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06-30-2018 | Metformin | Review | Article

Actions of metformin and statins on lipid and glucose metabolism and possible benefit of combination therapy

Journal: Cardiovascular Diabetology

Authors: Mariël F. van Stee, Albert A. de Graaf, Albert K. Groen

Publisher: BioMed Central

Abstract

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.

Bosi E. Metformin—the gold standard in type 2 diabetes: what does the evidence tell us? Diabetes Obes Metab. 2009;11(Suppl 2):3–8.PubMedCrossRef

Wu L, Parhofer KG. Diabetic dyslipidemia. Metabolism. 2014;63(12):1469–79.PubMedCrossRef

Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C, American Heart A, National Heart L, Blood I. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109(3):433–8.PubMedCrossRef

Kitao N, Miyoshi H, Furumoto T, Ono K, Nomoto H, Miya A, Yamamoto C, Inoue A, Tsuchida K, Manda N, et al. The effects of vildagliptin compared with metformin on vascular endothelial function and metabolic parameters: a randomized, controlled trial (Sapporo Athero-Incretin Study 3). Cardiovasc Diabetol. 2017;16(1):125.PubMedPubMedCentralCrossRef

Mortensen MB, Kulenovic I, Falk E. Statin use and cardiovascular risk factors in diabetic patients developing a first myocardial infarction. Cardiovasc Diabetol. 2016;15(1):81.PubMedPubMedCentralCrossRef

Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema JW, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735–42.PubMedCrossRef

Corrao G, Ibrahim B, Nicotra F, Soranna D, Merlino L, Catapano AL, Tragni E, Casula M, Grassi G, Mancia G. Statins and the risk of diabetes: evidence from a large population-based cohort study. Diabetes Care. 2014;37(8):2225–32.PubMedCrossRef

Fischer J, Ganellin CR, Ganesan A, Proudfoot J. Standalone drugs. In: Ganellin JFACR, editor. Analogue-based drug discovery. Weinheim: Wiley-VCH Verlag GmbH & Co; 2010.CrossRef

Timmins P, Donahue S, Meeker J, Marathe P. Steady-state pharmacokinetics of a novel extended-release metformin formulation. Clin Pharmacokinet. 2005;44(7):721–9.PubMedCrossRef

10.

Buse JB, DeFronzo RA, Rosenstock J, Kim T, Burns C, Skare S, Baron A, Fineman M. The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-week dose-ranging studies. Diabetes Care. 2016;39(2):198–205.PubMed

11.

Hashimoto Y, Tanaka M, Okada H, Mistuhashi K, Kimura T, Kitagawa N, Fukuda T, Majima S, Fukuda Y, Tanaka Y, et al. Postprandial hyperglycemia was ameliorated by taking metformin 30 min before a meal than taking metformin with a meal; a randomized, open-label, crossover pilot study. Endocrine. 2016;52(2):271–6.PubMedCrossRef

12.

Hernandez B, Pfluger F, Kruglik SG, Cohen R, Ghomi M. Protonation-deprotonation and structural dynamics of antidiabetic drug metformin. J Pharm Biomed Anal. 2015;114:42–8.PubMedCrossRef

13.

Bretnall AE, Clarke GS. Metformin hydrochloride. Anal Profiles Drug subst Excipients. 1998;25:243–93.CrossRef

14.

Orgovan G, Noszal B. Electrodeless, accurate pH determination in highly basic media using a new set of (1)H NMR pH indicators. J Pharm Biomed Anal. 2011;54(5):958–64.PubMedCrossRef

15.

Wilcock C, Wyre ND, Bailey CJ. Subcellular distribution of metformin in rat liver. J Pharm Pharmacol. 1991;43(6):442–4.PubMedCrossRef

16.

Wiernsperger NF. Membrane physiology as a basis for the cellular effects of metformin in insulin resistance and diabetes. Diabetes Metab. 1999;25(2):110–27.PubMed

17.

Kinaan M, Ding H, Triggle CR. Metformin: an old drug for the treatment of diabetes but a new drug for the protection of the endothelium. Med Princ Pract. 2015;24(5):401–15.PubMedPubMedCentralCrossRef

18.

Bridges HR, Sirvio VA, Agip AN, Hirst J. Molecular features of biguanides required for targeting of mitochondrial respiratory complex I and activation of AMP-kinase. BMC Biol. 2016;14:65.PubMedPubMedCentralCrossRef

19.

Chien HC, Zur AA, Maurer TS, Yee SW, Tolsma J, Jasper P, Scott DO, Giacomini KM. Rapid method to determine intracellular drug concentrations in cellular uptake assays: application to metformin in organic cation transporter 1-transfected human embryonic kidney 293 cells. Drug Metab Dispos. 2016;44(3):356–64.PubMedCrossRefPubMedCentral

20.

He L, Wondisford FE. Metformin action: concentrations matter. Cell Metab. 2015;21(2):159–62.PubMedCrossRef

21.

Wilcock C, Bailey CJ. Sites of metformin-stimulated glucose metabolism. Biochem Pharmacol. 1990;39(11):1831–4.PubMedCrossRef

22.

Gormsen LC, Sundelin EI, Jensen JB, Vendelbo MH, Jakobsen S, Munk OL, Christensen MM, Brosen K, Frokiaer J, Jessen N. In vivo imaging of human 11C-metformin in peripheral organs: dosimetry, biodistribution and kinetic analyses. J Nucl Med. 2016;57(12):1920–6.PubMedCrossRef

23.

Han TK, Proctor WR, Costales CL, Cai H, Everett RS, Thakker DR. Four cation-selective transporters contribute to apical uptake and accumulation of metformin in Caco-2 cell monolayers. J Pharmacol Exp Ther. 2015;352(3):519–28.PubMedCrossRef

24.

McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia. 2016;59(3):426–35.PubMedPubMedCentralCrossRef

25.

Liang X, Chien HC, Yee SW, Giacomini MM, Chen EC, Piao M, Hao J, Twelves J, Lepist EI, Ray AS, et al. Metformin is a substrate and inhibitor of the human thiamine transporter, THTR-2 (SLC19A3). Mol Pharm. 2015;12(12):4301–10.PubMedPubMedCentralCrossRef

26.

Zhou M, Xia L, Wang J. Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine. Drug Metab Dispos. 2007;35(10):1956–62.PubMedPubMedCentralCrossRef

27.

Dujic T, Zhou K, Donnelly LA, Tavendale R, Palmer CN, Pearson ER. Association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: a GoDARTS study. Diabetes. 2015;64(5):1786–93.PubMedCrossRef

28.

Muller J, Lips KS, Metzner L, Neubert RH, Koepsell H, Brandsch M. Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem Pharmacol. 2005;70(12):1851–60.PubMedCrossRef

29.

Proctor WR, Ming X, Bourdet D, Han TK, Everett RS, Thakker DR. Why does the intestine lack basolateral efflux transporters for cationic compounds? A provocative hypothesis. J Pharm Sci. 2016;105(2):484–96.PubMedCrossRef

30.

Bailey CJ, Wilcock C, Scarpello JH. Metformin and the intestine. Diabetologia. 2008;51(8):1552–3.PubMedCrossRef

31.

Duez H, Lamarche B, Uffelman KD, Valero R, Cohn JS, Lewis GF. Hyperinsulinemia is associated with increased production rate of intestinal apolipoprotein B-48-containing lipoproteins in humans. Arterioscler Thromb Vasc Biol. 2006;26(6):1357–63.PubMedCrossRef

32.

Xiao C, Dash S, Morgantini C, Adeli K, Lewis GF. Gut peptides are novel regulators of intestinal lipoprotein secretion: experimental and pharmacological manipulation of lipoprotein metabolism. Diabetes. 2015;64(7):2310–8.PubMedCrossRef

33.

Gutierrez-Repiso C, Rodriguez-Pacheco F, Garcia-Arnes J, Valdes S, Gonzalo M, Soriguer F, Moreno-Ruiz FJ, Rodriguez-Cañete A, Gallego-Perales JL, Alcain-Martinez G. The expression of genes involved in jejunal lipogenesis and lipoprotein synthesis is altered in morbidly obese subjects with insulin resistance. Lab Invest. 2015;95(12):1409–17.PubMedCrossRef

34.

Jeppesen J, Zhou MY, Chen YD, Reaven GM. Effect of metformin on postprandial lipemia in patients with fairly to poorly controlled NIDDM. Diabetes Care. 1994;17(10):1093–9.PubMedCrossRef

35.

Field FJ, Born E, Murthy S, Mathur SN. Gene expression of sterol regulatory element-binding proteins in hamster small intestine. J Lipid Res. 2001;42(1):1–8.PubMed

36.

Kohjima M, Higuchi N, Kato M, Kotoh K, Yoshimoto T, Fujino T, Yada M, Yada R, Harada N, Enjoji M, et al. SREBP-1c, regulated by the insulin and AMPK signaling pathways, plays a role in nonalcoholic fatty liver disease. Int J Mol Med. 2008;21(4):507–11.PubMed

37.

Srivastava RA, Pinkosky SL, Filippov S, Hanselman JC, Cramer CT, Newton RS. AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases. J Lipid Res. 2012;53(12):2490–514.PubMedPubMedCentralCrossRef

38.

Tso P, Sun W, Liu M. Gastrointestinal satiety signals IV. Apolipoprotein A-IV. Am J Physiol Gastrointest Liver Physiol. 2004;286(6):G885–90.PubMedCrossRef

39.

Lutz TA, Osto E. Glucagon-like peptide-1, glucagon-like peptide-2, and lipid metabolism. Curr Opin Lipidol. 2016;27(3):257–63.PubMedCrossRef

40.

Dash S, Xiao C, Morgantini C, Lewis GF. New insights into the regulation of chylomicron production. Annu Rev Nutr. 2015;35:265–94.PubMedCrossRef

41.

Harmel E, Grenier E, Bendjoudi Ouadda A, El Chebly M, Ziv E, Beaulieu JF, Sane A, Spahis S, Laville M, Levy E. AMPK in the small intestine in normal and pathophysiological conditions. Endocrinology. 2014;155(3):873–88.PubMedCrossRef

42.

Rajas F, Bruni N, Montano S, Zitoun C, Mithieux G. The glucose-6 phosphatase gene is expressed in human and rat small intestine: regulation of expression in fasted and diabetic rats. Gastroenterology. 1999;117(1):132–9.PubMedCrossRef

43.

Mithieux G, Gautier-Stein A. Intestinal glucose metabolism revisited. Diabetes Res Clin Pract. 2014;105(3):295–301.PubMedCrossRef

44.

Soty M, Penhoat A, Amigo-Correig M, Vinera J, Sardella A, Vullin-Bouilloux F, Zitoun C, Houberdon I, Mithieux G. A gut-brain neural circuit controlled by intestinal gluconeogenesis is crucial in metabolic health. Mol Metab. 2015;4(2):106–17.PubMedCrossRef

45.

Mithieux G, Rajas F, Zitoun C. Glucose utilization is suppressed in the gut of insulin-resistant high fat-fed rats and is restored by metformin. Biochem Pharmacol. 2006;72(12):1757–62.PubMedCrossRef

46.

Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E, Sunagawa S, Prifti E, Vieira-Silva S, Gudmundsdottir V, Krogh Pedersen H, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015;528(7581):262–6.PubMedPubMedCentralCrossRef

47.

Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Manneras-Holm L, Stahlman M, Olsson LM, Serino M, Planas-Felix M, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017. https://doi.org/10.1038/nm.4345.CrossRefPubMedPubMedCentral

48.

Duca FA, Cote CD, Rasmussen BA, Zadeh-Tahmasebi M, Rutter GA, Filippi BM, Lam TK. Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats. Nat Med. 2015;21(5):506–11.PubMedCrossRefPubMedCentral

49.

Hardie DG. AMP-activated protein kinase: a master switch in glucose and lipid metabolism. Rev Endocr Metab Disord. 2004;5(2):119–25.PubMedCrossRef

50.

Coughlan KA, Valentine RJ, Ruderman NB, Saha AK. AMPK activation: a therapeutic target for type 2 diabetes? Diabetes Metab Syndr Obes. 2014;7:241–53.PubMedPubMedCentral

51.

Ruderman NB, Carling D, Prentki M, Cacicedo JM. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest. 2013;123(7):2764–72.PubMedPubMedCentralCrossRef

52.

Sandoval DA, D’Alessio DA. Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol Rev. 2015;95(2):513–48.PubMedCrossRef

53.

Habener JF, Kieffer TJ. Glucagon and glucagon-like peptides, chap. 11. In: Ronald Kahn C, et al., editors. Joslin’s diabetes mellitus. Philadelphia: Lippincott Williams & Wilkins; 2005.

54.

Mannucci E, Tesi F, Bardini G, Ognibene A, Petracca MG, Ciani S, Pezzatini A, Brogi M, Dicembrini I, Cremasco F, et al. Effects of metformin on glucagon-like peptide-1 levels in obese patients with and without type 2 diabetes. Diabetes Nutr Metab. 2004;17(6):336–42.PubMed

55.

Napolitano A, Miller S, Nicholls AW, Baker D, Van Horn S, Thomas E, Rajpal D, Spivak A, Brown JR, Nunez DJ. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS ONE. 2014;9(7):e100778.PubMedPubMedCentralCrossRef

56.

Preiss D, Dawed A, Welsh P, Heggie A, Jones AG, Dekker J, Koivula R, Hansen TH, Consortium D, Stewart MC, et al. The sustained influence of metformin therapy on circulating GLP-1 levels in individuals with and without type 2 diabetes. Diabetes Obes Metab. 2016. https://doi.org/10.1111/dom.12826.PubMedPubMedCentralCrossRef

57.

Rohde U, Sonne DP, Christensen M, Hansen M, Bronden A, Torang S, Rehfeld JF, Holst JJ, Vilsboll T, Knop FK. Cholecystokinin-induced gallbladder emptying and metformin elicit additive glucagon-like peptide-1 responses. J Clin Endocrinol Metab. 2016;101(5):2076–83.PubMedCrossRef

58.

Kim MH, Jee JH, Park S, Lee MS, Kim KW, Lee MK. Metformin enhances glucagon-like peptide 1 via cooperation between insulin and Wnt signaling. J Endocrinol. 2014;220(2):117–28.PubMedCrossRef

59.

Liu YX, Si MM, Lu W, Zhang LX, Zhou CX, Deng SL, Wu HS. Effects and molecular mechanisms of the antidiabetic fraction of Acorus calamus L. on GLP-1 expression and secretion in vivo and in vitro. J Ethnopharmacol. 2015;166:168–75.PubMedCrossRef

60.

Trabelsi MS, Daoudi M, Prawitt J, Ducastel S, Touche V, Sayin SI, Perino A, Brighton CA, Sebti Y, Kluza J, et al. Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells. Nat Commun. 2015;6:7629.PubMedPubMedCentralCrossRef

61.

Jensen JB, Sundelin EI, Jakobsen S, Gormsen LC, Munk OL, Frokiaer J, Jessen N. [11C]-Labeled metformin distribution in the liver and small intestine using dynamic positron emission tomography in mice demonstrates tissue-specific transporter dependency. Diabetes. 2016;65(6):1724–30.PubMedCrossRef

62.

Zamek-Gliszczynski MJ, Bao JQ, Day JS, Higgins JW. Metformin sinusoidal efflux from the liver is consistent with negligible biliary excretion and absence of enterohepatic cycling. Drug Metab Dispos. 2013;41(11):1967–71.PubMedCrossRef

63.

Scarpello JH, Hodgson E, Howlett HC. Effect of metformin on bile salt circulation and intestinal motility in type 2 diabetes mellitus. Diabet Med. 1998;15(8):651–6.PubMedCrossRef

64.

Ryan P, Delzenne N. Gut microbiota and metabolism. In: Hyland N, Stanton C, editors. The Gut-Brain axis. New York: Elsevier; 2016.

65.

Wang Z, Koonen D, Hofker M, Fu J. Gut microbiome and lipid metabolism: from associations to mechanisms. Curr Opin Lipidol. 2016;27(3):216–24.PubMedCrossRef

66.

Wahlstrom A, Sayin SI, Marschall HU, Backhed F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 2016;24(1):41–50.PubMedCrossRef

67.

de la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V, Velásquez-Mejía EP, Carmona JA, Abad JM, Escobar JS. Metformin is associated with higher relative abundance of mucin-degrading Akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut. Diabetes Care. 2016. https://doi.org/10.2337/dc16-1324.PubMedCrossRef

68.

Dao MC, Everard A, Aron-Wisnewsky J, Sokolovska N, Prifti E, Verger EO, Kayser BD, Levenez F, Chilloux J, Hoyles L, et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut. 2016;65(3):426–36.PubMedCrossRef

69.

Zhou K, Pedersen HK, Dawed AY, Pearson ER. Pharmacogenomics in diabetes mellitus: insights into drug action and drug discovery. Nat Rev Endocrinol. 2016;12(6):337–46.PubMedCrossRef

70.

Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, Sugiyama Y. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther. 2002;302(2):510–5.PubMedCrossRef

71.

Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: from mechanisms of action to therapies. Cell Metab. 2014;20(6):953–66.PubMedCrossRef

72.

Gruszka A. New insight into the mechanisms of the anti-hyperglycemic action of metformin. Br J Med Med Res. 2016;13:1–9.CrossRef

73.

Baur JA, Birnbaum MJ. Control of gluconeogenesis by metformin: does redox trump energy charge? Cell Metab. 2014;20(2):197–9.PubMedPubMedCentralCrossRef

74.

Viollet B, Guigas B, Leclerc J, Hebrard S, Lantier L, Mounier R, Andreelli F, Foretz M. AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives. Acta Physiol (Oxf). 2009;196(1):81–98.CrossRef

75.

Madsen A, Bozickovic O, Bjune JI, Mellgren G, Sagen JV. Metformin inhibits hepatocellular glucose, lipid and cholesterol biosynthetic pathways by transcriptionally suppressing steroid receptor coactivator 2 (SRC-2). Sci Rep. 2015;5:16430.PubMedPubMedCentralCrossRef

76.

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167–74.PubMedPubMedCentralCrossRef

77.

Maziere JC, Maziere C, Mora L, Gardette J, Salmon S, Auclair M, Polonovski J. The antidiabetic drug metformin decreases cholesterol metabolism in cultured human fibroblasts. Atherosclerosis. 1988;71(1):27–33.PubMedCrossRef

78.

Koren-Gluzer M, Aviram M, Hayek T. Metformin inhibits macrophage cholesterol biosynthesis rate: possible role for metformin-induced oxidative stress. Biochem Biophys Res Commun. 2013;439(3):396–400.PubMedCrossRef

79.

Liu ZQ, Song XM, Chen QT, Liu T, Teng JT, Zhou K, Luo DQ. Effect of metformin on global gene expression in liver of KKAy mice. Pharmacol Rep. 2016;68(6):1332–8.PubMedCrossRef

80.

Scott LM, Tomkin GH. Changes in hepatic and intestinal cholesterol regulatory enzymes. The influence of metformin. Biochem Pharmacol. 1983;32(5):827–30.PubMedCrossRef

81.

Chakraborty A, Chowdhury S, Bhattacharyya M. Effect of metformin on oxidative stress, nitrosative stress and inflammatory biomarkers in type 2 diabetes patients. Diabetes Res Clin Pract. 2011;93(1):56–62.PubMedCrossRef

82.

Kashi Z, Mahrooz A, Kianmehr A, Alizadeh A. The role of metformin response in lipid metabolism in patients with recent-onset type 2 diabetes: HbA1c level as a criterion for designating patients as responders or nonresponders to metformin. PLoS ONE. 2016;11(3):e0151543.PubMedPubMedCentralCrossRef

83.

Ohira M, Miyashita Y, Ebisuno M, Saiki A, Endo K, Koide N, Oyama T, Murano T, Watanabe H, Shirai K. Effect of metformin on serum lipoprotein lipase mass levels and LDL particle size in type 2 diabetes mellitus patients. Diabetes Res Clin Pract. 2007;78(1):34–41.PubMedCrossRef

84.

Zhang C, Gao F, Luo H, Zhang CT, Zhang R. Differential response in levels of high-density lipoprotein cholesterol to one-year metformin treatment in prediabetic patients by race/ethnicity. Cardiovasc Diabetol. 2015;14:79.PubMedPubMedCentralCrossRef

85.

Sonne DP, Knop FK. Comment on Xu et al. Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes. Diabetes Care 2015;38:1858–1867. Diabetes Care. 2015; 38(12):e215.

86.

Hofmann AF, Hagey LR. Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades. J Lipid Res. 2014;55(8):1553–95.PubMedPubMedCentralCrossRef

87.

The lipid research clinics coronary primary prevention trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251(3):351–64.

88.

Luo F, Guo Y, Ruan G, Li X. Metformin promotes cholesterol efflux in macrophages by up-regulating FGF21 expression: a novel anti-atherosclerotic mechanism. Lipids Health Dis. 2016;15:109.PubMedPubMedCentralCrossRef

89.

Nygaard EB, Vienberg SG, Orskov C, Hansen HS, Andersen B. Metformin stimulates FGF21 expression in primary hepatocytes. Exp Diabetes Res. 2012;2012:465282.PubMedPubMedCentralCrossRef

90.

Fan H, Sun X, Zhang H, Liu J, Zhang P, Xu Y, Pan Q, Wang G. Effect of metformin on fibroblast growth factor-21 levels in patients with newly diagnosed type 2 diabetes. Diabetes Technol Ther. 2016;18(3):120–6.PubMedCrossRef

91.

Xu T, Brandmaier S, Messias AC, Herder C, Draisma HH, Demirkan A, Yu Z, Ried JS, Haller T, Heier M, et al. Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes. Diabetes Care. 2015;38(10):1858–67.PubMedCrossRef

92.

Sone Y, Kido T, Ainuki T, Sonoda M, Ichi I, Kodama S, Sone H, Kondo K, Morita Y, Egawa S, et al. Genetic variants of the fatty acid desaturase gene cluster are associated with plasma LDL cholesterol levels in Japanese males. J Nutr Sci Vitaminol (Tokyo). 2013;59(4):325–35.CrossRef

93.

Zang M, Zuccollo A, Hou X, Nagata D, Walsh K, Herscovitz H, Brecher P, Ruderman NB, Cohen RA. AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells. J Biol Chem. 2004;279(46):47898–905.PubMedCrossRef

94.

Wang J, Yang X, Zhang J. Bridges between mitochondrial oxidative stress, ER stress and mTOR signaling in pancreatic β cells. Cell Signal. 2016;28(8):1099–104.PubMedCrossRef

95.

Tanaka K, Saisho Y, Manesso E, Tanaka M, Meguro S, Irie J, Sugiura H, Kawai T, Jinzaki M, Cobelli C, et al. Effects of liraglutide monotherapy on beta cell function and pancreatic enzymes compared with metformin in Japanese overweight/obese patients with type 2 diabetes mellitus: a subpopulation analysis of the KIND-LM randomized trial. Clin Drug Investig. 2015;35(10):675–84.PubMedCrossRef

96.

Cobelli C, Dalla Man C, Toffolo G, Basu R, Vella A, Rizza R. The oral minimal model method. Diabetes. 2014;63(4):1203–13.PubMedPubMedCentralCrossRef

97.

Konopka AR, Esponda RR, Robinson MM, Johnson ML, Carter RE, Schiavon M, Cobelli C, Wondisford FE, Lanza IR, Nair KS. Hyperglucagonemia mitigates the effect of metformin on glucose production in prediabetes. Cell Rep. 2016;15(7):1394–400.PubMedPubMedCentralCrossRef

98.

Lupi R, Del Guerra S, Fierabracci V, Marselli L, Novelli M, Patane G, Boggi U, Mosca F, Piro S, Del Prato S, et al. Lipotoxicity in human pancreatic islets and the protective effect of metformin. Diabetes. 2002;51(Suppl 1):S134–7.PubMedCrossRef

99.

Natalicchio A, Biondi G, Marrano N, Labarbuta R, Tortosa F, Spagnuolo R, D’Oria R, Carchia E, Leonardini A, Cignarelli A, et al. Long-Term exposure of pancreatic beta-cells to palmitate results in SREBP-1C-dependent decreases in GLP-1 receptor signaling via CREB and AKT and insulin secretory response. Endocrinology. 2016;157(6):2243–58.PubMedCrossRef

100.

Dai YL, Huang SL, Leng Y. AICAR and metformin exert AMPK-dependent effects on INS-1E pancreatic beta-cell apoptosis via differential downstream mechanisms. Int J Biol Sci. 2015;11(11):1272–80.PubMedPubMedCentralCrossRef

101.

Chang TJ, Tseng HC, Liu MW, Chang YC, Hsieh ML, Chuang LM. Glucagon-like peptide-1 prevents methylglyoxal-induced apoptosis of beta cells through improving mitochondrial function and suppressing prolonged AMPK activation. Sci Rep. 2016;6:23403.PubMedPubMedCentralCrossRef

102.

Muhammed SJ, Lundquist I, Salehi A. Pancreatic beta-cell dysfunction, expression of iNOS and the effect of phosphodiesterase inhibitors in human pancreatic islets of type 2 diabetes. Diabetes Obes Metab. 2012;14(11):1010–9.PubMedCrossRef

103.

Mezghenna K, Pomies P, Chalancon A, Castex F, Leroy J, Niclauss N, Nadal B, Cambier L, Cazevieille C, Petit P, et al. Increased neuronal nitric oxide synthase dimerisation is involved in rat and human pancreatic beta cell hyperactivity in obesity. Diabetologia. 2011;54(11):2856–66.PubMedCrossRef

104.

Lundquist I, Mohammed Al-Amily I, Meidute Abaraviciene S, Salehi A. Metformin ameliorates dysfunctional traits of glibenclamide- and glucose-induced insulin secretion by suppression of imposed overactivity of the islet nitric oxide synthase-NO system. PLoS ONE. 2016;11(11):e0165668.PubMedPubMedCentralCrossRef

105.

Brereton MF, Rohm M, Shimomura K, Holland C, Tornovsky-Babeay S, Dadon D, Iberl M, Chibalina MV, Lee S, Glaser B, et al. Hyperglycaemia induces metabolic dysfunction and glycogen accumulation in pancreatic beta-cells. Nat Commun. 2016;7:13496.PubMedPubMedCentralCrossRef

106.

Consortium R. Restoring insulin secretion (RISE): design of studies of beta-cell preservation in prediabetes and early type 2 diabetes across the life span. Diabetes Care. 2014;37(3):780–8.CrossRef

107.

Force USPST, Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW Jr, Garcia FA, Gillman MW, Kemper AR, Krist AH, et al. Statin use for the primary prevention of cardiovascular disease in adults: US preventive services task force recommendation statement. JAMA. 2016;316(19):1997–2007.CrossRef

108.

Gruzdeva O, Uchasova E, Dyleva Y, Akbasheva O, Karetnikova V, Shilov A, Barbarash O. Effect of different doses of statins on the development of type 2 diabetes mellitus in patients with myocardial infarction. Diabetes Metab Syndr Obes Targets Ther. 2017;10:481.CrossRef

109.

Gruzdeva O, Uchasova E, Dyleva Y, Akbasheva O, Karetnikova V, Barbarash O. Early effects of treatment low-dose atorvastatin on markers of insulin resistance and inflammation in patients with myocardial infarction. Front Pharmacol. 2016;7:324.PubMedPubMedCentralCrossRef

110.

Anyanwagu U, Idris I, Donnelly R. Drug-induced diabetes mellitus: evidence for statins and other drugs affecting glucose metabolism. Clin Pharmacol Ther. 2016;99(4):390–400.PubMedCrossRef

111.

Wang S, Cai R, Yuan Y, Varghese Z, Moorhead J, Ruan XZ. Association between reductions in low-density lipoprotein cholesterol with statin therapy and the risk of new-onset diabetes: a meta-analysis. Sci Rep. 2017;7:39982.PubMedPubMedCentralCrossRef

112.

Gotoh S, Negishi M. Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis. Sci Rep. 2015;5:14076.PubMedPubMedCentralCrossRef

113.

Hakkola J, Rysa J, Hukkanen J. Regulation of hepatic energy metabolism by the nuclear receptor PXR. Biochim Biophys Acta. 2016;1859(9):1072–82.PubMedCrossRef

114.

He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009;43:67–93.PubMedPubMedCentralCrossRef

115.

Ling Z, Shu N, Xu P, Wang F, Zhong Z, Sun B, Li F, Zhang M, Zhao K, Tang X, et al. Involvement of pregnane X receptor in the impaired glucose utilization induced by atorvastatin in hepatocytes. Biochem Pharmacol. 2016;100:98–111.PubMedCrossRef

116.

Black RN, Ennis CN, Young IS, Hunter SJ, Atkinson AB, Bell PM. The peroxisome proliferator-activated receptor alpha agonist fenofibrate has no effect on insulin sensitivity compared to atorvastatin in type 2 diabetes mellitus; a randomised, double-blind controlled trial. J Diabetes Complications. 2014;28(3):323–7.PubMedCrossRef

117.

Szendroedi J, Anderwald C, Krssak M, Bayerle-Eder M, Esterbauer H, Pfeiler G, Brehm A, Nowotny P, Hofer A, Waldhausl W, et al. Effects of high-dose simvastatin therapy on glucose metabolism and ectopic lipid deposition in nonobese type 2 diabetic patients. Diabetes Care. 2009;32(2):209–14.PubMedPubMedCentralCrossRef

118.

Ruscica M, Macchi C, Morlotti B, Sirtori CR, Magni P. Statin therapy and related risk of new-onset type 2 diabetes mellitus. Eur J Intern Med. 2014;25(5):401–6.PubMedCrossRef

119.

Hao M, Head WS, Gunawardana SC, Hasty AH, Piston DW. Direct effect of cholesterol on insulin secretion: a novel mechanism for pancreatic beta-cell dysfunction. Diabetes. 2007;56(9):2328–38.PubMedCrossRef

120.

Zhou J, Li W, Xie Q, Hou Y, Zhan S, Yang X, Xu X, Cai J, Huang Z. Effects of simvastatin on glucose metabolism in mouse MIN6 cells. J Diabetes Res. 2014;2014:376570.PubMedPubMedCentral

121.

Vergeer M, Brunham LR, Koetsveld J, Kruit JK, Verchere CB, Kastelein JJ, Hayden MR, Stroes ES. Carriers of loss-of-function mutations in ABCA1 display pancreatic beta-cell dysfunction. Diabetes Care. 2010;33(4):869–74.PubMedPubMedCentralCrossRef

122.

Yaluri N, Modi S, Lopez Rodriguez M, Stancakova A, Kuusisto J, Kokkola T, Laakso M. Simvastatin impairs insulin secretion by multiple mechanisms in MIN6 cells. PLoS ONE. 2015;10(11):e0142902.PubMedPubMedCentralCrossRef

123.

Scattolini V, Luni C, Zambon A, Galvanin S, Gagliano O, Ciubotaru CD, Avogaro A, Mammano F, Elvassore N, Fadini GP. Simvastatin rapidly and reversibly inhibits insulin secretion in intact single-islet cultures. Diabetes Ther. 2016;7(4):679–93.PubMedPubMedCentralCrossRef

124.

Sun H, Li Y, Sun B, Hou N, Yang J, Zheng M, Xu J, Wang J, Zhang Y, Zeng X, et al. Atorvastatin inhibits insulin synthesis by inhibiting the Ras/Raf/ERK/CREB pathway in INS-1 cells. Medicine (Baltimore). 2016;95(39):e4906.CrossRef

125.

Schirris TJ, Renkema GH, Ritschel T, Voermans NC, Bilos A, van Engelen BG, Brandt U, Koopman WJ, Beyrath JD, Rodenburg RJ, et al. Statin-induced myopathy is associated with mitochondrial complex iii inhibition. Cell Metab. 2015;22(3):399–407.PubMedCrossRef

126.

Elbadawi-Sidhu M, Baillie RA, Zhu H, Chen YDI, Goodarzi MO, Rotter JI, Krauss RM, Fiehn O, Kaddurah-Daouk R. Pharmacometabolomic signature links simvastatin therapy and insulin resistance. Metabolomics. 2017;13(1):11.PubMedCrossRef

127.

Takaguri A, Satoh K, Itagaki M, Tokumitsu Y, Ichihara K. Effects of atorvastatin and pravastatin on signal transduction related to glucose uptake in 3T3L1 adipocytes. J Pharmacol Sci. 2008;107(1):80–9.PubMedCrossRef

128.

Nakata M, Nagasaka S, Kusaka I, Matsuoka H, Ishibashi S, Yada T. Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control. Diabetologia. 2006;49(8):1881–92.PubMedCrossRef

129.

Sugiyama T, Tsugawa Y, Tseng CH, Kobayashi Y, Shapiro MF. Different time trends of caloric and fat intake between statin users and nonusers among US adults: gluttony in the time of statins? JAMA Intern Med. 2014;174(7):1038–45.PubMedPubMedCentralCrossRef

130.

Schommers P, Thurau A, Bultmann-Mellin I, Guschlbauer M, Klatt AR, Rozman J, Klingenspor M, de Angelis MH, Alber J, Gründemann D. Metformin causes a futile intestinal—hepatic cycle which increases energy expenditure and slows down development of a type 2 diabetes-like state. Molecular Metabolism. 2017. https://doi.org/10.1016/j.molmet.2017.05.002.PubMedPubMedCentralCrossRef

131.

Islam M, Alam A, Rahman M, Ali Y, Mamun A, Rahman M, Hossain A, Rashid M. Effects of combination of antidiabetic agent and statin on alloxan-induced diabetes with cardiovascular diseases in rats. J Sci Res. 2012;4(3):709–20.

132.

Matafome P, Louro T, Rodrigues L, Crisostomo J, Nunes E, Amaral C, Monteiro P, Cipriano A, Seica R. Metformin and atorvastatin combination further protect the liver in type 2 diabetes with hyperlipidaemia. Diabetes Metab Res Rev. 2011;27(1):54–62.PubMedCrossRef

133.

Singh BK, Singh A, Kumar V. Ameliorative effect of adjunct therapy of metformin with atorvastatin on streptozotocin-induced diabetes mellitus in rats. Drug Res (Stuttg). 2016;66(1):28–32.

134.

Oh JH, Eun Lee J, Jeong Kim Y, Oh TO, Han S, Jeon EK, Shin K, Kim DH, Hye Park C, Lee YJ. Designing of the fixed-dose gastroretentive bilayer tablet for sustained release of metformin and immediate release of atorvastatin. Drug Dev Ind Pharm. 2016;42(2):340–9.PubMedCrossRef

135.

Kandhwal K, Dey S, Nazarudheen S, Arora R, Reyar S, Thudi NR, Monif T, Singh MK, Rao S. Pharmacokinetics of a fixed-dose combination of atorvastatin and metformin extended release versus concurrent administration of individual formulations: a randomized, open-label, two-treatment, two-period, two-sequence, single-dose, crossover, bioequivalence study. Clin Drug Investig. 2011;31(12):853–63.PubMedCrossRef

136.

Scheen AJ. Drug interactions of clinical importance with antihyperglycaemic agents: an update. Drug Saf. 2005;28(7):601–31.CrossRefPubMed

137.

Balasubramanian R, Varadharajan S, Kathale A, Nagraj LM, Periyandavar I, Nayak UP, Sharma A, Bolmall C, Baliga VP. Assessment of the efficacy and tolerability of a fixed dose combination of atorvastatin 10 mg+ metformin SR 500 mg in diabetic dyslipidaemia in adult Indian patients. J Indian Med Assoc. 2008;106(7):464–7.PubMed

138.

Krysiak R, Okopien B. Haemostatic effects of metformin in simvastatin-treated volunteers with impaired fasting glucose. Basic Clin Pharmacol Toxicol. 2012;111(6):380–4.PubMedCrossRef

139.

Krysiak R, Okopien B. Lymphocyte-suppressing and systemic anti-inflammatory effects of high-dose metformin in simvastatin-treated patients with impaired fasting glucose. Atherosclerosis. 2012;225(2):403–7.PubMedCrossRef

140.

Krysiak R, Okopien B. The effect of metformin on monocyte secretory function in simvastatin-treated patients with impaired fasting glucose. Metabolism. 2013;62(1):39–43.PubMedCrossRef

141.

Tousoulis D, Koniari K, Antoniades C, Papageorgiou N, Miliou A, Noutsou M, Nikolopoulou A, Marinou K, Stefanadi E, Siasos G, et al. Combined effects of atorvastatin and metformin on glucose-induced variations of inflammatory process in patients with diabetes mellitus. Int J Cardiol. 2011;149(1):46–9.PubMedCrossRef

142.

Tousoulis D, Koniari K, Antoniades C, Miliou A, Noutsou M, Nikolopoulou A, Papageorgiou N, Marinou K, Stefanadi E, Stefanadis C. Impact of 6 weeks of treatment with low-dose metformin and atorvastatin on glucose-induced changes of endothelial function in adults with newly diagnosed type 2 diabetes mellitus: a single-blind study. Clin Ther. 2010;32(10):1720–8.PubMedCrossRef

143.

Hao Z, Liu Y, Liao H, Zheng D, Xiao C, Li G. Atorvastatin plus metformin confer additive benefits on subjects with dyslipidemia and overweight/obese via reducing ROCK2 concentration. Exp Clin Endocrinol Diabetes. 2016;124(4):246–50.PubMedCrossRef

144.

Caparros-Martin JA, Lareu RR, Ramsay JP, Peplies J, Reen FJ, Headlam HA, Ward NC, Croft KD, Newsholme P, Hughes JD, et al. Statin therapy causes gut dysbiosis in mice through a PXR-dependent mechanism. Microbiome. 2017;5(1):95.PubMedPubMedCentralCrossRef

145.

Khan TJ, Ahmed YM, Zamzami MA, Mohamed SA, Khan I, Baothman OAS, Mehanna MG, Yasir M. Effect of atorvastatin on the gut microbiota of high fat diet-induced hypercholesterolemic rats. Sci Rep. 2018;8(1):662.PubMedPubMedCentralCrossRef

146.

Khan TJ, Ahmed YM, Zamzami MA, Siddiqui AM, Khan I, Baothman OAS, Mehanna MG, Kuerban A, Kaleemuddin M, Yasir M. Atorvastatin treatment modulates the gut microbiota of the hypercholesterolemic patients. OMICS. 2018;22(2):154–63.PubMedCrossRef

147.

Nascimbeni F, Aron-Wisnewsky J, Pais R, Tordjman J, Poitou C, Charlotte F, Bedossa P, Poynard T, Clement K, Ratziu V, et al. Statins, antidiabetic medications and liver histology in patients with diabetes with non-alcoholic fatty liver disease. BMJ Open Gastroenterol. 2016;3(1):e000075.PubMedPubMedCentralCrossRef

148.

Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. 2005;352(12):1223–36.PubMedCrossRef

149.

Sun J, Yuan Y, Cai R, Sun H, Zhou Y, Wang P, Huang R, Xia W, Wang S. An investigation into the therapeutic effects of statins with metformin on polycystic ovary syndrome: a meta-analysis of randomised controlled trials. BMJ Open. 2015;5(3):e007280.PubMedPubMedCentralCrossRef

150.

Chung Y-R, Park SW, Choi S-Y, Kim SW, Moon KY, Kim JH, Lee K. Association of statin use and hypertriglyceridemia with diabetic macular edema in patients with type 2 diabetes and diabetic retinopathy. Cardiovasc Diabetol. 2017;16(1):4.PubMedPubMedCentralCrossRef

151.

Jorgensen PG, Jensen MT, Biering-Sorensen T, Mogelvang R, Galatius S, Fritz-Hansen T, Rossing P, Vilsboll T, Jensen JS. Cholesterol remnants and triglycerides are associated with decreased myocardial function in patients with type 2 diabetes. Cardiovasc Diabetol. 2016;15(1):137.PubMedPubMedCentralCrossRef

152.

Hanefeld M, Traylor L, Gao L, Landgraf W. The use of lipid-lowering therapy and effects of antihyperglycaemic therapy on lipids in subjects with type 2 diabetes with or without cardiovascular disease: a pooled analysis of data from eleven randomized trials with insulin glargine 100 U/mL. Cardiovasc Diabetol. 2017;16(1):66.PubMedPubMedCentralCrossRef

153.

Besseling J, Hutten BA. Is there a link between diabetes and cholesterol metabolism? Expert Rev Cardiovasc Ther. 2016;14(3):259–61.PubMedCrossRef

154.

Cederberg H, Stancakova A, Yaluri N, Modi S, Kuusisto J, Laakso M. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. Diabetologia. 2015;58(5):1109–17.PubMedCrossRef

155.

Chehade JM, Gladysz M, Mooradian AD. Dyslipidemia in type 2 diabetes: prevalence, pathophysiology, and management. Drugs. 2013;73(4):327–39.PubMedCrossRef

156.

Feingold K, Grunfeld C. Role of glucose and lipids in the cardiovascular disease of patients with diabetes. In: De Groot LJ, Chrousos G, Dungan K, et al., editors. Endotext. South Dartmouth (MA): MDText.com, Inc.; 2000.

157.

Jaiswal M, Schinske A, Pop-Busui R. Lipids and lipid management in diabetes. Best Pract Res Clin Endocrinol Metab. 2014;28(3):325–38.PubMedCrossRef

158.

Ng DS. Diabetic dyslipidemia: from evolving pathophysiological insight to emerging therapeutic targets. Can J Diabetes. 2013;37(5):319–26.PubMedCrossRef

159.

Soran H, Schofield JD, Adam S, Durrington PN. Diabetic dyslipidaemia. Curr Opin Lipidol. 2016;27(4):313–22.PubMedCrossRef

160.

Schofield JD, Liu Y, Rao-Balakrishna P, Malik RA, Soran H. Diabetes dyslipidemia. Diabetes Ther. 2016;7(2):203–19.PubMedPubMedCentralCrossRef

161.

Verges B. Pathophysiology of diabetic dyslipidaemia: where are we? Diabetologia. 2015;58(5):886–99.PubMedPubMedCentralCrossRef

162.

Wang CCL, Hess CN, Hiatt WR, Goldfine AB. Clinical update: cardiovascular disease in diabetes mellitus atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus-mechanisms, management, and clinical considerations. Circulation. 2016;133(24):2459–502.CrossRef

163.

Arca M. Alterations of intestinal lipoprotein metabolism in diabetes mellitus and metabolic syndrome. Atheroscler Suppl. 2015;17:12–6.PubMedCrossRef

164.

Tomkin GH, Owens D. Dyslipidaemia of diabetes and the intestine. World J Diabetes. 2015;6(7):970–7.PubMedPubMedCentralCrossRef

165.

Arca M, Pigna G, Favoccia C. Mechanisms of diabetic dyslipidemia: relevance for atherogenesis. Curr Vasc Pharmacol. 2012;10(6):684–6.PubMedCrossRef

166.

Perry RJ, Samuel VT, Petersen KF, Shulman GI. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature. 2014;510(7503):84–91.PubMedPubMedCentralCrossRef

167.

Taskinen MR, Boren J. New insights into the pathophysiology of dyslipidemia in type 2 diabetes. Atherosclerosis. 2015;239(2):483–95.PubMedCrossRef

168.

Pagidipati NJ, Pencina M, Sniderman AD. The enigma of glucose and lipid metabolism. JAMA Cardiol. 2016;1(2):145–6.PubMedCrossRef

169.

Parhofer KG. Interaction between glucose and lipid metabolism: more than diabetic dyslipidemia. Diabetes Metab J. 2015;39(5):353–62.PubMedPubMedCentralCrossRef

170.

Patel TP, Rawal K, Bagchi AK, Akolkar G, Bernardes N, Dias Dda S, Gupta S, Singal PK. Insulin resistance: an additional risk factor in the pathogenesis of cardiovascular disease in type 2 diabetes. Heart Fail Rev. 2016;21(1):11–23.PubMedCrossRef

171.

Dake AW, Sora ND. Diabetic dyslipidemia review: an update on current concepts and management guidelines of diabetic dyslipidemia. Am J Med Sci. 2016;351(4):361–5.PubMedCrossRef

172.

Halcox J, Misra A. Type 2 diabetes mellitus, metabolic syndrome, and mixed dyslipidemia: how similar, how different, and how to treat? Metab Syndr Relat Disord. 2015;13(1):1–21.PubMedCrossRef

173.

Paneni F, Cosentino F. Diabetic dyslipidemia. In: Diabetes and cardiovascular disease. Cham: Springer; 2015. p. 101–13.CrossRef

174.

Szalat A, Durst R, Leitersdorf E. Managing dyslipidaemia in type 2 diabetes mellitus. Best Pract Res Clin Endocrinol Metab. 2016;30(3):431–44.PubMedCrossRef

175.

Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J. 2015;36(34):2288–96.PubMedCrossRef

176.

Balakumar P. Implications of fundamental signalling alterations in diabetes mellitus-associated cardiovascular disease. Indian J Biochem Biophys. 2014;51(6):441–8.PubMed

177.

Chen SC, Tseng CH. Dyslipidemia, kidney disease, and cardiovascular disease in diabetic patients. Rev Diabet Stud. 2013;10(2–3):88–100.PubMedPubMedCentralCrossRef

178.

Leon BM, Maddox TM. Diabetes and cardiovascular disease: epidemiology, biological mechanisms, treatment recommendations and future research. World J Diabetes. 2015;6(13):1246–58.PubMedPubMedCentralCrossRef

179.

Paneni F, Beckman JA, Creager MA, Cosentino F. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur Heart J. 2013;34(31):2436–43.PubMedPubMedCentralCrossRef

180.

Scheen AJ. Will delayed release metformin provide better management of diabetes type 2? Expert Opin Pharmacother. 2016;17(5):627–30.PubMedCrossRef

181.

Foster RH, Keam SJ. Metformin extended release. Am J Drug Deliv. 2006;4(3):177–86.CrossRef

182.

Ali S, Fonseca V. Overview of metformin: special focus on metformin extended release. Expert Opin Pharmacother. 2012;13(12):1797–805.PubMedCrossRef

183.

Campbell I, Clarke B, Duncan L. A clinical evaluation of a delayed release preparation of metformin. J Int Med Res. 1973;1(6):551–6.CrossRef

184.

Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica. 1994;24(1):49–57.PubMedCrossRef

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