• COVID-19
• Major adverse cardiovascular events
• Myocardial injury
• Nirmatrelvir–ritonavir

• 202240149 Shanghai Municipal Health Commission
• JYLJ202209 Clinical Research Program of Shanghai Ninth People's Hospital

• Anticoagulation therapy
• COVID-19
• Major adverse cardiovascular events
• Omicron variant

• Heart failure with preserved ejection fraction
• Heart failure with reduced ejection fraction
• Metabolic reprogramming
• Mitochondrial dysfunction

• Humans
• Heart Failure/diagnosis
• Stroke Volume
• Metabolic Reprogramming
• Myocardium/pathology
• Ventricular Dysfunction, Left/metabolism

• TET enzymes
• cardiovascular diseases
• epigenetics
• heart failure
• ten-eleven translocation enzymes

• Humans
• Cardiovascular Diseases/genetics
• Cardiovascular Diseases/therapy
• Epigenesis, Genetic
• Epigenomics
• Exercise
• Heart Disease Risk Factors

• heart failure
• immunometabolism
• myocardial infarction

• R01 HL122309 NHLBI NIH HHS
• R01 HL159964 NHLBI NIH HHS

• Anti-hyperglycemic drugs
• Epicardial adipose tissue
• Heart failure with preserved ejection fraction
• Inflammation
• Sodium-glucose cotransporter-2 inhibitors
• Type 2 diabetes mellitus

The cardiovascular protection effect of metformin on patients with type 2 diabetes mellitus (T2DM) remains inconclusive. This systemic review and meta-analysis were to estimate the effect of metformin on mortality and cardiovascular events among patients with T2DM.

A search of the Pubmed and EMBASE databases up to December 2021 was performed. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled by a random-effects model with an inverse variance method.

A total of 39 studies involving 2473009 T2DM patients were adopted. Compared to non-metformin therapy, the use of metformin was not significantly associated with a reduced risk of major adverse cardiovascular event (MACE) (HR = 1.06, 95%CI 0.91–1.22; I² = 82%), hospitalization (HR = 0.85, 95%CI 0.64–1.13; I² = 98%), heart failure (HR = 0.86, 95%CI 0.60–1.25; I² = 99%), stroke (HR = 1.16, 95%CI 0.88–1.53; I² = 84%), and risk of AMI (HR = 0.88, 95%CI 0.69–1.14; I² = 88%) in T2DM patients. Metformin was also not associated with significantly lowered risk of MACE compared to dipeptidyl peptidase-4 inhibitor (DPP-4i) in T2DM patients (HR = 0.95, 95%CI 0.73–1.23; I² = 84%).

The effect of metformin on some cardiovascular outcomes was not significantly better than the non-metformin therapy or DPP-4i in T2DM patients based on observational studies.

• cardiovascular diseases
• metformin
• protective effect

• cardiovascular diseases
• epi-drugs
• epigenetics
• heart failure
• non-coding RNAs

• Cardioprotection
• Metformin
• Type 2 diabetes

• Cardiovascular Diseases/prevention & control
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/drug therapy
• Glucagon-Like Peptide-1 Receptor/agonists
• Glucose
• Heart Failure/drug therapy
• Heart Failure/epidemiology
• Humans
• Metformin/therapeutic use
• Sodium-Glucose Transporter 2 Inhibitors/therapeutic use

• Aortic valve interstitial cells
• Apoptosis
• Calcific aortic valve disease
• Calcification
• Metformin
• PI3K/AKT signaling pathway

