Effect of SGLT2 Inhibitors and Metformin on Inflammatory and Prognostic
Biomarkers in Type 2 Diabetes Patients

Yang      Cao; Ning      Liang; Ting      Liu; Jingai      Fang; Xiaodong      Zhang

doi:10.2174/1871530322666220827150054

Abstract

Objective: To assess the combined effect of Sodium-Glucose Transporter 2 Inhibitors (SGLT2i) and metformin treatment on inflammatory and prognostic biomarkers in patients with T2DM.

Methods: Using the search terms “Sodium-Glucose Transporter 2 Inhibitors,” “Diabetes Mellitus, Type 2,” and “randomized controlled trial,” we screened the literature on PubMed, Cochrane Library, Embase, and Web of Science according to the inclusion and exclusion criteria. The studies selected were grouped to determine the combined effect of SGLT2i and metformin on inflammatory markers in patients with T2DM. Results were expressed using continuous variables, combined into weighted mean differences (WMD) and 95% confidence intervals (CI). The study was registered under the PROSPERO number CRD42022296480.

Results: Meta-analysis showed that, compared with the control and metformin treatment groups, the SGLT2i coupled with metformin group was more effective in reducing C-reactive protein (CRP) (WMD, −0.185, 95% CI, −0.330 to −0.040, P < 0.05), tumor necrosis factor (TNF-α) (WMD, −0.628, 95% CI, −1.046 to −0.210, P < 0.05), uric acid (WMD, −0.653, 95% CI, −0.734 to −0.572, P < 0.05), leptin (WMD, −3.663, 95% CI, −4.812 to −2.515, P < 0.05), glycated hemoglobin (HbA1c) (WMD = −0.172, 95% CI, −0.255 to −0.089, P < 0.05), and estimated glomerular filtration rate (eGFR)(WMD = 0.978, 95% CI (0.027, 1.928), P = 0.044). In parallel, we performed a Trial Sequential Analysis (TSA) of and the results showed reliable conclusions.

Conclusion: SGLT2i combined with metformin reduced inflammation levels and significantly improved glycemic control and prognosis in patients with T2DM.

Keywords: SGLT2i, metformin, type 2 diabetes, inflammation, systematic review; meta-analysis.

« Previous Next »

Graphical Abstract

[1]
Hotamisligil, G.S. Inflammation and metabolic disorders. Nature,  2006, 444(7121), 860-867.
 [http://dx.doi.org/10.1038/nature05485] [PMID:  17167474]

[2]
Stewart, K.J. Exercise training and the cardiovascular consequences of type 2 diabetes and hypertension: Plausible mechanisms for improving cardiovascular health. JAMA,  2002, 288(13), 1622-1631.
 [http://dx.doi.org/10.1001/jama.288.13.1622] [PMID:  12350193]

[3]
Mazzone, T.; Chait, A.; Plutzky, J. Cardiovascular disease risk in type 2 diabetes mellitus: Insights from mechanistic studies. Lancet,  2008, 371(9626), 1800-1809.
 [http://dx.doi.org/10.1016/S0140-6736(08)60768-0] [PMID:  18502305]

[4]
Powell, E.E.; Wong, V.W.; Rinella, M. Non-alcoholic fatty liver disease. Lancet,  2021, 397(10290), 2212-2224.
 [http://dx.doi.org/10.1016/S0140-6736(20)32511-3] [PMID:  33894145]

[5]
He, L. Metformin and systemic metabolism. Trends Pharmacol. Sci.,  2020, 41(11), 868-881.
 [http://dx.doi.org/10.1016/j.tips.2020.09.001] [PMID:  32994049]

[6]
Kurinami, N.; Sugiyama, S.; Yoshida, A.; Hieshima, K.; Miyamoto, F.; Kajiwara, K.; Jinnouch, K.; Jinnouchi, T.; Jinnouchi, H. Dapagliflozin significantly reduced liver fat accumulation associated with a decrease in abdominal subcutaneous fat in patients with inadequately controlled type 2 diabetes mellitus. Diabetes Res. Clin. Pract.,  2018, 142, 254-263.
 [http://dx.doi.org/10.1016/j.diabres.2018.05.017] [PMID:  29859912]

[7]
Bray, J.J.H.; Foster-Davies, H.; Stephens, J.W. A systematic review examining the effects of sodium-glucose cotransporter-2 inhibitors (SGLT2is) on biomarkers of inflammation and oxidative stress. Diabetes Res. Clin. Pract.,  2020, 168, 108368.
 [http://dx.doi.org/10.1016/j.diabres.2020.108368] [PMID:  32800932]

[8]
Sun, Y.; Yan, D.; Hao, Z.; Cui, L.; Li, G. Effects of dapagliflozin and sitagliptin on insulin resistant and body fat distribution in newly diagnosed type 2 diabetic patients. Med. Sci. Monit.,  2020, 26, e921891.
 [http://dx.doi.org/10.12659/MSM.921891] [PMID:  32240122]

[9]
Fadini, G.P.; Bonora, B.M.; Zatti, G.; Vitturi, N.; Iori, E.; Marescotti, M.C.; Albiero, M.; Avogaro, A. Effects of the SGLT2 inhibitor dapagliflozin on HDL cholesterol, particle size, and cholesterol efflux capacity in patients with type 2 diabetes: A randomized placebo-controlled trial. Cardiovasc. Diabetol.,  2017, 16(1), 42.
 [http://dx.doi.org/10.1186/s12933-017-0529-3] [PMID:  28376855]

[10]
Hattori, S. Anti-inflammatory effects of empagliflozin in patients with type 2 diabetes and insulin resistance. Diabetol. Metab. Syndr.,  2018, 10(1), 93.
 [http://dx.doi.org/10.1186/s13098-018-0395-5] [PMID:  30574207]

[11]
Jojima, T.; Sakurai, S.; Wakamatsu, S.; Iijima, T.; Saito, M.; Tomaru, T.; Kogai, T.; Usui, I.; Aso, Y. Empagliflozin increases plasma levels of campesterol, a marker of cholesterol absorption, in patients with type 2 diabetes: Association with a slight increase in high-density lipoprotein cholesterol. Int. J. Cardiol.,  2021, 331, 243-248.
 [http://dx.doi.org/10.1016/j.ijcard.2021.01.063] [PMID:  33556413]

[12]
Kashiwagi, A.; Kazuta, K.; Takinami, Y.; Yoshida, S.; Utsuno, A.; Nagase, I. Ipragliflozin improves glycemic control in Japanese patients with type 2 diabetes mellitus: The BRIGHTEN study. Diabetol. Int.,  2014, 6(1), 8-18.
 [http://dx.doi.org/10.1007/s13340-014-0164-0]

[13]
Katakami, N.; Mita, T.; Yoshii, H.; Shiraiwa, T.; Yasuda, T.; Okada, Y.; Torimoto, K.; Umayahara, Y.; Kaneto, H.; Osonoi, T.; Yamamoto, T.; Kuribayashi, N.; Maeda, K.; Yokoyama, H.; Kosugi, K.; Ohtoshi, K.; Hayashi, I.; Sumitani, S.; Tsugawa, M.; Ryomoto, K.; Taki, H.; Nakamura, T.; Kawashima, S.; Sato, Y.; Watada, H.; Shimomura, I. Tofogliflozin does not delay progression of carotid atherosclerosis in patients with type 2 diabetes: A prospective, randomized, open-label, parallel-group comparative study. Cardiovasc. Diabetol.,  2020, 19(1), 110.
 [http://dx.doi.org/10.1186/s12933-020-01079-4] [PMID:  32646498]

[14]
Kwak, S.H.; Hwang, Y.C.; Won, J.C.; Bae, J.C.; Kim, H.J.; Suh, S.; Lee, E.Y.; Lee, S.; Kim, S.Y.; Kim, J.H. Comparison of the effects of gemigliptin and dapagliflozin on glycaemic variability in type 2 diabetes: A randomized, open-label, active-controlled, 12-week study (STABLE II study). Diabetes Obes. Metab.,  2020, 22(2), 173-181.
 [http://dx.doi.org/10.1111/dom.13882] [PMID:  31502749]

