PPAR agonists as add-on treatment with metformin in management of type 2 diabetes: a systematic review and meta-analysis.
Gastrointestinal intolerance
Glycemic control
Insulin resistance
Lipids
Safety profile
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
16 Apr 2024
16 Apr 2024
Historique:
received:
12
12
2023
accepted:
10
04
2024
medline:
17
4
2024
pubmed:
17
4
2024
entrez:
16
4
2024
Statut:
epublish
Résumé
The combination of metformin and the peroxisome proliferator-activated receptors (PPAR) agonists offers a promising avenue for managing type 2 diabetes (T2D) through their potential complementary mechanisms of action. The results from randomized controlled trials (RCT) assessing the efficacy of PPAR agonists plus metformin versus metformin alone in T2D are inconsistent, which prompted the conduct of the systematic review and meta-analysis. We searched MEDLINE and EMBASE from inception (1966) to March 2023 to identify all RCTs comparing any PPAR agonists plus metformin versus metformin alone in T2D. Categorical variables were summarized as relative risk along with 95% confidence interval (CI). Twenty RCTs enrolling a total of 6058 patients met the inclusion criteria. The certainty of evidence ranged from moderate to very low. Pooled results show that using PPAR agonist plus metformin, as compared to metformin alone, results in lower concentrations of fasting glucose [MD = - 22.07 mg/dl (95% CI - 27.17, - 16.97), HbA1c [MD = - 0.53% (95% CI - 0.67, - 0.38)], HOMA-IR [MD = - 1.26 (95% CI - 2.16, - 0.37)], and fasting insulin [MD = - 19.83 pmol/L (95% CI - 29.54, - 10.13)] without significant increase in any adverse events. Thus, synthesized evidence from RCTs demonstrates the beneficial effects of PPAR agonist add-on treatment versus metformin alone in T2D patients. In particular, novel dual PPARα/γ agonist (tesaglitazar) demonstrate efficacy in improving glycaemic and lipid concentrations, so further RCTs should be performed to elucidate the long-term outcomes and safety profile of these novel combined and personalized therapeutic strategies in the management of T2D.PROSPERO registration no. CRD42023412603.
Identifiants
pubmed: 38627464
doi: 10.1038/s41598-024-59390-z
pii: 10.1038/s41598-024-59390-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8809Subventions
Organisme : Khalifa University
ID : 8474000253/FSU-2020-29/2020
Informations de copyright
© 2024. The Author(s).
Références
Khan, M. A. B. et al. Epidemiology of type 2 diabetes—Global burden of disease and forecasted trends. J. Epidemiol Glob. Health 10(1), 107–111 (2020).
pubmed: 32175717
pmcid: 7310804
doi: 10.2991/jegh.k.191028.001
IDF, International Diabetes Federation. IDF Diabetes Atlas—10th Edition (2021).
Manu, P., Rogozea, L. M. & Cernea, S. Pharmacological management of diabetes mellitus: A century of expert opinions in Cecil Textbook of Medicine. Am. J. Ther. 28(4), e397–e410 (2021).
pubmed: 34228650
doi: 10.1097/MJT.0000000000001401
ElSayed, N. A. et al. 9. Pharmacologic approaches to glycemic treatment: Standards of care in diabetes-2023. Diabetes Care 46(Suppl 1), S140–S157 (2023).
pubmed: 36507650
doi: 10.2337/dc23-S009
Ziqubu, K. et al. Anti-obesity effects of metformin: A scoping review evaluating the feasibility of brown adipose tissue as a therapeutic target. Int. J. Mol. Sci. 24(3), 2227 (2023).
pubmed: 36768561
pmcid: 9917329
doi: 10.3390/ijms24032227
Uddin, R. et al. New evidence for the mechanism of action of a type-2 diabetes drug using a magnetic bead-based automated biosensing platform. ACS Sens. 2(9), 1329–1336 (2017).
pubmed: 28776376
pmcid: 5613276
doi: 10.1021/acssensors.7b00384
Balakumar, P., Mahadevan, N. & Sambathkumar, R. A contemporary overview of PPARalpha/gamma dual agonists for the management of diabetic dyslipidemia. Curr. Mol. Pharmacol. 12(3), 195–201 (2019).
pubmed: 30636619
pmcid: 6875865
doi: 10.2174/1874467212666190111165015
Brown, J. D. & Plutzky, J. Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets. Circulation 115(4), 518–533 (2007).
pubmed: 17261671
doi: 10.1161/CIRCULATIONAHA.104.475673
Giglio, R. V. et al. An update on the current and emerging use of thiazolidinediones for type 2 diabetes. Medicina 58(10), 1475 (2022).
pubmed: 36295635
pmcid: 9609741
doi: 10.3390/medicina58101475
Engler, C. et al. Long-term trends in the prescription of antidiabetic drugs: Real-world evidence from the Diabetes Registry Tyrol 2012–2018. BMJ Open Diabetes Res. Care 8(1), e001279 (2020).
pubmed: 32873600
pmcid: 7467522
doi: 10.1136/bmjdrc-2020-001279
Mannucci, E. et al. Effects of pioglitazone on cardiovascular events and all-cause mortality in patients with type 2 diabetes: A meta-analysis of randomized controlled trials. Nutr. Metab. Cardiovasc. Dis. 32(3), 529–536 (2022).
pubmed: 35144855
doi: 10.1016/j.numecd.2021.12.006
Della Pepa, G. et al. Pioglitazone even at low dosage improves NAFLD in type 2 diabetes: Clinical and pathophysiological insights from a subgroup of the TOSCA.IT randomised trial. Diabetes Res. Clin. Pract. 178, 108984 (2021).
pubmed: 34311022
doi: 10.1016/j.diabres.2021.108984
Fagerberg, B. et al. Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population. Diabetologia 48(9), 1716–1725 (2005).
pubmed: 16001233
doi: 10.1007/s00125-005-1846-8
Schuster, H. et al. Tesaglitazar, a dual peroxisome proliferator-activated receptor alpha/gamma agonist, improves apolipoprotein levels in non-diabetic subjects with insulin resistance. Atherosclerosis 197(1), 355–362 (2008).
pubmed: 17631296
doi: 10.1016/j.atherosclerosis.2007.05.029
Goldstein, B. J. et al. Effect of tesaglitazar, a dual PPAR alpha/gamma agonist, on glucose and lipid abnormalities in patients with type 2 diabetes: A 12-week dose-ranging trial. Curr. Med. Res. Opin. 22(12), 2575–2590 (2006).
pubmed: 17166340
doi: 10.1185/030079906X154169
Chatterjee, S., Majumder, A. & Ray, S. Observational study of effects of Saroglitazar on glycaemic and lipid parameters on Indian patients with type 2 diabetes. Sci. Rep. 5, 7706 (2015).
pubmed: 25573251
pmcid: 4287720
doi: 10.1038/srep07706
Lincoff, A. M. et al. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: The AleCardio randomized clinical trial. JAMA 311(15), 1515–1525 (2014).
pubmed: 24682069
doi: 10.1001/jama.2014.3321
Kalliora, C. & Drosatos, K. The glitazars paradox: Cardiotoxicity of the metabolically beneficial dual PPARalpha and PPARgamma activation. J. Cardiovasc. Pharmacol. 76(5), 514–526 (2020).
pubmed: 33165133
pmcid: 7750030
doi: 10.1097/FJC.0000000000000891
Pai, V. et al. A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of Saroglitazar 2 and 4 mg compared to Pioglitazone 45 mg in diabetic dyslipidemia (PRESS V). J. Diabetes Sci. Technol. 8(1), 132–141 (2014).
pubmed: 24876549
pmcid: 4390522
doi: 10.1177/1932296813518680
Agrawal, R. The first approved agent in the Glitazar’s class: Saroglitazar. Curr. Drug Targets 15(2), 151–155 (2014).
pubmed: 23906191
doi: 10.2174/13894501113149990199
Ghosh, A. et al. Comparison of effectiveness and safety of add-on therapy of Saroglitazar and Fenofibrate with metformin in Indian patients with diabetic dyslipidaemia. J. Clin. Diagn. Res. 10(3), FC01–FC04 (2016).
pubmed: 27134886
pmcid: 4843272
Kadoglou, N. P. et al. Effects of rosiglitazone and metformin treatment on apelin, visfatin, and ghrelin levels in patients with type 2 diabetes mellitus. Metabolism 59(3), 373–379 (2010).
pubmed: 19815243
doi: 10.1016/j.metabol.2009.08.005
Negro, R. et al. Rosiglitazone effects on blood pressure and metabolic parameters in nondipper diabetic patients. Diabetes Res. Clin. Pract. 70(1), 20–25 (2005).
pubmed: 16126119
doi: 10.1016/j.diabres.2005.02.012
Hanefeld, M. et al. Double-blind, randomized, multicentre, and active comparator controlled investigation of the effect of pioglitazone, metformin, and the combination of both on cardiovascular risk in patients with type 2 diabetes receiving stable basal insulin therapy: The PIOCOMB study. Cardiovasc. Diabetol. 10, 65 (2011).
pubmed: 21756323
pmcid: 3160877
doi: 10.1186/1475-2840-10-65
Kaku, K. Efficacy and safety of therapy with metformin plus pioglitazone in the treatment of patients with type 2 diabetes: A double-blind, placebo-controlled, clinical trial. Curr. Med. Res. Opin. 25(5), 1111–1119 (2009).
pubmed: 19309251
doi: 10.1185/03007990902820816
Kendall, D. M. et al. Improvement of glycemic control, triglycerides, and HDL cholesterol levels with muraglitazar, a dual (alpha/gamma) peroxisome proliferator-activated receptor activator, in patients with type 2 diabetes inadequately controlled with metformin monotherapy: A double-blind, randomized, pioglitazone-comparative study. Diabetes Care 29(5), 1016–1023 (2006).
pubmed: 16644631
doi: 10.2337/dc05-1146
Page, M. J. et al. PRISMA 2020 explanation and elaboration: Updated guidance and exemplars for reporting systematic reviews. BMJ 372, n160 (2021).
pubmed: 33781993
pmcid: 8005925
doi: 10.1136/bmj.n160
Higgins, J. P. T, Chandler, J., Cumpston, M., Li, T., Page, M. J., Welch. V. A. (eds). Cochrane Handbook for Systematic Reviews of Interventions, version 6.4 (updated August 2023). Cochrane, 2023; www.training.cochrane.org/handbook .
The EndNote Team. 2023, Clarivate: Philadelphia, PA.
Ouzzani, M. et al. Rayyan-a web and mobile app for systematic reviews. Syst. Rev. 5(1), 210 (2016).
pubmed: 27919275
pmcid: 5139140
doi: 10.1186/s13643-016-0384-4
Review Manager (RevMan) 2020, The Cochrane Collaboration
Higgins, J. P. et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343, d5928 (2011).
pubmed: 22008217
pmcid: 3196245
doi: 10.1136/bmj.d5928
Schünemann, H., Guyatt, G., Oxman, A., (eds.) GRADE handbook for grading quality of evidence and strength of recommendations. 2013; https://gdt.gradepro.org/app/handbook/handbook.html .
Koperska, M., Omni Health Calculator. 2024.
DerSimonian, R. & Laird, N. Meta-analysis in clinical trials. Control Clin. Trials 7(3), 177–188 (1986).
pubmed: 3802833
doi: 10.1016/0197-2456(86)90046-2
Efficacy of Pioglitazone and Fortamet Combination Therapy in Subjects With Type 2 Diabetes. 2008, Takeda Global Research & Development Center.
Bailey, C. J. et al. Rosiglitazone/metformin fixed-dose combination compared with uptitrated metformin alone in type 2 diabetes mellitus: A 24-week, multicenter, randomized, double-blind, parallel-group study. Clin. Ther. 27(10), 1548–1561 (2005).
pubmed: 16330291
doi: 10.1016/j.clinthera.2005.10.012
Borges, J. L. et al. A randomized, parallel group, double-blind, multicentre study comparing the efficacy and safety of Avandamet (rosiglitazone/metformin) and metformin on long-term glycaemic control and bone mineral density after 80 weeks of treatment in drug-naive type 2 diabetes mellitus patients. Diabetes Obes. Metab. 13(11), 1036–1046 (2011).
pubmed: 21682834
doi: 10.1111/j.1463-1326.2011.01461.x
Derosa, G. et al. Direct comparison among oral hypoglycemic agents and their association with insulin resistance evaluated by euglycemic hyperinsulinemic clamp: The 60’s study. Metabolism 58(8), 1059–1066 (2009).
pubmed: 19394976
doi: 10.1016/j.metabol.2009.03.007
Einhorn, D. et al. Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: A randomized, placebo-controlled study. The Pioglitazone 027 Study Group. Clin. Ther. 22(12), 1395–409 (2000).
pubmed: 11192132
doi: 10.1016/S0149-2918(00)83039-8
Fonseca, V. et al. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: A randomized controlled trial. JAMA 283(13), 1695–1702 (2000).
pubmed: 10755495
doi: 10.1001/jama.283.13.1695
Genovese, S. et al. Pioglitazone randomised Italian Study on Metabolic Syndrome (PRISMA): Effect of pioglitazone with metformin on HDL-C levels in type 2 diabetic patients. J. Endocrinol. Invest. 36(8), 606–616 (2013).
pubmed: 23511244
Goke, B. et al. The effects of tesaglitazar as add-on treatment to metformin in patients with poorly controlled type 2 diabetes. Diab. Vasc. Dis. Res. 4(3), 204–213 (2007).
pubmed: 17907110
doi: 10.3132/dvdr.2007.041
Gomez-Perez, F. J. et al. Efficacy and safety of rosiglitazone plus metformin in Mexicans with type 2 diabetes. Diabetes Metab. Res. Rev. 18(2), 127–134 (2002).
pubmed: 11994904
doi: 10.1002/dmrr.264
Kadoglou, N. P. et al. Effects of rosiglitazone/metformin fixed-dose combination therapy and metformin monotherapy on serum vaspin, adiponectin and IL-6 levels in drug-naive patients with type 2 diabetes. Exp. Clin. Endocrinol. Diabetes 119(2), 63–68 (2011).
pubmed: 21031343
doi: 10.1055/s-0030-1265174
Perez, A. et al. Efficacy and safety of pioglitazone/metformin fixed-dose combination therapy compared with pioglitazone and metformin monotherapy in treating patients with T2DM. Curr. Med. Res. Opin. 25(12), 2915–2923 (2009).
pubmed: 19827910
doi: 10.1185/03007990903350011
Rosenstock, J. et al. Initial treatment with rosiglitazone/metformin fixed-dose combination therapy compared with monotherapy with either rosiglitazone or metformin in patients with uncontrolled type 2 diabetes. Diabetes Obes. Metab. 8(6), 650–660 (2006).
pubmed: 17026489
doi: 10.1111/j.1463-1326.2006.00659.x
Scott, R. et al. Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes Obes. Metab. 10(10), 959–969 (2008).
pubmed: 18201203
doi: 10.1111/j.1463-1326.2007.00839.x
Stewart, M. W. et al. Effect of metformin plus roziglitazone compared with metformin alone on glycaemic control in well-controlled Type 2 diabetes. Diabet. Med. 23(10), 1069–1078 (2006).
pubmed: 16978370
doi: 10.1111/j.1464-5491.2006.01942.x
Wang, C. H. et al. Pioglitazone increases the numbers and improves the functional capacity of endothelial progenitor cells in patients with diabetes mellitus. Am. Heart J. 152(6), 1051.e1-1051.e8 (2006).
pubmed: 17161050
doi: 10.1016/j.ahj.2006.07.029
Weissman, P. et al. Effects of rosiglitazone added to submaximal doses of metformin compared with dose escalation of metformin in type 2 diabetes: The EMPIRE Study. Curr. Med. Res. Opin. 21(12), 2029–2035 (2005).
pubmed: 16368054
doi: 10.1185/030079905X74844
Wang, Z. et al. Pioglitazone attenuates drug-eluting stent-induced proinflammatory state in patients by blocking ubiquitination of PPAR. PPAR Res. 2016, 7407153 (2016).
pubmed: 27403152
pmcid: 4923578
doi: 10.1155/2016/7407153
Wilding, J. P. et al. Tesaglitazar, as add-on therapy to sulphonylurea, dose-dependently improves glucose and lipid abnormalities in patients with type 2 diabetes. Diab. Vasc. Dis. Res. 4(3), 194–203 (2007).
pubmed: 17907109
doi: 10.3132/dvdr.2007.040
Cox, S. L. Tesaglitazar: A promising approach in type 2 diabetes. Drugs Today 42(3), 139–146 (2006).
doi: 10.1358/dot.2006.42.3.937961
Yau, H. et al. The future of thiazolidinedione therapy in the management of type 2 diabetes mellitus. Curr. Diab. Rep. 13(3), 329–341 (2013).
pubmed: 23625197
doi: 10.1007/s11892-013-0378-8
Satoh, N. et al. Antiatherogenic effect of pioglitazone in type 2 diabetic patients irrespective of the responsiveness to its antidiabetic effect. Diabetes Care 26(9), 2493–2499 (2003).
pubmed: 12941708
doi: 10.2337/diacare.26.9.2493
Osei, K., Gaillard, T. & Schuster, D. Thiazolidinediones increase hepatic insulin extraction in African Americans with impaired glucose tolerance and type 2 diabetes mellitus. A pilot study of rosiglitazone. Metabolism 56(1), 24–29 (2007).
pubmed: 17161222
doi: 10.1016/j.metabol.2006.08.018
Kahn, S. E. et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N. Engl. J. Med. 355(23), 2427–2443 (2006).
pubmed: 17145742
doi: 10.1056/NEJMoa066224
Lin, K. D. et al. Thiazolidinedione addition reduces the serum retinol-binding protein 4 in type 2 diabetic patients treated with metformin and sulfonylurea. Transl. Res. 151(6), 309–314 (2008).
pubmed: 18514142
doi: 10.1016/j.trsl.2008.04.003
Jani, R. H. et al. A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of Saroglitazar 2 and 4 mg compared with placebo in type 2 diabetes mellitus patients having hypertriglyceridemia not controlled with atorvastatin therapy (PRESS VI). Diabetes Technol. Ther. 16(2), 63–71 (2014).
pubmed: 24138536
pmcid: 3894674
doi: 10.1089/dia.2013.0253
Krishnappa, M. et al. Effect of saroglitazar 2 mg and 4 mg on glycemic control, lipid profile and cardiovascular disease risk in patients with type 2 diabetes mellitus: A 56-week, randomized, double blind, phase 3 study (PRESS XII study). Cardiovasc. Diabetol. 19(1), 93 (2020).
pubmed: 32560724
pmcid: 7305598
doi: 10.1186/s12933-020-01073-w
Tarry-Adkins, J. L. et al. Efficacy and side effect profile of different formulations of metformin: A systematic review and meta-analysis. Diabetes Ther. 12(7), 1901–1914 (2021).
pubmed: 34075573
pmcid: 8266931
doi: 10.1007/s13300-021-01058-2
Abdalla, M. A. et al. Effect of pharmacological interventions on lipid profiles and C-reactive protein in polycystic ovary syndrome: A systematic review and meta-analysis. Clin. Endocrinol. 96(4), 443–459 (2022).
doi: 10.1111/cen.14636
Chiquette, E., Ramirez, G. & Defronzo, R. A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factors. Arch. Intern. Med. 164(19), 2097–2104 (2004).
pubmed: 15505122
doi: 10.1001/archinte.164.19.2097
Soccio, R. E., Chen, E. R. & Lazar, M. A. Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell Metab. 20(4), 573–591 (2014).
pubmed: 25242225
pmcid: 4192012
doi: 10.1016/j.cmet.2014.08.005
Goldberg, R. B. et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 28(7), 1547–1554 (2005).
pubmed: 15983299
doi: 10.2337/diacare.28.7.1547
Consoli, A. & Devangelio, E. Thiazolidinediones and inflammation. Lupus 14(9), 794–797 (2005).
pubmed: 16218490
doi: 10.1191/0961203305lu2223oa
Agarwal, R. Anti-inflammatory effects of short-term pioglitazone therapy in men with advanced diabetic nephropathy. Am. J. Physiol. Renal. Physiol. 290(3), F600–F605 (2006).
pubmed: 16159895
doi: 10.1152/ajprenal.00289.2005
Kahn, S. E. et al. Rosiglitazone-associated fractures in type 2 diabetes: An Analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care 31(5), 845–851 (2008).
pubmed: 18223031
doi: 10.2337/dc07-2270
Nissen, S. E. & Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 356(24), 2457–2471 (2007).
pubmed: 17517853
doi: 10.1056/NEJMoa072761