Type 2 diabetes mellitus (T2DM) is a worldwide major health burden and heart failure (HF) is the most common cardiovascular (CV) complication in affected patients. Therefore, identifying the best pharmacological approach for glycemic control, which is also useful to prevent and ameliorate the prognosis of HF, represents a crucial issue. Currently, the choice is between the new drugs sodium/glucose co-transporter 2 inhibitors that have consistently shown in large CV outcome trials (CVOTs) to reduce the risk of HF-related outcomes in T2DM, and metformin, an old medicament that might end up relegated to the background while exerting interesting protective effects on multiple organs among which include heart failure. When compared with other antihyperglycemic medications, metformin has been demonstrated to be safe and to lower morbidity and mortality for HF, even if these results are difficult to interpret as they emerged mainly from observational studies. Meta-analyses of randomized controlled clinical trials have not produced positive results on the risk or clinical course of HF and sadly, large CV outcome trials are lacking. The point of force of metformin with respect to new diabetic drugs is the amount of data from experimental investigations that, for more than twenty years, still continues to provide mechanistic explanations of the several favorable actions in heart failure such as, the improvement of the myocardial energy metabolic status by modulation of glucose and lipid metabolism, the attenuation of oxidative stress and inflammation, and the inhibition of myocardial cell apoptosis, leading to reduced cardiac remodeling and preserved left ventricular function. In the hope that specific large-scale trials will be carried out to definitively establish the metformin benefit in terms of HF failure outcomes, we reviewed the literature in this field, summarizing the available evidence from experimental and clinical studies reporting on effects in heart metabolism, function, and structure, and the prominent pathophysiological mechanisms involved.

• heart failure
• metformin
• type 2 diabetes

• coronary artery disease
• heart failure
• percutaneous coronary intervention
• prognosis
• risk factor

• epidrugs
• heart failure
• personalized therapy

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.

• heart failure with preserved ejection fraction
• metformin
• mortality
• survival analysis (source: MeSH NLM)
• type 2 diabetes mellitus—exenatide

• Cardioprotection
• Diabetic complications
• GLP-1
• Management of T2D
• Pathophysiology
• Type 2 Diabetes

• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/drug therapy
• Diabetes Mellitus, Type 2/epidemiology
• Dipeptidyl-Peptidase IV Inhibitors/therapeutic use
• Glucagon-Like Peptide 1
• Humans
• Hypoglycemic Agents/therapeutic use

• diastolic dysfunction
• metformin
• myocardial strain
• type 2 diabetes mellitus

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.

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.

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).

Metformin treatment is associated with a reduction in mortality in patients with HFpEF.

• Diabetes mellitus
• Ejection fraction
• Heart failure
• Metformin

• drug research
• hypertension
• metformin
• systems biology
• transcriptome

• Animals
• Blood Pressure/drug effects
• Blood Pressure/genetics
• Computational Biology/methods
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Female
• Gene Expression Profiling
• Gene Expression Regulation/drug effects
• Hypertension/etiology
• Hypoglycemic Agents/adverse effects
• Hypoglycemic Agents/pharmacology
• Male
• Metformin/adverse effects
• Metformin/pharmacology
• Mice
• Molecular Sequence Annotation
• Organ Specificity/drug effects
• Organ Specificity/genetics
• Time Factors
• Transcriptome

• National Natural Science Foundation of China

Left ventricular ejection fraction (LVEF) trajectories and functional recovery with current heart failure (HF) management is increasingly recognized. Type 2 diabetes mellitus (T2D) leads to a worse prognosis in HF patients. However, it is unknown whether T2D interferes with LVEF trajectories. The aim of this study was to prospectively assess very long-term (up to 15 years) LVEF trajectories in patients with and without T2D and underlying HF.

Ambulatory patients admitted to a multidisciplinary HF clinic were prospectively evaluated by scheduled two-dimensional echocardiography at baseline, 1 year, and then every 2 years afterwards, up to 15 years. Statistical analyses of LVEF change with time were performed using the linear mixed effects (LME) models, and locally weighted error sum of squares (Loess) curves were plotted.

Of the 1921 patients, 461 diabetic and 699 non-diabetic patients with LVEF < 50% were included in the study. The mean number of echocardiography measurements performed in diabetic patients was 3.3 ± 1.6. Early LVEF recovery was similar in diabetic and non-diabetic patients, but Loess curves showed a more pronounced inverted U shape in diabetics with a more pronounced decline after 9 years. LME analysis showed a statistical interaction between T2D and LVEF trajectory over time (p = 0.009), which was statistically significant in patients with ischemic etiologies (p < 0.001). Other variables that showed an interaction between LVEF trajectories and T2D were male sex (p = 0.04) and HF duration (p = 0.008).

LVEF trajectories in T2D patients with depressed systolic function showed a pronounced inverted U shape with a marked decline after 9 years. Diabetic cardiomyopathy may underlie the functional decline observed.

• Diabetes mellitus
• Ejection fraction
• Etiology
• Follow-up
• Heart failure
• Long-term