[15]
Latva-Rasku, A.; Honka, M.J.; Kullberg, J.; Mononen, N.; Lehtimäki, T.; Saltevo, J.; Kirjavainen, A.K.; Saunavaara, V.; Iozzo, P.; Johansson, L.; Oscarsson, J.; Hannukainen, J.C.; Nuutila, P. The SGLT2 inhibitor dapagliflozin reduces liver fat but does not affect tissue insulin sensitivity: A randomized, double-blind, placebo-controlled study with 8-week treatment in type 2 diabetes patients. Diabetes Care,  2019, 42(5), 931-937.
 [http://dx.doi.org/10.2337/dc18-1569] [PMID:  30885955]

[16]
Oldgren, J.; Laurila, S.; Åkerblom, A.; Latva-Rasku, A.; Rebelos, E.; Isackson, H.; Saarenhovi, M.; Eriksson, O.; Heurling, K.; Johansson, E.; Wilderäng, U.; Karlsson, C.; Esterline, R.; Ferrannini, E.; Oscarsson, J.; Nuutila, P. Effects of 6 weeks of treatment with dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on myocardial function and metabolism in patients with type 2 diabetes: A randomized, placebo-controlled, exploratory study. Diabetes Obes. Metab.,  2021, 23(7), 1505-1517.
 [http://dx.doi.org/10.1111/dom.14363] [PMID:  33625777]

[17]
Phrommintikul, A.; Wongcharoen, W.; Kumfu, S.; Jaiwongkam, T.; Gunaparn, S.; Chattipakorn, S.; Chattipakorn, N. Effects of dapagliflozin vs. vildagliptin on cardiometabolic parameters in diabetic patients with coronary artery disease: A randomised study. Br. J. Clin. Pharmacol.,  2019, 85(6), 1337-1347.
 [http://dx.doi.org/10.1111/bcp.13903] [PMID:  30767253]

[18]
Phrueksotsai, S.; Pinyopornpanish, K.; Euathrongchit, J.; Leerapun, A.; Phrommintikul, A.; Buranapin, S.; Chattipakorn, N.; Thongsawat, S. The effects of dapagliflozin on hepatic and visceral fat in type 2 diabetes patients with non-alcoholic fatty liver disease. J. Gastroenterol. Hepatol.,  2021, 36(10), 2952-2959.
 [http://dx.doi.org/10.1111/jgh.15580] [PMID:  34129252]

[19]
Sato, T.; Aizawa, Y.; Yuasa, S.; Fujita, S.; Ikeda, Y.; Okabe, M. The effect of dapagliflozin treatment on epicardial adipose tissue volume and p-wave indices: An ad-hoc analysis of the previous randomized clinical trial. J. Atheroscler. Thromb.,  2020, 27(12), 1348-1358.
 [http://dx.doi.org/10.5551/jat.48009] [PMID:  32115470]

[20]
Shigiyama, F.; Kumashiro, N.; Miyagi, M.; Ikehara, K.; Kanda, E.; Uchino, H.; Hirose, T. Effectiveness of dapagliflozin on vascular endothelial function and glycemic control in patients with early-stage type 2 diabetes mellitus: DEFENCE study. Cardiovasc. Diabetol.,  2017, 16(1), 84.
 [http://dx.doi.org/10.1186/s12933-017-0564-0] [PMID:  28683796]

[21]
Wolf, V.L.W.; Breder, I.; de Carvalho, L.S.F.; Soares, A.A.S.; Cintra, R.M.; Barreto, J.; Munhoz, D.B.; Kimura-Medorima, S.T.; Nadruz, W.; Guerra-Júnior, G.; Quinaglia, T.; Muscelli, E.; Sposito, A.C. Dapagliflozin increases the lean-to total mass ratio in type 2 diabetes mellitus. Nutr. Diabetes,  2021, 11(1), 17.
 [http://dx.doi.org/10.1038/s41387-021-00160-5] [PMID:  34120150]

[22]
Yoneda, M.; Honda, Y.; Ogawa, Y.; Kessoku, T.; Kobayashi, T.; Imajo, K.; Ozaki, A.; Nogami, A.; Taguri, M.; Yamanaka, T.; Kirikoshi, H.; Iwasaki, T.; Kurihashi, T.; Saito, S.; Nakajima, A. Comparing the effects of tofogliflozin and pioglitazone in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus (ToPiND study): A randomized prospective open-label controlled trial. BMJ Open Diabetes Res. Care,  2021, 9(1), e001990.
 [http://dx.doi.org/10.1136/bmjdrc-2020-001990] [PMID:  33593749]

[23]
Shimizu, M.; Suzuki, K.; Kato, K.; Jojima, T.; Iijima, T.; Murohisa, T.; Iijima, M.; Takekawa, H.; Usui, I.; Hiraishi, H.; Aso, Y. Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease. Diabetes Obes. Metab.,  2019, 21(2), 285-292.
 [http://dx.doi.org/10.1111/dom.13520] [PMID:  30178600]

[24]
Halden, T.A.S.; Kvitne, K.E.; Midtvedt, K.; Rajakumar, L.; Robertsen, I.; Brox, J.; Bollerslev, J.; Hartmann, A.; Åsberg, A.; Jenssen, T. Efficacy and safety of empagliflozin in renal transplant recipients with posttransplant diabetes mellitus. Diabetes Care,  2019, 42(6), 1067-1074.
 [http://dx.doi.org/10.2337/dc19-0093] [PMID:  30862658]

[25]
Hashikata, T.; Ikutomi, M.; Jimba, T.; Shindo, A.; Kakuda, N.; Katsushika, S.; Yokoyama, M.; Kishi, M.; Sato, T.; Matsushita, M.; Ohnishi, S.; Yamasaki, M. Empagliflozin attenuates neointimal hyperplasia after drug-eluting-stent implantation in patients with type 2 diabetes. Heart Vessels,  2020, 35(10), 1378-1389.
 [http://dx.doi.org/10.1007/s00380-020-01621-0] [PMID:  32399662]

[26]
Hoshika, Y.; Kubota, Y.; Mozawa, K.; Tara, S.; Tokita, Y.; Yodogawa, K.; Iwasaki, Y.K.; Yamamoto, T.; Takano, H.; Tsukada, Y.; Asai, K.; Miyamoto, M.; Miyauchi, Y.; Kodani, E.; Maruyama, M.; Tanabe, J.; Shimizu, W. Effect of empagliflozin versus placebo on plasma volume status in patients with acute myocardial infarction and type 2 diabetes mellitus. Diabetes Ther.,  2021, 12(8), 2241-2248.
 [http://dx.doi.org/10.1007/s13300-021-01103-0] [PMID:  34236577]

[27]
Kim, S.R.; Lee, S.G.; Kim, S.H.; Kim, J.H.; Choi, E.; Cho, W.; Rim, J.H.; Hwang, I.; Lee, C.J.; Lee, M.; Oh, C.M.; Jeon, J.Y.; Gee, H.Y.; Kim, J.H.; Lee, B.W.; Kang, E.S.; Cha, B.S.; Lee, M.S.; Yu, J.W.; Cho, J.W.; Kim, J.S.; Lee, Y.H. SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease. Nat. Commun.,  2020, 11(1), 2127.
 [http://dx.doi.org/10.1038/s41467-020-15983-6] [PMID:  32358544]

[28]
Kohler, S.; Zeller, C.; Iliev, H.; Kaspers, S. Safety and tolerability of empagliflozin in patients with type 2 diabetes: Pooled analysis of phase i-iii clinical trials. Adv. Ther.,  2017, 34(7), 1707-1726.
 [http://dx.doi.org/10.1007/s12325-017-0573-0] [PMID:  28631216]

[29]
Lee, S.H.; Min, K.W.; Lee, B.W.; Jeong, I.K.; Yoo, S.J.; Kwon, H.S.; Choi, Y.H.; Yoon, K.H. Effect of dapagliflozin as an add-on therapy to insulin on the glycemic variability in subjects with type 2 diabetes mellitus (DIVE): A multicenter, placebo-controlled, double-blind, randomized study. Diabetes Metab. J.,  2021, 45(3), 339-348.
 [http://dx.doi.org/10.4093/dmj.2019.0203] [PMID:  32602273]

