Linagliptin for Type 2 Diabetes Mellitus: A Systematic Review of Efficacy, Safety, Combination Therapy, and Use in High Risk Populations
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https://doi.org/10.22487/vytnfy72Keywords:
Type 2 Diabetes Mellitus, Linagliptin, Systematic Review, Efficacy, SafetyAbstract
Background: Type 2 diabetes mellitus requires glucose-lowering therapy that balances efficacy and safety, particularly in patients with renal or cardiovascular comorbidities. Linagliptin is a dipeptidyl peptidase-4 inhibitor with predominantly nonrenal elimination. Objectives: To evaluate the efficacy, safety, combination therapy, and clinical use of linagliptin in selected high-risk populations. Methods: PubMed and Google Scholar were searched for primary clinical studies published from 2015 through 19 August 2026. Eleven eligible studies were synthesized according to PRISMA 2020 principles. Risk of bias was assessed using RoB 2, and clinically heterogeneous outcomes were summarized narratively. Results: Linagliptin reduced HbA1c compared with placebo and demonstrated cardiovascular noninferiority in CARMELINA. Compared with glimepiride, glycemic control was broadly comparable, with less hypoglycemia and weight gain. Empagliflozin produced greater glycemic and metabolic improvements than linagliptin when added to premixed insulin, whereas linagliptin reduced HbA1c more effectively than voglibose in hemodialysis patients. Combination benefits and adverse effects varied according to the partner drug. Conclusions: Linagliptin provides modest glucose lowering with a generally low risk of hypoglycemia, although comparative benefits depend on population, comparator, and clinical outcome.
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References
1. International Diabetes Federation. IDF Diabetes Atlas. Published online 2025.
2. Galicia Garcia U, Benito Vicente A, Jebari S. Pathophysiology of type 2 diabetes mellitus. Int J Mol Sci. 2020;21(17):6275. doi:10.3390/ijms21176275
3. Krause M, De Vito G. Type 1 and type 2 diabetes mellitus: commonalities, differences and the importance of exercise and nutrition. Nutrients. 2023;15(19):4279. doi:10.3390/nu15194279
4. Perkumpulan Endokrin Indonesia. Pedoman Pengelolaan Dan Pencegahan Diabetes Melitus Tipe 2 Di Indonesia 2021. PB PERKENI; 2021.
5. Kasina SVSK, Baradhi KM. Dipeptidyl Peptidase IV (DPP IV) Inhibitors. Dipeptidyl Pept IV (DPP IV) Inhib. Published online May 22, 2023:1-5. https://www.ncbi.nlm.nih.gov/books/NBK542331/
6. Ceriello A, Inagaki N. Pharmacokinetic and pharmacodynamic evaluation of linagliptin for the treatment of type 2 diabetes mellitus, with consideration of Asian patient populations. J Diabetes Investig. 2017;8(1):19-28. doi:10.1111/JDI.12528;PAGE:STRING:ARTICLE/CHAPTER
7. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Bmj. 2021;372. doi:10.1136/bmj.n71
8. Sterne JAC, Savovic J, Page MJ. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898
9. Groop PH, Cooper ME, Perkovic V, et al. Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: the randomized MARLINA-T2D trial. Diabetes, Obes Metab. 2017;19(11):1610-1619. doi:10.1111/DOM.13041;WGROUP:STRING:PUBLICATION
10. Rosenstock J, Perkovic V, Johansen OE. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA. 2019;321(1):69-79. doi:10.1001/jama.2018.18269
11. Deshmukh V, Sathyanarayana S, Menon S, et al. Safety and efficacy of initial combination of linagliptin and metformin in patients with type 2 diabetes: A subgroup analysis of Indian patients from a randomized, double-blind, placebo-controlled study. Indian J Endocrinol Metab. 2015;19(2):256-261. doi:10.4103/2230-8210.149319
12. Lewin A, DeFronzo RA, Patel S, et al. Initial Combination of Empagliflozin and Linagliptin in Subjects With Type 2 Diabetes. Diabetes Care. 2015;38(3):394-402. doi:10.2337/DC14-2365
13. Nauck MA, Di Domenico M, Patel S, Kobe M, Toorawa R, Woerle HJ. Linagliptin and pioglitazone combination therapy versus monotherapy with linagliptin or pioglitazone: A randomised, double-blind, parallel-group, multinational clinical trial. Diabetes Vasc Dis Res. 2016;13(4):286-298. doi:10.1177/1479164116639229
14. McGill JB, Yki-Järvinen H, Crowe S, Woerle HJ, Von Eynatten M. Combination of the dipeptidyl peptidase-4 inhibitor linagliptin with insulin-based regimens in type 2 diabetes and chronic kidney disease. Diabetes Vasc Dis Res. 2015;12(4):249-257. doi:10.1177/1479164115579001;WEBSITE:WEBSITE:SAGE;ISSUE:ISSUE:DOI
15. Rosenstock J, Kahn SE, Johansen OE, et al. Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial. JAMA. 2019;322(12):1. doi:10.1001/JAMA.2019.13772
16. Liu SC, Lee CC, Chuang SM, Sun FJ, Zeng YH. Comparison of efficacy and safety of empagliflozin vs linagliptin added to premixed insulin in patients with uncontrolled type 2 diabetes: a randomized, open label study. Diabetes Metab. 2021;47(3):101184. doi:10.1016/j.diabet.2020.08.001
17. Hiramatsu T, Asano Y, Mabuchi M, Imai K, Iguchi D, Furuta S. Liraglutide relieves cardiac dilated function than DPP-4 inhibitors. Eur J Clin Invest. 2018;48(10):e13007. doi:10.1111/ECI.13007;REQUESTEDJOURNAL:JOURNAL:13652362;PAGE:STRING:ARTICLE/CHAPTER
18. Mori K, