There is an increasing interest in using metformin in cardiovascular diseases and its potential new roles. Only two randomized controlled trials investigated the effect of metformin in nondiabetic heart failure (HF) patients. However, none of these studies assess the role of metformin in reducing oxidative stress. We hypothesized that metformin might improve oxidative stress and left ventricular remodeling in nondiabetic HF patients with reduced ejection fraction (HFrEF).
Methods and Methods:
Seventy HFrEF patients (EF 37% ± 8%; median age 66 years) were randomized to metformin (n = 35) or standard of care (SOC) for HF (n = 35) for 6 months in addition to standard therapy. Outcomes included the difference in the change (Δ) in total antioxidant capacity (TAC) and malondialdehyde (MDA), both assessed colorimetrically and left ventricular mass index (LVMI) assessed through transthoracic echocardiography.
Results:
Compared with the SOC, metformin treatment increased TAC [Δ = 0.12 mmol/L, confidence intervals (95% CIs): 0.03–0.21; P = 0.007]. TAC increased significantly only in the metformin group (0.90 ± 0.08 mmol/L at baseline vs. 1.04 ± 0.99 mmol/L at 6 months, P < 0.05). Metformin therapy preserved LVMI (Δ = −23 g/m2, 95% CI: −42.91 to −4.92; P = 0.014) and reduced fasting plasma glucose (Δ = −6.16, 95% CI: −12.31 to −0.02, P = 0.047) compared with the SOC. Results did not change after adjusting for baseline values. Changes in MDA left ventricular ejection fraction (LVEF) and blood pressure were not significantly different between groups.
Conclusion:
Metformin treatment in HF patients with reduced LVEF improved TAC and prevented the increase in LVMI compared with the SOC. These effects of metformin warrant further research in HF patients without diabetes to explore the potential benefits of metformin.
Trial Registration Number:
This protocol was registered in ClinicalTrials.gov under the number NCT05177588.
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References
1.
KirpichnikovD, McFarlaneSI, SowersJR. Metformin: An update. Ann Intern Med, 2002; 137(1):25–33; doi: 10.7326/0003-4819-137-1-200207020-00009
2.
NestiL, NataliA. Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data. Nutr Metab Cardiovasc Dis, 2017; 27(8):657–669; doi: 10.1016/j.numecd.2017.04.009
3.
RenaG, HardieDG, PearsonER. The mechanisms of action of metformin. Diabetologia, 2017; 60(9):1577–1585; doi: 10.1007/s00125-017-4342-z
4.
FerranniniE, DeFronzoRA. Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J, 2015; 36(34):2288–2296; doi: 10.1093/eurheartj/ehv239
5.
WeirDL, AbrahamowiczM, BeauchampME, et al.Acute vs cumulative benefits of metformin use in patients with type 2 diabetes and heart failure. Diabetes Obes Metab, 2018; 20(11):2653–2660; doi: 10.1111/dom.13448
6.
MohanM, Al-TalabanyS, McKinnieA, et al.A randomized controlled trial of metformin on left ventricular hypertrophy in patients with coronary artery disease without diabetes: The MET-REMODEL trial. Eur Heart J, 2019; 40(41):1–9; doi: 10.1093/eurheartj/ehz203
7.
Abdel MonemMS, FaridSF, AbbassiMM, et al.The potential hepatoprotective effect of metformin in hepatitis C virus-infected adolescent patients with beta thalassemia major: Randomised clinical trial. Int J Clin Pract, 2021; 75(6):1–15; doi: 10.1111/ijcp.14104
8.
DriverC, BamitaleKDS, KaziA, et al.Cardioprotective effects of metformin. J Cardiovasc Pharmacol, 2018; 72(2):121–127; doi: 10.1097/FJC.0000000000000599
9.
KamelAM, IsmailB, Abdel HafizG, et al.Total antioxidant capacity and prediabetes are associated with left ventricular geometry in heart-failure patients with reduced ejection fraction: A cross-sectional study. Metab Syndr Relat Disord, 2023; 21(5):282–291; doi: 10.1089/met.2023.0019
Ladeiras-LopesR, SampaioF, LeiteS, et al.Metformin in non-diabetic patients with metabolic syndrome and diastolic dysfunction: The MET-DIME randomized trial. Endocrine, 2021; 72(3):699–710; doi: 10.1007/s12020-021-02687-0
12.
LarsenAH, JessenN, NørrelundH, et al.A randomised, double-blind, placebo-controlled trial of metformin on myocardial efficiency in insulin-resistant chronic heart failure patients without diabetes. Eur J Heart Fail, 2020; 22(9):1628–1637; doi: 10.1002/ejhf.1656
13.
KinsaraAJ, IsmailYM. Metformin in heart failure patients. Indian Heart J, 2018; 70(1):175–176; doi: 10.1016/j.ihj.2017.05.009
14.
LeveyAS, StevensLA, SchmidCH, et al.A new equation to estimate glomerular filtration rate. Ann Intern Med, 2009; 150(9):604; doi: 10.7326/0003-4819-150-9-200905050-00006
15.
American Diabetes Association. 2. Classification and diagnosis of diabetes: Standards of medical care in diabetes-2020. Diabetes Care, 2020; 43(Suppl 1):S14–S31; doi: 10.2337/dc20-S002
16.
American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2018. Diabetes Care, 2018; 41(Suppl 1):S13–S27; doi: 10.2337/dc18-S002.
17.
LangRM, BadanoLP, VictorMA, et al.Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr, 2015; 28(1):1–39.e14; doi: 10.1016/j.echo.2014.10.003
18.
Anònim. Human Experimentation Code of Ethics of the World Medical Association. Br Med J, 1964; 2(5402):177; doi: 10.1136/bmj.2.5402.177.
19.
LiB, PoSS, ZhangB, et al.Metformin regulates adiponectin signalling in epicardial adipose tissue and reduces atrial fibrillation vulnerability. J Cell Mol Med, 2020; 24(14):7751–7766; doi: 10.1111/jcmm.15407
20.
ZiyrekM, KahramanS, OzdemirE, et al.Metformin monotherapy significantly decreases epicardial adipose tissue thickness in newly diagnosed type 2 diabetes patients. Rev Port Cardiol, 2019; 38(6):419–423; doi: 10.1016/j.repc.2018.08.010
21.
MongirdienėA, LiuizėA, KarčiauskaitėD, et al.Relationship between oxidative stress and left ventricle markers in patients with chronic heart failure. Cells, 2023; 12(5); doi: 10.3390/cells12050803
22.
SarduC, PaolissoP, SacraC, et al.Effects of metformin therapy on coronary endothelial dysfunction in patients with prediabetes with stable angina and nonobstructive coronary artery stenosis: The codyce multicenter prospective study. Diabetes Care, 2019; 42(10):1946–1955; doi: 10.2337/dc18-2356
23.
MeaneyE, VelaA, SamaniegoV, et al.Metformin, arterial function, intima-media thickness and nitroxidation in metabolic syndrome: The mefisto study. Clin Exp Pharmacol Physiol, 2008; 35(8):895–903; doi: 10.1111/j.1440-1681.2008.04920.x
24.
Diniz VilelaD, Gomes PeixotoL, TeixeiraRR, et al.The role of metformin in controlling oxidative stress in muscle of diabetic rats. Oxid Med Cell Longev, 2016; 2016; doi: 10.1155/2016/6978625
25.
Bułdak Ł, ŁabuzekK, BułdakRJ, et al.Metformin affects macrophages' phenotype and improves the activity of glutathione peroxidase, superoxide dismutase, catalase and decreases malondialdehyde concentration in a partially AMPK-independent manner in LPS-stimulated human monocytes/macrophages. Pharmacol Rep, 2014; 66(3):418–429; doi: 10.1016/j.pharep.2013.11.008
26.
EsteghamatiA, EskandariD, MirmiranpourH, et al.Effects of metformin on markers of oxidative stress and antioxidant reserve in patients with newly diagnosed type 2 diabetes: A randomized clinical trial. Clin Nutr, 2013; 32(2):179–185; doi: 10.1016/j.clnu.2012.08.006
27.
OhiraM, YamaguchiT, SaikiA, et al.Metformin reduces circulating malondialdehyde-modified low-density lipoprotein in type 2 diabetes mellitus. Clin Investig Med, 2014; 37(4):243; doi: 10.2501/1/cim.v37i4.21730
28.
EsteghamatiA, MonnavarPH, NakhjavaniM, et al.Comparative effect of metformin alone or in combination with glibenclamide on oxidative stress markers of patients with type 2 diabetes: A randomized open clinical trial. Ann Clin Diabetes Endocrinol, 2018; 2018:1007.
29.
ChuangCC, ShieshSC, ChiCH, et al.Serum total antioxidant capacity reflects severity of illness in patients with severe sepsis. Crit Care, 2006; 10(1):1–7; doi: 10.1186/cc4826
30.
GundewarS, CalvertJW, JhaS, et al.Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure. Circ Res, 2009; 104(3):403–411; doi: 10.1161/CIRCRESAHA.108.190918
31.
CittadiniA, NapoliR, MontiMG, et al.Metformin prevents the development of chronic heart failure in the SHHF rat model. Diabetes, 2012; 61(4):944–953; doi: 10.2337/db11-1132
32.
SasakiH, AsanumaH, FujitaM, et al.Metformin prevents progression of heart failure in dogs role of AMP-activated protein kinase. Circulation, 2009; 119(19):2568–2577; doi: 10.1161/CIRCULATIONAHA.108.798561
33.
KamelAM, SabryN, FaridS. Effect of metformin on left ventricular mass and functional parameters in non-diabetic patients: A meta-analysis of randomized clinical trials. BMC Cardiovasc Disord, 2022; 22(1):405; doi: 10.1186/s12872-022-02845-w
34.
VelázquezH, MeaneyA, GaleanaC, et al.Metformin enhances left ventricular function in patients with metabolic syndrome. Rev Mex Cardiol, 2016; 27(1):16–25.
35.
SarduC, TrottaMC, PierettiG, et al.MicroRNAs modulation and clinical outcomes at 1 year of follow-up in obese patients with pre-diabetes treated with metformin vs. placebo. Acta Diabetol, 2021; 58(10):1381–1393; doi: 10.1007/s00592-021-01743-5
36.
LexisCPHH, Van Der HorstICCC, LipsicE, et al.Metformin in non-diabetic patients presenting with st elevation myocardial infarction: Rationale and design of the glycometabolic intervention as adjunct to primary percutaneous intervention in st elevation myocardial infarction (gips)-iii trial. Cardiovasc Drugs Ther, 2012; 26(5):417–426; doi: 10.1007/s10557-012-6413-1
37.
KanamoriH, NaruseG, YoshidaA, et al.Metformin enhances autophagy and provides cardioprotection in δ-sarcoglycan deficiency-induced dilated cardiomyopathy. Circ Hear Fail, 2019; 12(4):1–13; doi: 10.1161/CIRCHEARTFAILURE.118.005418
38.
CameronAR, MorrisonVL, LevinD, et al.Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res, 2016; 119(5):652–665; doi: 10.1161/CIRCRESAHA.116.308445.
39.
Santos-GallegoCG, Requena-IbanezJA, San AntonioR, et al.Empagliflozin ameliorates adverse left ventricular remodeling in non-diabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol, 2019; 73(15):1931–1944; doi: 10.1016/j.jacc.2019.01.056.
40.
WongAKFF, SymonR, AlZadjaliMA, et al.The effect of metformin on insulin resistance and exercise parameters in patients with heart failure. Eur J Hear Fail, 2012; 14(11):1303–1310; doi: 10.1093/eurjhf/hfs106
41.
LarsenAH, JessenN, NørrelundH, et al.A randomised, double-blind, placebo-controlled trial of metformin on myocardial efficiency in insulin-resistant chronic heart failure patients without diabetes. Eur J Hear Fail, 2019; 22(9):1628–1637; doi: 10.1002/ejhf.1656
FærchK, BlondMB, BruhnL, et al.The effects of dapagliflozin, metformin or exercise on glycaemic variability in overweight or obese individuals with prediabetes (the PRE-D Trial): A multi-arm, randomised, controlled trial. Diabetologia, 2021; 64(1):42–55; doi: 10.1007/s00125-020-05306-1
44.
HongJ, ZhangY, LaiS, et al.Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care, 2013; 36(5):1304–1311; doi: 10.2337/dc12-0719
45.
BenesJ, KotrcM, KroupovaK, et al.Metformin treatment is associated with improved outcome in patients with diabetes and advanced heart failure (HFrEF). Sci Rep, 2022; 12(1):1–10; doi: 10.1038/s41598-022-17327-4
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