[30]
Lee, M.M.Y.; Brooksbank, K.J.M.; Wetherall, K.; Mangion, K.; Roditi, G.; Campbell, R.T.; Berry, C.; Chong, V.; Coyle, L.; Docherty, K.F.; Dreisbach, J.G.; Labinjoh, C.; Lang, N.N.; Lennie, V.; McConnachie, A.; Murphy, C.L.; Petrie, C.J.; Petrie, J.R.; Speirits, I.A.; Sourbron, S.; Welsh, P.; Woodward, R.; Radjenovic, A.; Mark, P.B.; McMurray, J.J.V.; Jhund, P.S.; Petrie, M.C.; Sattar, N. Effect of empagliflozin on left ventricular volumes in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF). Circulation,  2021, 143(6), 516-525.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.120.052186] [PMID:  33186500]

[31]
Jensen, J.; Omar, M.; Kistorp, C.; Tuxen, C.; Gustafsson, I.; Køber, L.; Gustafsson, F.; Faber, J.; Malik, M.E.; Fosbøl, E.L.; Bruun, N.E.; Forman, J.L.; Jensen, L.T.; Møller, J.E.; Schou, M. Effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate in patients with heart failure (Empire HF Renal): A prespecified substudy of a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol.,  2021, 9(2), 106-116.
 [http://dx.doi.org/10.1016/S2213-8587(20)30382-X] [PMID:  33357505]

[32]
Eriksson, J.W.; Lundkvist, P.; Jansson, P.A.; Johansson, L.; Kvarnström, M.; Moris, L.; Miliotis, T.; Forsberg, G.B.; Risérus, U.; Lind, L.; Oscarsson, J. Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: A double-blind randomised placebo-controlled study. Diabetologia,  2018, 61(9), 1923-1934.
 [http://dx.doi.org/10.1007/s00125-018-4675-2] [PMID:  29971527]

[33]
Fathi, S.; Borzouei, S.; Goodarzi, M.T.; Poorolajal, J.; Ahmadi-Motamayel, F. Evaluation of salivary antioxidants and oxidative stress markers in type 2 diabetes mellitus: A retrospective cohort study. Endocr. Metab. Immune Disord. Drug Targets,  2020, 20(4), 584-590.
 [http://dx.doi.org/10.2174/1871530319666191016103222] [PMID:  31622212]

[34]
Minze, M.G.; Will, K.J.; Terrell, B.T.; Black, R.L.; Irons, B.K. Benefits of SGLT2 inhibitors beyond glycemic control - a focus on metabolic, cardiovascular and renal outcomes. Curr. Diabetes Rev.,  2018, 14(6), 509-517.
 [http://dx.doi.org/10.2174/1573399813666170816142351] [PMID:  28814245]

[35]
Hawley, S.A.; Ross, F.A.; Chevtzoff, C.; Green, K.A.; Evans, A.; Fogarty, S.; Towler, M.C.; Brown, L.J.; Ogunbayo, O.A.; Evans, A.M.; Hardie, D.G. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab.,  2010, 11(6), 554-565.
 [http://dx.doi.org/10.1016/j.cmet.2010.04.001] [PMID:  20519126]

[36]
Louro, T.M.; Matafome, P.N.; Nunes, E.C.; da Cunha, F.X.; Seiça, R.M. Insulin and metformin may prevent renal injury in young type 2 diabetic Goto-Kakizaki rats. Eur. J. Pharmacol.,  2011, 653(1-3), 89-94.
 [http://dx.doi.org/10.1016/j.ejphar.2010.11.029] [PMID:  21167150]

[37]
Arow, M.; Waldman, M.; Yadin, D.; Nudelman, V.; Shainberg, A.; Abraham, N.G.; Freimark, D.; Kornowski, R.; Aravot, D.; Hochhauser, E.; Arad, M. Sodium-glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy. Cardiovasc. Diabetol.,  2020, 19(1), 7.
 [http://dx.doi.org/10.1186/s12933-019-0980-4] [PMID:  31924211]

Rights & Permissions Print Cite

Article Metrics

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1871530322666220827150054	Print ISSN 1871-5303
Publisher Name Bentham Science Publisher	Online ISSN 2212-3873

Endocrine, Metabolic & Immune Disorders - Drug Targets

Effect of SGLT2 Inhibitors and Metformin on Inflammatory and Prognostic Biomarkers in Type 2 Diabetes Patients

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract