Metformin in non-diabetic patients with metabolic syndrome and diastolic dysfunction: the MET-DIME randomized trial

Ladeiras-Lopes, Ricardo; Sampaio, Francisco; Leite, Sara; Santos-Ferreira, Diogo; Vilela, Eduardo; Leite‐Moreira, Adelino; Bettencourt, Nuno; Gama, Vasco; Braga, Pedro; Fontes‐Carvalho, Ricardo

doi:10.1007/s12020-021-02687-0

Cited by 13 publications

(17 citation statements)

References 31 publications

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“…Evidence from the nine RCTs included in a recent systematic review only supports a metformin beneficial effect in improving MVO2 and reducing NT-proBNP levels in insulin-resistant or T2DM patients with HF, especially those without overt signs of CVD [ 177 ]. Instead, in a recent trial enrolling 54 non-diabetic patients with metabolic syndrome, metformin treatment on top of lifestyle counseling ameliorated diastolic dysfunction [ 178 ].…”

Section: Mechanisms Of Beneficial Impact Of Metformin On Heart Failurementioning

confidence: 99%

Effects of Metformin in Heart Failure: From Pathophysiological Rationale to Clinical Evidence

et al. 2021

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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.

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Section: Mechanisms Of Beneficial Impact Of Metformin On Heart Failurementioning

confidence: 99%

Effects of Metformin in Heart Failure: From Pathophysiological Rationale to Clinical Evidence

et al. 2021

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“…A total of 3303 records were identified in the initial search, and 2841 records were screened following duplicate removal. A full-text review was conducted for 140 articles and 7 randomized controlled trials, [25][26][27][28][29][30][31] involving 2897 non-diabetic patients, were included in the final analysis (Figure 1). The included studies were conducted in the following countries: Denmark, [25][26][27] the United States of America, 28,29 Portugal, 30 and the United Kingdom.…”

Section: Summary Of Included Articlesmentioning

confidence: 99%

“…31 All studies were placebo controlled. Two of the trials were with SGLT2i 29,31 (2689 subjects, duration from 4-6 months), three with GLP1-RA 25,26,28 (123 subjects, 2-168 days) and two with metformin 27,30 (85 subjects, 3-24 months). There were no SGLT1/2 inhibitors such as sotagliflozin in the analysis.…”

Section: Summary Of Included Articlesmentioning

confidence: 99%

“…A total of six studies included subjects with HFrEF: of which, three studies 25,28,31 defined HFrEF as LVEF ≤ 40%, two 26,27 defined as LVEF ≤ 45%, and one 29 defined as LVEF < 50%. Only one study 30 examined the use of metformin in HFpEF patients, which defined HFpEF as LVEF ≥ 50%. Five trials each were included in the analysis for NT-proBNP, 25,27,28,30,31 LVEF, [25][26][27][28][29] and peak VO 2 .…”

Section: Summary Of Included Articlesmentioning

confidence: 99%

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Can glucose‐lowering medications improve outcomes in non‐diabetic heart failure patients? A Bayesian network meta‐analysis

et al. 2022

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AimsThe cardioprotective effects of glucose-lowering medications in diabetic patients with heart failure (HF) are well known. Several large randomized controlled trials (RCTs) have recently suggested that the cardioprotective effects of glucose-lowering medications extend to HF patients regardless of diabetic status. The aim of this study was to conduct a Bayesian network meta-analysis to evaluate the impact of various glucose-lowering medications on the outcomes of non-diabetic HF patients. Methods and results Medline and Embase were searched for RCTs investigating the use of glucose-lowering medications in non-diabetic HF patients in August 2021. Studies were included in accordance with the inclusion and exclusion criteria, and data were extracted with a pre-defined datasheet. Primary outcomes include serum N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels, left ventricular ejection fraction (LVEF), and maximal oxygen consumption (PVO 2 ). A Bayesian network meta-analysis was performed to compare the effectiveness of different classes of glucose-lowering medications in improving HF outcomes. Risk-of-bias was assessed using Cochrane Risk-of-Bias tool 2.0 for randomized trials (ROB2). Seven RCTs involving 2897 patients were included. Sodium-glucose transporter 2 inhibitor (SGLT2i) was the most favourable in lowering NT-proBNP, with the significant reduction in NT-proBNP when compared with glucagon-like peptide-1 receptor agonists (GLP1-RA) [mean differences (MD): À229.59 pg/mL, 95%-credible intervals (95%-CrI): À238.31 to À220.91], metformin (MD: À237.15 pg/mL, 95%-CrI: À256.19 to À218.14), and placebo (MD: À228.00 pg/mL, 95%-CrI: À233.99 to À221.99). SGLT2i was more effective in improving LVEF for HF with reduced ejection fraction patients relative to GLP1-RA (MD: 8.09%, 95%-CrI: 6.30 to 9.88) and placebo (MD: 6.10%, 95%-CrI: 4.37 to 7.84). SGLT2i and GLP1-RA were more favourable to placebo in improving PVO 2 , with significant increase of PVO 2 at a MD of 1.60 mL/kg/min (95%-CrI: 0.63 to 2.57) and 0.86 mL/kg/min (95%-CrI: 0.66 to 1.06), respectively. All three drugs had comparable safety profiles when compared with placebo. Conclusions This Bayesian network meta-analysis demonstrated that SGLT2i, when compared with GLP1-RA and metformin, was superior in improving LVEF in HF with reduced ejection fraction patients, as well as improving PVO 2 and NT-proBNP in non-diabetic HF patients. Further large-scale prospective studies are needed to confirm these preliminary findings.

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“…In patients with type 2 diabetes mellitus, metformin is the most widely used oral antihyperglycemic agent. Recently, new potential therapeutic applications in non-diabetic patients have been described, such as cardioprotection (6,7), major depressive disorder (8) and cancer (9)(10)(11). The mechanisms of action are still not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Metformin and Bone Metabolism in Endogenous Glucocorticoid Excess: An Exploratory Study

et al. 2021

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ContextGlucocorticoid excess exhibits multiple detrimental effects by its catabolic properties. Metformin was recently suggested to protect from adverse metabolic side-effects of glucocorticoid treatment. Whether metformin is beneficial in patients with endogenous glucocorticoid excess has not been clarified.ObjectiveTo evaluate the phenotype in patients with endogenous Cushing’s syndrome (CS) treated with metformin at the time of diagnosis.Patients and MethodsAs part of the German Cushing’s Registry we selected from our prospective cohort of 96 patients all 10 patients who had been on pre-existing metformin treatment at time of diagnosis (CS-MET). These 10 patients were matched for age, sex and BMI with 16 patients without metformin treatment (CS-NOMET). All patients had florid CS at time of diagnosis. We analyzed body composition, metabolic parameters, bone mineral density and bone remodeling markers, muscle function and quality of life.ResultsAs expected, diabetes was more prevalent in the CS-MET group, and HbA1c was higher. In terms of comorbidities and the degree of hypercortisolism, the two groups were comparable. We did not observe differences in terms of muscle function or body composition. In contrast, bone mineral density in metformin-treated patients was superior to the CS-NOMET group at time of diagnosis (median T-Score -0.8 versus -1.4, p = 0.030). CS-MET patients showed decreased β-CTX levels at baseline (p = 0.041), suggesting reduced bone resorption under metformin treatment during glucocorticoid excess.ConclusionThis retrospective cohort study supports potential protective effects of metformin in patients with endogenous glucocorticoid excess, in particular on bone metabolism.

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Metformin in non-diabetic patients with metabolic syndrome and diastolic dysfunction: the MET-DIME randomized trial

Cited by 13 publications

References 31 publications

Effects of Metformin in Heart Failure: From Pathophysiological Rationale to Clinical Evidence

Effects of Metformin in Heart Failure: From Pathophysiological Rationale to Clinical Evidence

Can glucose‐lowering medications improve outcomes in non‐diabetic heart failure patients? A Bayesian network meta‐analysis

Metformin and Bone Metabolism in Endogenous Glucocorticoid Excess: An Exploratory Study

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