Effect of Metformin on Circulating Levels of Inflammatory Markers in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials
Restricted accessResearch articleFirst published online September, 2021
Effect of Metformin on Circulating Levels of Inflammatory Markers in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials
Emerging evidence indicates that metformin has anti-inflammatory effect; however, the results differ concerning randomized controlled trails of the effect of metformin on inflammatory markers in type 2 diabetes (T2D) patients.
Objective:
This study reassessed the data on the effect of metformin treatment on inflammatory markers in T2D patients through a systematic review and meta-analysis.
Methods:
A systematic search was performed in the PubMed, ISI Web of Science, EMBASE, Cochrane Library and Scopus databases to collect relevant published data up to September 2020. Data of each study was combined using random-effects model. Subgroup analysis was performed based on subgroups of the treatment duration, dose and target population.
Results:
Thirteen RCTs including 1776 participants with T2D were analyzed. Although CRP levels significantly decreased [SMD: –0.76 mg/L; 95% CI (–1.48, –0.049); P = 0.036] in patients with T2D following metformin treatment, circulating levels of TNF-α [SMD: –0.17 pg/mL; 95% CI (–0.55, 0.20); P = 0.37] and IL-6 [SMD: –0.06 pg/mL; 95% CI (–0.38, 0.25); P = 0.69] were insignificant after metformin treatment. Compared to treatment duration of less than 24 weeks, longer treatment duration (more than 24 weeks) was associated with reduced level of CRP.
Relevance to Patient Care and Clinical Practice:
Based on available evidence from RCTs in this meta-analysis, metformin decreased CRP level. However, strategies for the treatment of inflammation should focus on metformin in patients with T2D.
Conclusion:
The present study evidences that therapy with metformin can reduce CRP level significantly in T2D patients compared to other inflammatory markers.
BadawiAKlipAHaddadP, et al. Type 2 diabetes mellitus and inflammation: prospects for biomarkers of risk and nutritional intervention. Diabetes Metab Syndr Obes. 2010;3:173-186. doi:10.2147/dmsott.s9089
2.
SaltielARKahnCR.Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414:799-806. doi:10.1038/414799a
3.
PickupJCCrookMA.Is type II diabetes mellitus a disease of the innate immune system?Diabetologia. 1998;41:1241-1248.
4.
LauterbachMAWunderlichFT.Macrophage function in obesity-induced inflammation and insulin resistance. Pflugers Arch. 2017;469:385-396. doi:10.1007/s00424-017-1955-5
5.
MauerJChaurasiaBGoldauJ, et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol. 2014;15:423-430. doi:10.1038/ni.2865
6.
de FerrantiSMozaffarianD. The perfect storm: obesity, adipocyte dysfunction, and metabolic consequences. Clin Chem. 2008;54:945-955. doi:10.1373/clinchem.2007.100156
7.
KhodabandehlooHGorgani-FiruzjaeeSPanahiGMeshkaniR.Molecular and cellular mechanisms linking inflammation to insulin resistance and β-cell dysfunction. Transl Res. 2016;167:228-256. doi:10.1016/j.trsl.2015.08.011
8.
Emerging Risk Factors Collaboration; KaptogeSDi AngelantonioE, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375:132-140. doi:10.1016/S0140-6736(09)61717-7
9.
KoushkiMDashatanNAMeshkaniR.Effect of resveratrol supplementation on inflammatory markers: a systematic review and meta-analysis of randomized controlled trials. Clin Ther. 2018;40:1180-1192.e5. doi:10.1016/j.clinthera.2018.05.015
10.
HosseiniHKoushkiMKhodabandehlooH, et al. The effect of resveratrol supplementation on C-reactive protein (CRP) in type 2 diabetic patients: results from a systematic review and meta-analysis of randomized controlled trials. Complement Ther Med. 2020;49:102251. doi:10.1016/j.ctim.2019.102251
11.
KoushkiMAmiri-DashatanNPourfarjamYDoustimotlaghAH.Effect of garlic intake on inflammatory mediators: a systematic review and meta-analysis of randomised controlled trials. Postgrad Med J. Published online February 12, 2020. doi:10.1136/postgradmedj-2019-137267
12.
LiMLiXZhangHLuY.Molecular mechanisms of metformin for diabetes and cancer treatment. Front Physiol. 2018;9:1039. doi:10.3389/fphys.2018.01039
13.
SaishoY.Metformin and inflammation: its potential beyond glucose-lowering effect. Endocr Metab Immune Disord Drug Targets. 2015;15:196-205. doi:10.2174/1871530315666150316124019
14.
AnHHeL.Current understanding of metformin effect on the control of hyperglycemia in diabetes. J Endocrinol. 2016;228:R97-R106. doi:10.1530/JOE-15-0447
15.
de JagerJKooyASchalkwijkC, et al. Long-term effects of metformin on endothelial function in type 2 diabetes: a randomized controlled trial. J Intern Med. 2014;275:59-70. doi:10.1111/joim.12128
16.
de LimaLMAWiernspergerNKraemer-AguiarLGBouskelaE.Short-term treatment with metformin improves the cardiovascular risk profile in first-degree relatives of subjects with type 2 diabetes mellitus who have a metabolic syndrome and normal glucose tolerance without changes in C-reactive protein or fibrinogen. Clinics (Sao Paulo). 2009;64:415-420. doi:10.1590/s1807-59322009000500008
17.
CaballeroAEDelgadoAAguilar-SalinasCA, et al. The differential effects of metformin on markers of endothelial activation and inflammation in subjects with impaired glucose tolerance: a placebo-controlled, randomized clinical trial. J Clin Endocrinol Metab. 2004;89:3943-3948. doi:10.1210/jc.2004-0019
18.
Gómez-DíazRATalaveraJOPoolEC, et al. Metformin decreases plasma resistin concentrations in pediatric patients with impaired glucose tolerance: a placebo-controlled randomized clinical trial. Metabolism. 2012;61:1247-1255. doi:10.1016/j.metabol.2012.02.003
19.
MoherDLiberatiATetzlaffJAltmanDG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8:336-341. doi:10.1371/journal.pmed.1000097
20.
Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. National Diabetes Data Group. Diabetes. 1979;28:1039-1057. doi:10.2337/diab.28.12.1039
21.
HigginsJWellsG. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. Cochrane Collaboration; 2011.
22.
HigginsJPGreenS. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.0.0. Cochrane Collaboration; 2008.
23.
GuyattGHOxmanADVistGE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924-926. doi:10.1136/bmj.39489.470347.AD
24.
HozoSPDjulbegovicBHozoI.Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005;5:13. doi:10.1186/1471-2288-5-13
25.
BorensteinMHedgesLHigginsJPTRothsteinHR.Comprehensive Meta-Analysis [computer software]. Version 2.2.027. Biostat Inc; 2005.
26.
MoDLiuSMaH, et al. Effects of acarbose and metformin on the inflammatory state in newly diagnosed type 2 diabetes patients: a one-year randomized clinical study. Drug Des Devel Ther. 2019;13:2769-2776. doi:10.2147/DDDT.S208327
27.
ErikssonAAttvallSBonnierMErikssonJWRosanderBKarlssonFA.Short-term effects of metformin in type 2 diabetes. Diabetes Obes Metab. 2007;9:483-489. doi:10.1111/j.1463-1326.2006.00624.x
28.
ChakrabortyAChowdhurySBhattacharyyaM.Effect of metformin on oxidative stress, nitrosative stress and inflammatory biomarkers in type 2 diabetes patients. Diabetes Res Clin Pract. 2011;93:56-62. doi:10.1016/j.diabres.2010.11.030
29.
PradhanADEverettBMCookNRRifaiNRidkerPM.Effects of initiating insulin and metformin on glycemic control and inflammatory biomarkers among patients with type 2 diabetes: the LANCET randomized trial. JAMA. 2009;302:1186-1194. doi:10.1001/jama.2009.1347
30.
De JagerJKooyALehertP, et al. Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med. 2005;257:100-109. doi:10.1111/j.1365-2796.2004.01420.x
31.
GoldbergRBTemprosaMGMatherKJOrchardTJKitabchiAEWatsonKE; Diabetes Prevention Program Research Group. Lifestyle and metformin interventions have a durable effect to lower CRP and tPA levels in the diabetes prevention program except in those who develop diabetes. Diabetes Care. 2014;37:2253-2260. doi:10.2337/dc13-2471
32.
GoldbergRBBrayGAMarcovinaSM, et al. Non-traditional biomarkers and incident diabetes in the Diabetes Prevention Program: comparative effects of lifestyle and metformin interventions. Diabetologia. 2019;62:58-69. doi:10.1007/s00125-018-4748-2
33.
MalinSKNightingaleJChoiSEChipkinSRBraunB.Metformin modifies the exercise training effects on risk factors for cardiovascular disease in impaired glucose tolerant adults. Obesity (Silver Spring). 2013;21:93-100. doi:10.1002/oby.20235
34.
GamitNKanthariaNVaghasiyaKVataliyaAShahA.Study of effects of metformin on C-reactive protein level in type-2 diabetes mellitus. Int J Basic Clin Pharmacol. 2015;4(1). doi:10.5455/2319-2003.ijbcp20150205
35.
DehkordiAHAbbaszadehAMirSHasanvandA.Metformin and its anti-inflammatory and anti-oxidative effects; new concepts. J Renal Inj Prev. 2019;8:54-61. doi:10.15171/jrip.2019.11
36.
PernicovaIKorbonitsM.Metformin—mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014;10:143-156. doi:10.1038/nrendo.2013.256
37.
MclntyreHDMaABirdDMPatersonCARavenscroftPJCameronDP.Metformin increases insulin sensitivity and basal glucose clearance in type 2 (non-insulin dependent) diabetes mellitus. Aust N Z J Med. 1991;21:714-719. doi:10.1111/j.1445-5994.1991.tb01375.x
38.
KhalafBAbdulridhaMKKadhimKHussainSR.Influence of large daily doses of metformin on the expression of interleukin-1β and C-reactive protein in type 2 diabetes patients. Int J Pharm Pharm Sci. 2014;6:506-509.
39.
ChenYLiMDengH, et al. Impact of metformin on C-reactive protein levels in women with polycystic ovary syndrome: a meta-analysis. Oncotarget. 2017;8:35425-35434. doi:10.18632/oncotarget.16019
40.
LinYSTsaiSJLinMWYangCTHuangMFWuMH.Interleukin-6 as an early chronic inflammatory marker in polycystic ovary syndrome with insulin receptor substrate-2 polymorphism. Am J Reprod Immunol. 2011;66:527-533. doi:10.1111/j.1600-0897.2011.01059.x
41.
Luque-RamirezMEscobar-MorrealeHF.Treatment of polycystic ovary syndrome (PCOS) with metformin ameliorates insulin resistance in parallel with the decrease of serum interleukin-6 concentrations. Horm Metab Res. 2010;42:815-820. doi:10.1055/s-0030-1262855
42.
WangJZhuLHuK, et al. Effects of metformin treatment on serum levels of C-reactive protein and interleukin-6 in women with polycystic ovary syndrome: a meta-analysis: a PRISMA-compliant article. Medicine (Baltimore). 2017;96:e8183. doi:10.1097/MD.0000000000008183
43.
HaffnerSTemprosaMCrandallJ, et al. Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance. Diabetes. 2005;54:1566-1572. doi:10.2337/diabetes.54.5.1566
44.
FismanEZTenenbaumA.The ubiquitous interleukin-6: a time for reappraisal. Cardiovasc Diabetol. 2010;9:62. doi:10.1186/1475-2840-9-62
45.
BautistaLEVeraLMArenasIAGamarraG.Independent association between inflammatory markers (C-reactive protein, interleukin-6, and TNF-alpha) and essential hypertension. J Hum Hypertens. 2005;19:149-154. doi:10.1038/sj.jhh.1001785
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