therapy of choice for people with type 2 diabetes without contraindications, despite recent randomised trials that have demonstrated significant improvements in cardiovascular outcomes with newer classes of antidiabetic therapies. The purpose of this review is to summarise the current state of knowledge of metformin's therapeutic actions on blood glucose and cardiovascular clinical evidence, and to consider the mechanisms which underlie them. The effects of metformin on glycaemia occur mainly in the liver, but metformin‐stimulated glucose disposal by the gut has emerged as an increasingly import site of action of metformin. Additionally, metformin induces increased secretion of GLP‐1 from intestinal L‐cells. Clinical cardiovascular protection with metformin is supported by three randomised outcomes trials (in newly‐diagnosed and late stage, insulin‐treated type 2 diabetes patients) and a wealth of observational data. Initial evidence suggests that co‐treatment with metformin may enhance the impact of newer, incretin‐based therapies on cardiovascular outcomes, an important observation as metformin can be combined with any other antidiabetic agent. Multiple potential mechanisms support the concept of cardiovascular protection with metformin beyond those provided by reduced blood glucose, including weight loss, improvements in haemostatic function, reduced inflammation and oxidative stress, and inhibition of key steps in the process of atherosclerosis. Accordingly, metformin remains well placed to support improvements in cardiovascular outcomes, from diagnosis and throughout the course of type 2 diabetes, even in this new age of improved outcomes in type 2 diabetes.
Background:
Risk of cardiovascular disease (CVD) and mortality for patients with versus without type 2 diabetes mellitus (T2DM) appears to vary by the age at T2DM diagnosis, but few population studies have analyzed mortality and CVD outcomes associations across the full age range.
Methods:
With use of the Swedish National Diabetes Registry, everyone with T2DM registered in the Registry between 1998 and 2012 was included. Controls were randomly selected from the general population matched for age, sex, and county. The analysis cohort comprised 318 083 patients with T2DM matched with just <1.6 million controls. Participants were followed from 1998 to 2013 for CVD outcomes and to 2014 for mortality. Outcomes of interest were total mortality, cardiovascular mortality, noncardiovascular mortality, coronary heart disease, acute myocardial infarction, stroke, heart failure, and atrial fibrillation. We also examined life expectancy by age at diagnosis. We conducted the primary analyses using Cox proportional hazards models in those with no previous CVD and repeated the work in the entire cohort.
Results:
Over a median follow-up period of 5.63 years, patients with T2DM diagnosed at ≤40 years had the highest excess risk for most outcomes relative to controls with adjusted hazard ratio (95% CI) of 2.05 (1.81-2.33) for total mortality, 2.72 (2.13-3.48) for cardiovascular-related mortality, 1.95 (1.68-2.25) for noncardiovascular mortality, 4.77 (3.86-5.89) for heart failure, and 4.33 (3.82-4.91) for coronary heart disease. All risks attenuated progressively with each increasing decade at diagnostic age; by the time T2DM was diagnosed at >80 years, the adjusted hazard ratios for CVD and non-CVD mortality were <1, with excess risks for other CVD outcomes substantially attenuated. Moreover, survival in those diagnosed beyond 80 was the same as controls, whereas it was more than a decade less when T2DM was diagnosed in adolescence. Finally, hazard ratios for most outcomes were numerically greater in younger women with T2DM.
Conclusions:
Age at diagnosis of T2DM is prognostically important for survival and cardiovascular risks, with implications for determining the timing and intensity of risk factor interventions for clinical decision making and for guideline-directed care. These observations amplify support for preventing/delaying T2DM onset in younger individuals.
Transient, reversible blockade of complex I during early reperfusion after ischemia limits cardiac injury. We studied the cardioprotection of high dose of metformin in cultured cells and mouse hearts via the novel mechanism of acute downregulation of complex I. The effect of high dose of metformin on complex I activity was studied in isolated heart mitochondria and cultured H9c2 cells. Protection with metformin was evaluated in H9c2 cells at reoxygenation and at early reperfusion in isolated perfused mouse hearts and in vivo regional ischemia reperfusion. Acute, high-dose metformin treatment inhibited complex I in ischemia-damaged mitochondria and in H9c2 cells following hypoxia. Accompanying the complex I modulation, high-dose metformin at reoxygenation decreased death in H9c2 cells. Acute treatment with high-dose metformin at the end of ischemia reduced infarct size following ischemia reperfusion in vitro and in vivo, including in the AMP kinase-dead mouse. Metformin treatment during early reperfusion improved mitochondrial calcium retention capacity, indicating decreased permeability transition pore (MPTP) opening. Acute, high-dose metformin therapy decreased cardiac injury through inhibition of complex I accompanied by attenuation of MPTP opening. Moreover, in contrast to chronic metformin treatment, protection by acute, high-dose metformin is independent of AMP-activated protein kinase activation. Thus, a single, high-dose metformin treatment at reperfusion reduces cardiac injury via modulation of complex I. U.S. Government work not protected by U.S.
Objective
Congenital heart disease (CHD) is the most frequent birth defect worldwide. The number of adult patients with CHD, now referred to as ACHD, is increasing with improved surgical and treatment interventions. However the mechanisms whereby ACHD predisposes patients to heart dysfunction are still unclear. ACHD is strongly associated with metabolic syndrome, but how ACHD interacts with poor modern lifestyle choices and other comorbidities, such as hypertension, obesity, and diabetes, is mostly unknown.
Methods
We used a newly characterized mouse genetic model of ACHD to investigate the consequences and the mechanisms associated with combined obesity and ACHD predisposition. Metformin intervention was used to further evaluate potential therapeutic amelioration of cardiac dysfunction in this model.
Results
ACHD mice placed under metabolic stress (high fat diet) displayed decreased left ventricular ejection fraction. Comprehensive physiological, biochemical, and molecular analysis showed that ACHD hearts exhibited early changes in energy metabolism with increased glucose dependence as main cardiac energy source. These changes preceded cardiac dysfunction mediated by exposure to high fat diet and were associated with increased disease severity. Restoration of metabolic balance by metformin administration prevented the development of heart dysfunction in ACHD predisposed mice.
Conclusions
This study reveals that early metabolic impairment reinforces heart dysfunction in ACHD predisposed individuals and diet or pharmacological interventions can be used to modulate heart function and attenuate heart failure. Our study suggests that interactions between genetic and metabolic disturbances ultimately lead to the clinical presentation of heart failure in patients with ACHD. Early manipulation of energy metabolism may be an important avenue for intervention in ACHD patients to prevent or delay onset of heart failure and secondary comorbidities. These interactions raise the prospect for a translational reassessment of ACHD presentation in the clinic.
Aims
Metformin is a commonly prescribed antihyperglycemic pharmacological agent and it remains a staple in the management of type II diabetes. In addition to metformin's glucose lowering effects, research has indicated that metformin inhibits glycation‐mediated and oxidative modification of lipoprotein residues. The purpose was to discuss the effects of metformin as it relates to high‐density lipoprotein (HDL) and low‐density lipoprotein (LDL) modification.
Materials and methods
Conduct a narrative and pragmatic review on the effects of metformin as it pertains to HDL and LDL modification.
Results
HDL concentration is a quantitative measure and therefore does not provide insight into its function, which is a qualitative property. Dysfunctional HDL are unable to carry out functions normally associated with HDL because they can be modified by glycating agents. Metformin may counteract HDL dysfunction by abating HDL modification. Reductions in HDL modification may improve reverse cholesterol transport ability and thus possibly diminish cardiovascular risk. Similarly, metformin‐mediated attenuations in LDL modification may reduce their atherogenic potency.
Conclusion
Metformin may partially ameliorate HDL dysfunction and reduce LDL modification by inhibiting alpha‐dicarbonyl‐mediated modification of apolipoprotein residues; consequently, the results are salient because cardiovascular disease incidence may be reduced given that reverse cholesterol transport activity predicts risk, and modified LDL are proatherogenic.
Oxidative stress and inflammation interact in the development of diabetic atherosclerosis. Intracellular hyperglycemia promotes production of mitochondrial reactive oxygen species (ROS), increased formation of intracellular advanced glycation end-products, activation of protein kinase C, and increased polyol pathway flux. ROS directly increase the expression of inflammatory and adhesion factors, formation of oxidized-low density lipoprotein, and insulin resistance. They activate the ubiquitin pathway, inhibit the activation of AMP-protein kinase and adiponectin, decrease endothelial nitric oxide synthase activity, all of which accelerate atherosclerosis. Changes in the composition of the gut microbiota and changes in microRNA expression that influence the regulation of target genes that occur in diabetes interact with increased ROS and inflammation to promote atherosclerosis. This review highlights the consequences of the sustained increase of ROS production and inflammation that influence the acceleration of atherosclerosis by diabetes. The potential contributions of changes in the gut microbiota and microRNA expression are discussed.
Accumulating evidence shows that metformin is an insulin-sensitizing antidiabetic drug widely used in the treatment of type 2 diabetes mellitus (T2DM), which can exert favorable effects on cardiovascular risk and may be safely used in patients with heart failure (HF), and even able to reduce the incidence of HF and to reduce HF mortality. In failing hearts, metformin improves myocardial energy metabolic status through the activation of AMP (adenosine monophosphate)-activated protein kinase (AMPK) and the regulation of lipid and glucose metabolism. By increasing nitric oxide (NO) bioavailability, limiting interstitial fibrosis, reducing the deposition of advanced glycation end-products (AGEs), and inhibiting myocardial cell apoptosis metformin reduces cardiac remodeling and hypertrophy, and thereby preserves left ventricular systolic and diastolic functions. While a lot of preclinical and clinical studies showed the cardiovascular safety of metformin therapy in diabetic patients and HF, to confirm observed benefits, the specific large-scale trials configured for HF development in diabetic patients as a primary endpoints are necessary.
Patients with diabetes type 2 have an increased risk for cardiovascular disease and commonly use combination therapy consisting of the anti-diabetic drug metformin and a cholesterol-lowering statin. However, both drugs act on glucose and lipid metabolism which could lead to adverse effects when used in combination as compared to monotherapy. In this review, the proposed molecular mechanisms of action of statin and metformin therapy in patients with diabetes and dyslipidemia are critically assessed, and a hypothesis for mechanisms underlying interactions between these drugs in combination therapy is developed.
Introduction: The majority of patients with type 2 diabetes also have obesity. Obesity increases the risk of developing diabetes and is associated with worsened glycemic control and increased morbidity and mortality in individuals with diabetes. Sustained weight loss is associated with improved glycemic control, potential for diabetes remission, and decreased medical expenditures.
Areas covered: Herein, the impact of commonly utilized, non-insulin, glucose-lowering drugs on body weight in patients with type 2 diabetes are discussed. The weight change magnitudes, mechanisms, and any within-class differences are also explored.
Expert opinion: The weight impact of diabetes medications should be considered when designing treatment regimens, especially in patients who are overweight or have obesity. Lifestyle modification is paramount for optimal diabetes management. Therapeutic regimens should ideally be designed to maximize weight loss and at least minimize or avoid weight gain. Future glucose-lowering medications should continue to offer improvement in cardiovascular risk factors, including weight, in order to be accepted into the armamentarium of diabetes therapy. Therapeutic regimens should be designed to help patients with diabetes and obesity achieve both glycemic and weight goals. Management of these disease states is expected to become increasingly integrated.
Accumulating evidence implicates gut microbiota as promising targets for the treatment of type 2 diabetes mellitus (T2DM). With a randomized clinical trial, we tested the hypothesis that alteration of gut microbiota may be involved in the alleviation of T2DM with hyperlipidemia by metformin and a specifically designed herbal formula (AMC). Four hundred fifty patients with T2DM and hyperlipidemia were randomly assigned to either the metformin- or AMC-treated group. After 12 weeks of treatment, 100 patients were randomly selected from each group and assessed for clinical improvement. The effects of the two drugs on the intestinal microbiota were evaluated by analyzing the V3 and V4 regions of the 16S rRNA gene by Illumina sequencing and multivariate statistical methods. Both metformin and AMC significantly alleviated hyperglycemia and hyperlipidemia and shifted gut microbiota structure in diabetic patients. They significantly increased a coabundant group represented by Blautia spp., which significantly correlated with the improvements in glucose and lipid homeostasis. However, AMC showed better efficacies in improving homeostasis model assessment of insulin resistance (HOMA-IR) and plasma triglyceride and also exerted a larger effect on gut microbiota. Furthermore, only AMC increased the coabundant group represented by Faecalibacterium spp., which was previously reported to be associated with the alleviation of T2DM in a randomized clinical trial. Metformin and the Chinese herbal formula may ameliorate type 2 diabetes with hyperlipidemia via enriching beneficial bacteria, such as Blautia and Faecalibacterium spp.
Previous studies suggested a possible gut microbiota dysbiosis in chronic heart failure (CHF). However, direct evidence was lacking. In this study, we investigated the composition and metabolic patterns of gut microbiota in CHF patients to provide direct evidence and comprehensive understanding of gut microbiota dysbiosis in CHF. We enrolled 53 CHF patients and 41 controls. Metagenomic analyses of faecal samples and metabolomic analyses of faecal and plasma samples were then performed. We found that the composition of gut microbiota in CHF was significantly different from controls. Faecalibacterium prausnitzii decrease and Ruminococcus gnavus increase were the essential characteristics in CHF patients' gut microbiota. We also observed an imbalance of gut microbes involved in the metabolism of protective metabolites such as butyrate and harmful metabolites such as trimethylamine N-oxide in CHF patients. Metabolic features of both faecal and plasma samples from CHF patients also significantly changed. Moreover, alterations in faecal and plasma metabolic patterns correlated with gut microbiota dysbiosis in CHF. Taken together, we found that CHF was associated with distinct gut microbiota dysbiosis and pinpointed the specific core bacteria imbalance in CHF, along with correlations between changes in certain metabolites and gut microbes.
Aims/hypothesis:
Metformin is the most-prescribed oral medication to lower blood glucose worldwide. Yet previous systematic reviews have raised doubts about its effectiveness in reducing risk of cardiovascular disease, the most costly complication of type 2 diabetes. We aimed to systematically identify and pool randomised trials reporting cardiovascular outcomes in which the effect of metformin was 'isolated' through comparison to diet, lifestyle or placebo.
Methods:
We performed an electronic literature search of MEDLINE, EMBASE and the Cochrane Library. We also manually screened the reference lists of previous meta-analyses of trials of metformin identified through a MEDLINE search. We included randomised controlled trials of adults with type 2 diabetes comparing any dose and preparation of oral metformin with no intervention, placebo or a lifestyle intervention and reporting mortality or a cardiovascular outcome.
Results:
We included ten articles reporting 13 trials (including a total of 2079 individuals with type 2 diabetes allocated to metformin and a similar number to comparison groups) of which only four compared metformin with placebo and collected data on cardiovascular outcomes. Participants were mainly white, aged ≤65 years, overweight/obese and with poor glycaemic control. Summary estimates were based on a small number of events: 416 myocardial infarctions/ischaemic heart disease events in seven studies and 111 strokes in four studies. The UK Prospective Diabetes Study (UKPDS) contributed the majority of data to the summary estimates, with weights ranging from 52.3% for myocardial infarction to 70.5% for stroke. All outcomes, with the exception of stroke, favoured metformin, with limited heterogeneity between studies, but none achieved statistical significance. Effect sizes (Mantel-Haenszel RR) were: all-cause mortality 0.96 (95% CI 0.84, 1.09); cardiovascular death 0.97 (95% CI 0.80, 1.16); myocardial infarction 0.89 (95% CI 0.75, 1.06); stroke 1.04 (95% CI 0.73, 1.48); and peripheral vascular disease 0.81 (95% CI 0.50, 1.31).
Conclusions/interpretation:
There remains uncertainty about whether metformin reduces risk of cardiovascular disease among patients with type 2 diabetes, for whom it is the recommended first-line drug. Although this is mainly due to absence of evidence, it is unlikely that a definitive placebo-controlled cardiovascular endpoint trial among people with diabetes will be forthcoming. Alternative approaches to reduce the uncertainty include the use of electronic health records in long-term pragmatic evaluations, inclusion of metformin in factorial trials, publication of cardiovascular outcome data from adverse event reporting in trials of metformin and a cardiovascular endpoint trial of metformin among people without diabetes.
Metformin is widely used in the treatment of type 2 diabetes (T2D), but its mechanism of action is poorly defined. Recent evidence implicates the gut microbiota as a site of metformin action. In a double-blind study, we randomized individuals with treatment-naive T2D to placebo or metformin for 4 months and showed that metformin had strong effects on the gut microbiome. These results were verified in a subset of the placebo group that switched to metformin 6 months after the start of the trial. Transfer of fecal samples (obtained before and 4 months after treatment) from metformin-treated donors to germ-free mice showed that glucose tolerance was improved in mice that received metformin-altered microbiota. By directly investigating metformin–microbiota interactions in a gut simulator, we showed that metformin affected pathways with common biological functions in species from two different phyla, and many of the metformin-regulated genes in these species encoded metalloproteins or metal transporters. Our findings provide support for the notion that altered gut microbiota mediates some of metformin's antidiabetic effects.
Background
Sodium–glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain.
Methods
In this double-blind trial, we randomly assigned 5988 patients with class II–IV heart failure and an ejection fraction of more than 40% to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure.
Results
Over a median of 26.2 months, a primary outcome event occurred in 415 of 2997 patients (13.8%) in the empagliflozin group and in 511 of 2991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin.
Conclusions
Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951).
Aim:
To determine whether metformin's effects on carotid artery intima-media thickness (cIMT) in type 1 diabetes differ according to smoking status.
Methods:
Regression model effect estimates for the effect of metformin versus placebo (double-blind) on carotid IMT were calculated as a subgroup analysis of the REMOVAL trial.
Results:
In 428 randomized participants (227 never-smokers, 201 ever-smokers), averaged mean carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (-0.012 mm, 95% CI -0.021 to -0.002; p = .0137) but not in ever-smokers (0.003 mm, 95% CI -0.008 to 0.014; p = .5767); and similarly in non-current smokers (-0.008 mm, 95% CI -0.015 to -0.00001; p = .0497) but not in current smokers (0.013 mm, 95% CI -0.007 to 0.032; p = .1887). Three-way interaction terms (treatment*time*smoking status) were significant for never versus ever smoking (p = .0373, prespecified) and non-current versus current smoking (p = .0496, exploratory). Averaged maximal carotid IMT progression (per year) was reduced by metformin versus placebo in never-smokers (-0.020 mm, 95% CI -0.034 to -0.006; p = .0067) but not in ever-smokers (-0.006 mm, 95% CI -0.020 to 0.008; p = .4067), although this analysis was not supported by a significant three-way interaction term.
Conclusions:
This subgroup analysis of the REMOVAL trial provides additional support for a potentially wider role of adjunct metformin therapy in cardiovascular risk management in type 1 diabetes, particularly for individuals who have never smoked cigarettes.
Aims
To evaluate the effect of sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) on major cardiovascular events (MACE) in metformin-naïve patients with type 2 diabetes (T2D).
Methods and results
A meta-analysis was performed of randomized controlled clinical trials of GLP-1RAs and SGLT-2 inhibitors on T2D populations, after searching the PubMed/MEDLINE, Embase, and Cochrane Controlled Trials databases. The primary endpoint was MACE. The secondary endpoint, explored in the subgroup of SGLT-2 inhibitors studies, was cardiovascular death or hospitalization for heart failure. A random-effects meta-analysis model was applied. Six eligible trials (three studies of SGLT-2 inhibitors and three trials of GLP-1RAs), including 11 235 patients, were identified and considered eligible for the analyses. The new antidiabetic drugs were associated with a significant reduction in MACE [odds ratio (OR): 0.82, 95% confidence interval: 0.70–0.95; I2: 48%]. The subgroup analysis showed the following findings: GLP-1RAs group, OR: 0.79 (95% confidence interval 0.68–0.93); SGLT-2 inhibitors, OR: 0.85 (95% confidence interval 0.63–1.15). SGLT-2 inhibitors were associated with a significant reduction in hospitalization for heart failure or cardiovascular mortality incidence (OR: 0.67, 95% confidence interval: 0.47–0.95; I2: 78%).
Conclusion
In this meta-analysis, new antidiabetic drugs reduced the incidence of MACE in metformin-naïve T2D patients. The beneficial effect was especially observed in the GLP-1RAs subgroup. The use of SGLT-2 inhibitors was associated with a reduction in cardiovascular death or hospitalization for heart failure. These results support the fact that metformin would not be indispensable to obtain positive cardiovascular effects when new antidiabetic drugs are administered.
Aims
The Italian Society of Diabetology and the Italian Association of Clinical Diabetologists are developing new guidelines for drug treatment of type 2 diabetes. The effects of anti-hyperglycaemic drugs on all-cause mortality and major adverse cardiovascular events (MACEs) were included among the critical clinical outcomes. We have therefore carried out an updated meta-analysis on the effects of metformin on these outcomes.
Data Synthesis
A MEDLINE and EMBASE search was performed to identify all randomized controlled trials (RCTs) with duration ≥52 weeks (published up to August 2020), in which metformin was compared with either placebo/no therapy or active comparators. MACEs (restricted for RCT reporting MACEs within their study endpoints) and all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified endpoints) were considered as the primary endpoints. Mantel-Haenszel odds ratio (MH-OR) with 95% confidence interval was calculated for all endpoints considered. Metformin was associated with a nonsignificant reduction of all-cause mortality (n=13 RCTs; MH-OR 0.80 [95% CI 0.60, 1.07]). However, this association became statistically significant after excluding RCTs comparing metformin with sulfonylureas, SGLT-2 inhibitors or GLP-1 analogues (MH-OR 0.71 [0.51, 0.99]). Metformin was associated with a lower risk of MACEs compared with comparator treatments (n=2 RCTs; MH-OR 0.52 [0.37, 0.73]), p<0.001). Similar results were obtained in a post-hoc analysis including all RCTs fulfilling criteria for inclusion in the analysis (MH-OR: 0.57 [0.42, 0.76]).
Conclusions
This updated meta-analysis suggests that metfomin is significantly associated with lower risk of MACEs and tendentially lower all-cause mortality compared to placebo or other anti-hyperglycaemic drugs.
The DANHEART trial is a multicenter, randomized (1:1), parallel-group, double-blind,
placebo-controlled study in chronic heart failure patients with reduced ejection fraction (HFrEF). This investigator driven study will include 1,500 HFrEF patients and test in a 2 x 2 factorial design: 1) if hydralazine-isosorbide dinitrate reduces the incidence of death and hospitalization with worsening heart failure vs. placebo (H-HeFT) and 2) if metformin reduces the incidence of death, worsening heart failure, acute myocardial infarction, and stroke vs. placebo in patients with diabetes or prediabetes (Met-HeFT).
The H-HeFT and Met-HeFT studies will yield new knowledge about the potential
benefit and safety of two commonly prescribed drugs with limited randomized data in patients with
HFrEF.
Background
Persistence hyperglycemia results in the formation of advanced glycation end products (AGEs) by non-enzymatic glycation. AGEs and their receptor RAGE play an important role in generation of inflammatory molecules and oxidative stress. Metformin regulates insulin responsive gene and helps to achieve glycemic control however, no extensive study reported about its role against glycation induced oxidative stress and vascular inflammation. Therefore, present work focused on clinical relevance of three months metformin therapy in type 2 diabetes mellitus patients against glycation induced oxidative stress and vascular inflammation.
Methods
Among recruited 40 medicated-naive type 2 diabetes mellitus patients, 31 patients were continued with metformin therapy. Biomarkers of plasma protein glycation (fructosamine, protein carbonyls, β-amyloid) antioxidants and oxidative stress markers (GSH, catalase, NO, PON-1, AOPP, LPO; RAGE isoforms (sRAGE, esRAGE); inflammatory markers (IL-6, TNF-α) were determined at baseline and after 3-months of treatment. The expression profile of membrane RAGE, NF-κB, CML was studied in PBMNCs and GLUT-1 in erythrocyte ghost by western blotting.
Results
Metformin showed maximum percent declined from baseline to three months therapy in levels of fructosamine, β-amyloid, sRAGE, inflammatory cytokines (IL-6, TNF-α) and percent increment in esRAGE and antioxidants levels. It showed reduced levels of IL-6 and TNF-α by declining expression of CML, membrane RAGE and NF-κB in type 2 diabetes mellitus patients after three months therapy.
Conclusions
First report in Indian diabetes mellitus patients, where metformin showed effective inhibition against glycation and receptor mediated cellular inflammation. However, these findings need to be tested in a randomized trial.
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.
Aim:
In order to disclose relations between reduction of haemoglobin A1c (HbA1c) levels and risk of major cardiovascular events (MACE), we performed a meta-analysis with metaregression of all cardiovascular outcome trials (CVOTs) so far published in patients with type 2 diabetes (T2D).
Materials and methods:
An electronic search up to February 10, 2020 was conducted to determine eligible trials. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression.
Results:
The 15 CVOTs included evaluated 138,250 patients. In the pooled analysis, the risk of MACE was significantly reduced by 9% (hazard ratio, HR = 0.91, 0.87-0.95, P <0.001) as compared with placebo, with significant heterogeneity between trials (I2 = 44%, P = 0.060) There was a robust relation between the reduction in achieved HbA1c at the end of the trial and the HR reduction for MACE (beta = -0.3169, P = 0.029), explaining most (78%) of the between-study variance; this relation was totally driven by the risk reduction of non-fatal stroke only, which explained 100% of between-study variance, and apparently restricted to the class of glucagon-like peptide 1 receptor agonists (GLP-1RAs). There was no relation between the reduction in achieved HbA1c and the HR for heart failure (variance explained = 0%) or all-cause mortality (variance explained = 6%).
Conclusion:
The blood glucose reduction observed in CVOTs may play some role in reducing the risk of non-fatal stroke, at least during treatment with GLP-1RAs, without affecting the other two components of MACE.
Aim:
Pharmacologic therapy for T2DM has proven benefits in terms of reducing elevated blood glucose levels and reducing microvascular complications. However, the impact of metformin on adverse cardiovascular outcomes and cardiovascular mortality is less clear. We carried out this meta-analysis on all published studies to estimate the overall cardiovascular risk following metformin treatment in patients with T2DM.
Methods:
We searched the PubMed, Embase and CNKI (China National Knowledge Infrastructure) databases for all articles. The odds ratio (OR) corresponding to the 95% confidence interval (95% CI) was used to assess the cardiovascular risk following metformin treatment in patients with T2DM. The statistical heterogeneity among studies was assessed with the Q-test and I2 statistics.
Results:
we collected 16 studies including 25 comparisons with 1,160,254 patients of type 2 diabetes mellitus and 701,843 patients of T2DM following metformin treatment. Our results found statistical evidence of significantly decreased cardiovascular risk to be associated with following treatment with metformin in patients with type 2 diabetes mellitus (OR = 0.57, 95% CI = 0.48 - 0.68) (shown in Table 1 and figure 2), both with the mortality (OR = 0.44, 95% CI = 0.34 - 0.57) and incidence (OR = 0.73, 95% CI = 0.59 - 0.90).
Conclusions:
our meta-analysis indicated that following metformin treatment in patients with T2DM was associated with decreased cardiovascular risk, both with the mortality and incidence. However, the heterogeneity among studies may potentially affect the final results.
Aims:
The present study tested the hypothesis that metformin treatment may increase myocardial efficiency (stroke work/myocardial oxygen consumption) in insulin-resistant patients with heart failure and reduced ejection fraction (HFrEF) without diabetes.
Methods and results:
Thirty-six HFrEF patients (ejection fraction 37 ± 8%; median age 66 years) were randomised to metformin (n = 19) or placebo (n = 17) for 3 months in addition to standard heart failure therapy. The primary endpoint was change in myocardial efficiency expressed as the work metabolic index (WMI), assessed by 11 C-acetate positron emission tomography and transthoracic echocardiography. Compared with placebo, metformin treatment (1450 ± 550 mg/day) increased WMI [absolute mean difference, 1.0 mmHg·mL·m-2 ·106 ; 95% confidence interval (CI) 0.1 to 1.8; P = 0.03], equivalent to a 20% relative efficiency increase. Patients with above-median plasma metformin levels displayed greater WMI increase (25% vs. -4%; P = 0.02). Metformin reduced myocardial oxygen consumption (-1.6 mL O2 ·100 g-1 ·min-1 ; P = 0.014). Cardiac stroke work was preserved (-2 J; 95% CI -11 to 7; P = 0.69). Metformin reduced body weight (-2.2 kg; 95% CI -3.6 to -0.8; P = 0.003) and glycated haemoglobin levels (-0.2%; 95% CI -0.3 to 0.0; P = 0.02). Changes in resting and exercise ejection fraction, global longitudinal strain, and exercise capacity did not differ between groups.
Conclusion:
Metformin treatment in non-diabetic HFrEF patients improved myocardial efficiency by reducing myocardial oxygen consumption. Measurement of circulating metformin levels differentiated responders from non-responders. These energy-sparing effects of metformin encourage further large-scale investigations in heart failure patients without diabetes.
Objective:
To investigate the factors that are associated with the effect of metformin on endothelial dysfunction in polycystic ovary syndrome (PCOS).
Patients and methods:
From March 24, 2014, to November 18, 2016, 48 women with PCOS were randomly assigned to 1500 mg/d of metformin (N=29) or no treatment (N=13) for 3 months; 42 patients (29 in the initial treatment group and 13 in the no treatment group) completed the study. Study variables were measured at baseline and after 3 months. Participants who did not receive metformin initially were then treated with metformin for another 3 months, and study variables were measured again. Endothelial function was measured as reactive hyperemia-peripheral arterial tonometry (RH-PAT) from the index finger.
Results:
The age and baseline endothelial function (mean ± SD) of the participants were 32.7±6.9 years and 1.8±0.5, respectively. No notable change was observed in endothelial function after 3 months with metformin compared with no treatment. However, after stratifying participants who received metformin based on baseline endothelial function, there was a significant improvement following metformin treatment in participants with abnormal baseline endothelial function (1.3±0.3 vs 1.7±0.3; P<.001) but not in those with normal baseline endothelial function (2.1±0.4 vs 2.0±0.5; P=.11).
Conclusion:
Metformin improves endothelial function in women with PCOS and endothelial dysfunction independent of changes in glucose metabolism, dyslipidemia, or presence of prediabetes. Metformin has a direct effect on endothelial function in PCOS, and measurement of endothelial function can stratify and follow response to metformin treatment in PCOS.
Trial registration:
clinicaltrials.gov Identifier: NCT02086526.
Background:
Type 2 diabetes mellitus (T2DM) and hypertension are independently related to increasing risk of subsequent incident heart failure with preserved ejection fraction (HFpEF). This study was designed to evaluate the influences of long-term metformin prescription in these patients.
Methods:
Using a propensity score matching of 1:2 ratio, this retrospective claims database study compared metformin prescription (n = 130) and non-metformin therapy (n = 260) in patients with T2DM and hypertension and without clinical signs or symptoms of heart failure.
Results:
With a follow-up of 6 years, the new-onset symptomatic HFpEF occurred in 6 of 130 patients in metformin group and 31 of 260 patients in non-metformin group (P = .020). Metformin also generated more prominent improvement in left ventricular (LV) diastolic function and hypertrophy. And Cox proportional hazards regression model revealed that metformin prescription (HR 0.351, 95% CI: 0.145-0.846, P = .020) was associated with a reduced risk of new onset of symptomatic HFpEF.
Conclusions:
Long-term metformin exposure was associated with protective effects in terms of the incidence of new-onset symptomatic HFpEF, LV diastolic dysfunction and hypertrophy in patients with T2DM and hypertension, which might be beneficial for the delay of HFpEF progression.
Full access is available until September 19 via:
https://authors.elsevier.com/c/1ZUKucOiQDkQo
The future of new drugs for diabetes management
Clifford J. Bailey and Caroline Day
https://doi.org/10.1016/j.diabres.2019.107785
Abstract
The future of the newer classes of glucose-lowering drugs, namely dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium/glucose co-transporter-2 (SGLT-2) inhibitors, is being redefined by the large prospective cardiovascular outcome trials (CVOTs). These trials have more than confirmed cardiovascular (CV) safety: indeed, various cardio-renal parameters have improved during some of the trials with GLP-1RAs and SGLT-2 inhibitors in type 2 diabetes. Benefits have included reductions in major adverse cardiovascular events such as fatal and non-fatal myocardial infarction and stroke, decreased hospitalization for heart failure, a slower decline in glomerular filtration rate and reduced onset and progression of albuminuria. In consequence, the CVOTs have raised expectations that newer glucose-lowering agents should offer advantages that extend beyond glycaemic control and weight management to address complications and comorbidities of type 2 diabetes, particularly cardio-renal diseases. Although large prospective outcome trials incur a high cost which may prompt reconsideration of their design, these trials are generating evidence to enable more exacting and more effective management of type 2 diabetes and its accompanying cardio-renal diseases.
Background:
Lifestyle interventions can delay the onset of type 2 diabetes in people with impaired glucose tolerance, but whether this leads subsequently to fewer complications or to increased longevity is uncertain. We aimed to assess the long-term effects of lifestyle interventions in people with impaired glucose tolerance on the incidence of diabetes, its complications, and mortality.
Methods:
The original study was a cluster randomised trial, started in 1986, in which 33 clinics in Da Qing, China, were randomly assigned to either be a control clinic or provide one of three interventions (diet, exercise, or diet plus exercise) for 6 years for 577 adults with impaired glucose tolerance who usually receive their medical care from the clinics. Subsequently, participants were followed for up to 30 years to assess the effects of intervention on the incidence of diabetes, cardiovascular disease events, composite microvascular complications, cardiovascular disease death, all-cause mortality, and life expectancy.
Findings:
Of the 577 participants, 438 were assigned to an intervention group and 138 to the control group (one refused baseline examination). After 30 years of follow-up, 540 (94%) of 576 participants were assessed for outcomes (135 in the control group, 405 in the intervention group). During the 30-year follow-up, compared with control, the combined intervention group had a median delay in diabetes onset of 3·96 years (95% CI 1·25 to 6·67; p=0·0042), fewer cardiovascular disease events (hazard ratio 0·74, 95% CI 0·59-0·92; p=0·0060), a lower incidence of microvascular complications (0·65, 0·45-0·95; p=0·025), fewer cardiovascular disease deaths (0·67, 0·48-0·94; p=0·022), fewer all-cause deaths (0·74, 0·61-0·89; p=0·0015), and an average increase in life expectancy of 1·44 years (95% CI 0·20-2·68; p=0·023).
Interpretation:
Lifestyle intervention in people with impaired glucose tolerance delayed the onset of type 2 diabetes and reduced the incidence of cardiovascular events, microvascular complications, and cardiovascular and all-cause mortality, and increased life expectancy. These findings provide strong justification to continue to implement and expand the use of such interventions to curb the global epidemic of type 2 diabetes and its consequences.
Funding:
US Centers for Disease Control and Prevention, WHO, Chinese Center for Disease Control and Prevention, World Bank, Ministry of Public Health of the People's Republic of China, Da Qing First Hospital, China-Japan Friendship Hospital, and National Center for Cardiovascular Diseases & Fuwai Hospital.
OBJECTIVE
To evaluate the effect of metformin therapy on coronary endothelial function and major adverse cardiac events (MACE) in patients with prediabetes with stable angina and nonobstructive coronary stenosis (NOCS).
RESEARCH DESIGN AND METHODS
Metformin therapy may be needed to reduce coronary heart disease risk in patients with prediabetes. A total of 258 propensity score–matched (PSM) patients with stable angina undergoing coronary angiography were enrolled in the study. Data from 86 PSM subjects with normoglycemia (NG), 86 PSM subjects with prediabetes (pre-DM), and 86 PSM subjects with prediabetes treated with metformin (pre-DM metformin) were analyzed. During coronary angiography, NOCS was categorized by luminal stenosis <40% and fractional flow reserve >0.80. In addition, we assessed the endothelial function, measuring coronary artery diameter of left anterior descending coronary (LAD) at baseline and after the infusion of acetylcholine, by means of an intracoronary Doppler guide wire. MACE, as cardiac death, myocardial
infarction, and heart failure, was evaluated at 24 months of follow-up.
RESULTS
At baseline, NG patients had a lower percentage of LAD endothelial dysfunction compared with pre-DM patients (P < 0.05). The patients with pre-DM had a higher percentage of endothelial LAD dysfunction as compared to patients with pre-DM treated with metformin (P<0.05). At the 24th monthof follow-up,MACEwas higher in pre-DM versus NG (P < 0.05). In pre-DM metformin patients, MACE was lower compared with pre-DM patients (P < 0.05).
CONCLUSIONS
Metformin therapy may reduce the high risk of cardiovascular events in pre-DM patients by reducing coronary endothelial dysfunction.
The heart consumes large amounts of energy in the form of ATP that is continuously replenished by oxidative phosphorylation in mitochondria and, to a lesser extent, by glycolysis. To adapt the ATP supply efficiently to the constantly varying demand of cardiac myocytes, a complex network of enzymatic and signalling pathways controls the metabolic flux of substrates towards their oxidation in mitochondria. In patients with heart failure, derangements of substrate utilization and intermediate metabolism, an energetic deficit, and oxidative stress are thought to underlie contractile dysfunction and the progression of the disease. In this Review, we give an overview of the physiological processes of cardiac energy metabolism and their pathological alterations in heart failure and diabetes mellitus. Although the energetic deficit in failing hearts - discovered >2 decades ago - might account for contractile dysfunction during maximal exertion, we suggest that the alterations of intermediate substrate metabolism and oxidative stress rather than an ATP deficit per se account for maladaptive cardiac remodelling and dysfunction under resting conditions. Treatments targeting substrate utilization and/or oxidative stress in mitochondria are currently being tested in patients with heart failure and might be promising tools to improve cardiac function beyond that achieved with neuroendocrine inhibition.
Background:
Metformin (MET) is one of antihyperglycaemic substances that reduces risk of major cardiovascular events, including fatal ones. Although it is formally contraindicated in moderate and severe functional stages of heart failure (HF), it is commonly used in patients with concomitant type 2 diabetes mellitus (T2DM).
Aim:
Evaluation of the effect of MET and T2DM on total mortality and hospitalization rates in patients with HF.
Methods:
1030 adult patients (>18 years) with HF from the Polish section of HF Long-Term Registry were included in years 2011-2014 into this retrospective analysis. Patients with T2DM (n=350) were identified and divided into two groups: those receiving MET and those not. Both groups were subjected to 1-year follow-up.
Results:
Mean patient age was 65.3±13.5 years, with predominance of male (n=726) and obesity (mean body mass index 30.3±5.5 kg/m²). The mean left ventricular ejection fraction (LVEF) in this population was 34.3% ±14.1. Among patients with T2DM (n=350) only 135 were treated with MET (38.6%). During 1-year follow-up, 128 patients with HF died, of which 53 had T2DM (15.1% vs. 10.9%, HR 0.89, 95%CI: 0.87-0.91, p=0.045). MET was associated with a significantly lower mortality rate compared to other antihyperglycaemic agents (9.6% vs. 18.6%, HR 0.85; 95%CI: 0.81-0.89, p=0.023). There were no significant differences in the reduction in hospitalization, including HF decompensation (53.5% vs. 40.0%, HR 0.93, 95%CI: 0.82-1.04, p=0.433).
Conclusions:
MET treatment in patients with different degrees of HF and T2DM is associated with a reduction in mortality and does not affect the incidence of hospitalizations.