Horm Metab Res 2022; 54(12): 833-844
DOI: 10.1055/a-1897-6121
Original Article: Endocrine Care

Influence of Sodium-Glucose Cotransporter-2 Inhibitors on Plasma Adiponectin in Patients with Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials

Yang Wang
1   Guangxi Medical University First Affiliated Hospital, 6th Building Shuangyong Road, Nanning, China
,
Ning Xia
1   Guangxi Medical University First Affiliated Hospital, 6th Building Shuangyong Road, Nanning, China
› Author Affiliations

Abstract

The influence of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on plasma adiponectin remains not comprehensively evaluated. We performed a meta-analysis to systematically evaluate the effect of SGLT2 inhibitors on plasma level of adiponectin in patients with type 2 diabetes mellitus (T2DM). Randomized controlled trials comparing SGLT-2 inhibitors with non-active controls on plasma adiponectin in T2DM patients were retrieved by search of the Medline (PubMed), Embase, and CENTER (Cochrane Library) databases from inception to April 5, 2022. Study characteristics and outcome data were independently extracted by two authors. A random-effect model by incorporating the potential between-study heterogeneity was used to combine the results. Fourteen studies with 2142 patients contributed to the meta-analysis. Compared to placebo, SGLT-2 inhibitors significantly increased plasma adiponectin [standard mean difference (SMD): 0.35, 95% CI: 0.24 to 0.46, p<0.001] with mild heterogeneity (I2=19%). Predefined subgroup analyses suggested that tofogliflozin (SMD: 0.37, p<0.001), luseogliflozin (SMD: 0.51, p<0.001), and ipragliflozin (SMD: 0.34, p<0.001) were associated with increased adiponectin, but not for dapagliflozin (SMD: 0.14, p 0.26). In addition, SGLT-2 inhibitors were associated with increased adiponectin in studies from Asia (SMD: 0.42, p<0.001), but not in studies from the western countries (SMD: 0.16, p 0.17). Moreover, the increment of adiponectin was more significant in patients with body mass index (BMI)<30 kg/m2 (SMD: 0.46, p<0.001) than that in patients with BMI≤30 kg/m2 (SMD: 0.19, p 0.02, p for subgroup difference 0.01). In conclusion, SGLT-2 inhibitors could significantly increase plasma adiponectin as compared with placebo in T2DM patients.



Publication History

Received: 01 June 2022

Accepted after revision: 28 June 2022

Article published online:
01 September 2022

© 2022. Thieme. All rights reserved.

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  • References

  • 1 Draznin B, Aroda VR, Bakris G. et al. Chronic kidney disease and risk management: standards of medical care in diabetes-2022. Diabetes Care 2022; 45: S175-S184
  • 2 Anon. Cardiovascular disease and risk management: standards of medical care in diabetes-2022. Diabetes Care 2022; 45: S144-S174
  • 3 McCullough PA, Amin A, Pantalone KM. et al. Cardiorenal nexus: a review with focus on combined chronic heart and kidney failure, and insights from recent clinical trials. J Am Heart Assoc 2022; e024139
  • 4 Caruso I, Giorgino F. SGLT-2 inhibitors as cardio-renal protective agents. Metabolism 2022; 127: 154937
  • 5 Zelniker TA, Wiviott SD, Raz I. et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019; 393: 31-39
  • 6 Toyama T, Neuen BL, Jun M. et al. Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: A systematic review and meta-analysis. Diabetes Obes Metab 2019; 21: 1237-1250
  • 7 Sha W, Wen S, Chen L. et al. The role of SGLT2 inhibitor on the treatment of diabetic Rretinopathy. J Diabetes Res 2020; 8867875
  • 8 Sheu WHH, Chan SP, Matawaran BJ. et al. Use of SGLT-2 inhibitors in patients with type 2 diabetes mellitus and abdominal obesity: an Asian perspective and expert recommendations. Diabetes Metab J 2020; 44: 1132
  • 9 Wong J, Chan KY, Lo K. Sodium-glucose co-transporter 2 inhibitors on weight change and cardiometabolic profiles in individuals with overweight or obesity and without diabetes: a meta-analysis. Obes Rev 2021; 22: e13336
  • 10 Onyali CB, Anim-Koranteng C, Shah HE. et al. Role of selective sodium-glucose co-transporter-2 inhibitors in managing cardio-renal complications in type 2 diabetes mellitus: beyond glycemic control. Cureus 2021; 13: e17452
  • 11 Brown E, Wilding JPH, Alam U. et al. The expanding role of SGLT2 inhibitors beyond glucose-lowering to cardiorenal protection. Ann Med 2021; 53: 2072-2089
  • 12 Zelniker TA, Braunwald E. Mechanisms of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors: JACC state-of-the-art review. J Am Coll Cardiol 2020; 75: 422-434
  • 13 Achari AE, Jain SK. Adiponectin, a therapeutic target for obesity, diabetes, and endothelial dysfunction. Int J Mol Sci 2017; 18: 1321
  • 14 Sowka A, Dobrzyn P. Role of perivascular adipose tissue-derived adiponectin in vascular homeostasis. Cells 2021; 10: 1485
  • 15 Choi HM, Doss HM, Kim KS. Multifaceted physiological roles of adiponectin in inflammation and diseases. Int J Mol Sci 2020; 21: 1219
  • 16 Karamian M, Moossavi M, Hemmati M. From diabetes to renal aging: the therapeutic potential of adiponectin. J Physiol Biochem 2021; 77: 205-214
  • 17 Zhao S, Kusminski CM, Scherer PE. Adiponectin, leptin and cardiovascular disorders. Circ Res 2021; 128: 136-149
  • 18 Liu C, Feng X, Li Q, Wang Y. et al. Adiponectin, TNF-alpha and inflammatory cytokines and risk of type 2 diabetes: a systematic review and meta-analysis. Cytokine 2016; 86: 100-109
  • 19 Yang L, Li B, Zhao Y. et al. Prognostic value of adiponectin level in patients with coronary artery disease: a systematic review and meta-analysis. Lipids Health Dis 2019; 18: 227
  • 20 Sakaue TA, Fujishima Y, Fukushima Y. et al. Adiponectin accumulation in the retinal vascular endothelium and its possible role in preventing early diabetic microvascular damage. Sci Rep 2022; 12: 4159
  • 21 Bray JJH, Foster-Davies H, Stephens JW. 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
  • 22 Bailey CJ, Iqbal N, T’Joen C. et al. Dapagliflozin monotherapy in drug-naive patients with diabetes: a randomized-controlled trial of low-dose range. Diabetes Obes Metab 2012; 14: 951-959
  • 23 Kaku K, Watada H, Iwamoto Y. et al. Efficacy and safety of monotherapy with the novel sodium/glucose cotransporter-2 inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus: a combined Phase 2 and 3 randomized, placebo-controlled, double-blind, parallel-group comparative study. Cardiovasc Diabetol 2014; 13: 65
  • 24 Seino Y, Sasaki T, Fukatsu A. et al. Efficacy and safety of luseogliflozin as monotherapy in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, phase 3 study. Curr Med Res Opin 2014; 30: 1245-1255
  • 25 Ikeda S, Takano Y, Cynshi O. et al. A novel and selective sodium-glucose cotransporter-2 inhibitor, tofogliflozin, improves glycaemic control and lowers body weight in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2015; 17: 984-993
  • 26 Kashiwagi A, Kazuta K, Goto K. et al. Ipragliflozin in combination with metformin for the treatment of Japanese patients with type 2 diabetes: ILLUMINATE, a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 2015; 17: 304-308
  • 27 Kashiwagi A, Takahashi H, Ishikawa H. et al. A randomized, double-blind, placebo-controlled study on long-term efficacy and safety of ipragliflozin treatment in patients with type 2 diabetes mellitus and renal impairment: results of the long-term ASP1941 safety evaluation in patients with type 2 diabetes with renal impairment (LANTERN) study. Diabetes Obes Metab 2015; 17: 152-160
  • 28 Haneda M, Seino Y, Inagaki N. et al. Influence of renal function on the 52-week efficacy and safety of the sodium glucose cotransporter 2 inhibitor luseogliflozin in Japanese patients with type 2 diabetes mellitus. Clin Ther 2016; 38: 66-88 e20
  • 29 Ishihara H, Yamaguchi S, Nakao I. et al. Efficacy and safety of ipragliflozin as add-on therapy to insulin in Japanese patients with type 2 diabetes mellitus (IOLITE): a multi-centre, randomized, placebo-controlled, double-blind study. Diabetes Obes Metab 2016; 18: 1207-1216
  • 30 Liao X, Wang X, Li H. et al. Sodium-glucose cotransporter 2 (SGLT2) inhibitor increases circulating zinc-alpha2-glycoprotein levels in patients with type 2 diabetes. Sci Rep 2016; 6: 32887
  • 31 Fadini GP, Bonora BM, Zatti G. et al. 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: 42
  • 32 Eriksson JW, Lundkvist P, Jansson PA. et al. 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: 1923-1934
  • 33 Kahl S, Gancheva S, Strassburger K. et al. Empagliflozin effectively lowers liver fat content in well-controlled type 2 diabetes: a randomized, double-blind, phase 4, placebo-controlled trial. Diabetes Care 2020; 43: 298-305
  • 34 Nandula SR, Kundu N, Awal HB. et al. Role of canagliflozin on function of CD34+ve endothelial progenitor cells (EPC) in patients with type 2 diabetes. Cardiovasc Diabetol 2021; 20: 44
  • 35 Phrueksotsai S, Pinyopornpanish K, Euathrongchit J. et al. 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: 2952-2959
  • 36 Wu P, Wen W, Li J. et al. Systematic review and meta-analysis of randomized controlled trials on the effect of SGLT2 inhibitor on blood leptin and adiponectin level in patients with type 2 diabetes. Horm Metab Res 2019; 51: 487-494
  • 37 Page MJ, McKenzie JE, Bossuyt PM. et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ (Clinical research ed) 2021; 372: n71
  • 38 Page MJ, Moher D, Bossuyt PM. et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ (Clinical research ed) 2021; 372: n160
  • 39 Higgins J, Thomas J, Chandler J. et al. Cochrane handbook for systematic reviews of interventions version 6.2. The Cochrane Collaboration. 2021 www.training.cochrane.org/handbook
  • 40 Moher D, Pham B, Jones A. et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses?. Lancet 1998; 352: 609-613
  • 41 Higgins JP, Thompson SG, Deeks JJ. et al. Measuring inconsistency in meta-analyses. BMJ (Clinical research ed) 2003; 327: 557-560
  • 42 Ma X, Lin L, Qu Z. et al. Performance of between-study heterogeneity measures in the Cochrane library. Epidemiology 2018; 29: 821-824
  • 43 Egger M, Davey Smith G, Schneider M. et al. Bias in meta-analysis detected by a simple, graphical test. BMJ (Clinical research ed) 1997; 315: 629-634
  • 44 Sahebkar A, Ponzo V, Bo S. Effect of dipeptidyl peptidase-4 inhibitors on plasma adiponectin: a systematic review and meta-analysis of randomized controlled trials. Curr Med Chem 2016; 23: 1356-1369
  • 45 Simental-Mendia LE, Sanchez-Garcia A, Linden-Torres E. et al. Impact of glucagon-like peptide-1 receptor agonists on adiponectin concentrations: A meta-analysis of randomized controlled trials. Br J Clin Pharmacol 2021; 87: 4140-4149
  • 46 Nishitani S, Fukuhara A, Shin J. et al. Metabolomic and microarray analyses of adipose tissue of dapagliflozin-treated mice, and effects of 3-hydroxybutyrate on induction of adiponectin in adipocytes. Sci Rep 2018; 8: 8805
  • 47 Mori Y, Terasaki M, Hiromura M. et al. Luseogliflozin attenuates neointimal hyperplasia after wire injury in high-fat diet-fed mice via inhibition of perivascular adipose tissue remodeling. Cardiovasc Diabetol 2019; 18: 143
  • 48 Hoong CWS, Chua MWJ. SGLT2 inhibitors as calorie restriction mimetics: insights on longevity pathways and age-related diseases. Endocrinology 2021; 162 bqab079
  • 49 Rogozina OP, Bonorden MJ, Seppanen CN. et al. Effect of chronic and intermittent calorie restriction on serum adiponectin and leptin and mammary tumorigenesis. Cancer Prev Res (Phila) 2011; 4: 568-581
  • 50 Xu L, Nagata N, Chen G. et al. Empagliflozin reverses obesity and insulin resistance through fat browning and alternative macrophage activation in mice fed a high-fat diet. BMJ Open Diabetes Res Care 2019; 7: e000783
  • 51 Giugliano D, Esposito K. Class effect for SGLT-2 inhibitors: a tale of 9 drugs. Cardiovasc Diabetol 2019; 18: 94
  • 52 Yang CT, Peng ZY, Chen YC. et al. Cardiovascular benefits with favorable renal, amputation and hypoglycemic outcomes of SGLT-2 inhibitors in type 2 diabetes from the Asian perspective: a population-based cohort study and systematic review. Front Endocrinol (Lausanne) 2022; 13: 836365
  • 53 Fang H, Judd RL. Adiponectin regulation and function. Compr Physiol 2018; 8: 1031-1063