Objective  To evaluate different treatment strategies for type 2 diabetes mellitus (T2DM) patients with poor response to basal insulin in combination with first-line oral hypoglycemic agents (metformin/sulfonylureas), and provide scientific basis for recommending the optimal treatment strategy for patients.

Methods  The databases of PubMed, EMbase, The Cochrane Library, SinoMed, CNKI, WanFang Data and VIP were searched to collect the systematic review (SR) / Meta-analysis (MA) on the poor effects after basal insulin in combination with first-line oral hypoglycemic agents from inception to September 13, 2023. The original studies for SR/MA were randomized controlled trials (RCTs). Literature screening, data extraction, and quality assessment were carried out independently by two researchers, and data analysis was carried out by the umbrella package of R 4.2.2 software.

Results  A total of 1 SR and 8 MA were included in this study, totaling 72 RCTs involving 24 095 patients were included. The main subsequent therapeutic agents involved in the included literature were GLP-1 receptor agonists (GLP-1RA), DPP-4 inhibitors (DPP-4i), SGLT-2 inhibitors (SGLT-2i) and thiazolidinediones (TZD). The result of umbrella review showed that, compared with placebo, GLP-1RA (WMD=﹣3.67, 95%CI ﹣5.81 to﹣1.53, P=0.001), DPP-4i (WMD=﹣5.56, 95%CI ﹣ 7.40 to ﹣3.73, P<0.001), SGLT-2i (WMD=﹣5.34, 95%CI ﹣9.56  to ﹣1.13, P=0.013) significantly reduced HbA1c(%); GLP-1RA vs. IGlarLixi (WMD=7.49, 95%CI 7.01 to 7.92, P<0.001), GLP-1RA vs. IDegLira (WMD=0.83, 95%CI 0.11 to 1.54, P=0.023), showing that GLP-1RA had a lower effect to reduce HbA1c (%) than IGlarLixi and IDegLira. Compared with placebo, GLP-1RA significant reduced weight (kg) (WMD=﹣3.46, 95%CI ﹣5.30 to ﹣1.63, P<0.001) ; GLP-1RA vs. IGlarLixi (WMD=-8.40, 95%CI -8.86 to -7.93, P<0.001), GLP-1RA vs. IDegLira (WMD=- 0.53, 95%CI -0.99 to -0.07, P=0.025 ), showing that GLP-1RA has a better weight-loss effect than IGlarLixi and IDegLira. Compared with placebo, TZD (OR=1.51, 95%CI 1.11 to 2.05, P=0.009) and GLP- 1RA (OR=1.24, 95%CI 1.03 to 1.49, P=0.023) significantly increased the risk of hypoglycemia; GLP- 1RA vs. IDegLira (OR=1.22, 95%CI 1.04 to 1.43, P=0.014), showing that GLP-1RA had an higher risk of hypoglycemia than IDegLira.

Conclusion  Subsequent treatment with GLP- 1RA, DPP-4i, and SGLT-2i resulted in better glycemic control, and there was a weight reduction advantage with GLP-1RA, but GLP-1RA may increase the risk of hypoglycemia.

1.Raccah D, Chou E, Colagiuri S, et al. A global study of the unmet need for glycemic control and predictor factors among patients with type 2 diabetes mellitus who have achieved optimal fasting plasma glucose control on basal insulin[J]. Diabetes Metab Res Rev, 2017, 33(3): e2858. DOI: 10.1002/dmrr.2858.

2.中华医学会糖尿病学分会. 中国2型糖尿病防治指南(2020年版)[J]. 中华糖尿病杂志, 2021, 13(4): 315-409. DOI: 10.3760/cma.j.cn115791-20210221-00095.

3.Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both[J]. BMJ, 2017, 358: j4008. DOI: 10.1136/bmj.j4008.

4.Hultcrantz M, Rind D, Akl EA, et al. The GRADE Working Group clarifies the construct of certainty of evidence[J]. J Clin Epidemiol, 2017, 87: 4-13. DOI: 10.1016/j.jclinepi.2017.05.006.

5.Fusar-Poli P, Radua J. Ten simple rules for conducting umbrella reviews[J]. Evid Based Ment Health, 2018, 21(3): 95-100. DOI: 10.1136/ebmental-2018-300014.

6.Chen C, Yu Q, Zhang S, et al. Assessing the efficacy and safety of combined DPP-4 inhibitor and insulin treatment in patients with type 2 diabetes: a meta-analysis[J]. Int J Clin Exp Pathol, 2015, 8(11): 14141-14150. https://pubmed.ncbi.nlm.nih.gov/26823727/.

7.Cimmaruta D, Maiorino MI, Scavone C, et al. Efficacy and safety of insulin-GLP-1 receptor agonists combination in type 2 diabetes mellitus: a systematic review[J]. Expert Opin Drug Saf, 2016, 15(sup2): 77-83. DOI: 10.1080/14740338.2016.1221402.

8.Kim YG, Min SH, Hahn S, et al. Efficacy and safety of the addition of a dipeptidyl peptidase-4 inhibitor to insulin therapy in patients with type 2 diabetes: a systematic review and meta-analysis[J]. Diabetes Res Clin Pract, 2016, 116: 86-95. DOI: 10.1016/j.diabres.2016.03.011.

9.Maiorino MI, Chiodini P, Bellastella G, et al. Insulin and glucagon-like peptide 1 receptor agonist combination therapy in type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials[J]. Diabetes Care, 2017, 40(4): 614-624. DOI: 10.2337/dc16-1957.

10.Min SH, Yoon JH, Hahn S, et al. Comparison between SGLT2 inhibitors and DPP4 inhibitors added to insulin therapy in type 2 diabetes: a systematic review with indirect comparison meta-analysis[J]. Diabetes Metab Res Rev, 2017, 33(1): e2818. DOI: 10.1002/dmrr.2818.

11.Cho YK, Kim YJ, Kang YM, et al. Comparison between sodium-glucose cotransporter 2 inhibitors and pioglitazone as additions to insulin therapy in type 2 diabetes patients: a systematic review with an indirect comparison meta-analysis[J]. J Diabetes Investig, 2018, 9(4): 882-892. DOI: 10.1111/jdi.12787.

12.Yang W, Cai X, Gao X, et al. Addition of dipeptidyl peptidase-4 inhibitors to insulin treatment in type 2 diabetes patients: a meta-analysis[J]. J Diabetes Investig, 2018, 9(4): 813-821. DOI: 10.1111/jdi.12764.

13.Yoon JH, Min SH, Ahn CH, et al. Comparison of non-insulin antidiabetic agents as an add-on drug to insulin therapy in type 2 diabetes: a network meta-analysis[J]. Sci Rep, 2018, 8(1): 4095. DOI: 10.1038/s41598-018-22443-1.

14.Maiorino MI, Chiodini P, Bellastella G, et al. The good companions: insulin and glucagon-like peptide-1 receptor agonist in type 2 diabetes. A systematic review and meta-analysis of randomized controlled trials[J]. Diabetes Res Clin Pract, 2019, 154: 101-115. DOI:10.1016/j.diabres.2019.06.009.

15.American Diabetes Association. Standards of Medical Care in Diabetes-2021[J]. Diabetes Care, 2021, 44(Supplement_1):  S1-S232. DOI: 10/gh4kbc.

16.Hernandez AV, Usmani A, Rajamanickam A, et al. Thiazolidinediones and risk of heart failure in patients with or at high risk of type 2 diabetes mellitus: a meta-analysis and meta-regression analysis of placebo-controlled randomized clinical trials[J]. Am J Cardiovasc Drugs, 2011, 11(2): 115-128. DOI: 10.2165/11587580-000000000-00000.

17.Abd El Aziz MS, Kahle M, Meier JJ, et al. A meta-analysis comparing clinical effects of short- or long-acting GLP-1 receptor agonists versus insulin treatment from head-to-head studies in type 2 diabetic patients[J]. Diabetes Obes Metab, 2017, 19(2): 216-227. DOI: 10.1111/dom.12804.

18.Lee CM, Woodward M, Colagiuri S. Triple therapy combinations for the treatment of type 2 diabetes - a network meta-analysis[J]. Diabetes Res Clin Pract, 2016, 116: 149-158. DOI: 10.1016/j.diabres.2016.04.037.

19.Wu B, Zheng H, Gu J, et al. Effects of sodium-glucose cotransporter 2 inhibitors in addition to insulin therapy on cardiovascular risk factors in type 2 diabetes patients: a meta-analysis of randomized controlled trials[J]. J Diabetes Investig, 2019, 10(2): 446-457. DOI:10.1111/jdi.12876.

20.Harris S, Abrahamson MJ, Ceriello A, et al. Clinical considerations when initiating and titrating insulin degludec/liraglutide (IDegLira) in people with type 2 diabetes[J]. Drugs, 2020, 80(2): 147-165. DOI: 10.1007/s40265-019-01245-3.

21.Rosenstock J, Aronson R, Grunberger G, et al. Benefits of lixilan, a titratable fixed-ratio combination of insulin glargine plus lixisenatide, versus insulin glargine and lixisenatide monocomponents in type 2 diabetes inadequately controlled on oral agents: the LixiLan-O randomized trial[J]. Diabetes Care, 2016, 39(11): 2026-2035. DOI: 10.2337/dc16-0917.

22.Karagiannis T, Avgerinos I, Liakos A, et al. Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: a systematic review and meta-analysis[J]. Diabetologia, 2022, 65(8): 1251-1261. DOI: 10.1007/s00125-022-05715-4.

23.Zheng H, Sigal RJ, Coyle D, et al. Comparative efficacy and safety of antihyperglycemic drug classes for patients with type 2 diabetes following failure with metformin monotherapy: a systematic review and network meta-analysis of randomized controlled trials[J]. Diabetes Metab Res Rev, 2022, 38(4): e3515. DOI: 10.1002/dmrr.3515.

24.中华医学会内分泌学分会, 中华医学会糖尿病学分会. 胰高糖素样肽-1(GLP-1)受体激动剂用于治疗2型糖尿病的临床专家共识[J]. 中华内科杂志, 2020, 59(11): 836-846. DOI: 10.3760/cma.j.cn112138-20200704-00646.

25.Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)[J]. Diabetes Care, 2022, 45(11): 2753-2786. DOI: 10.2337/dci22-0034.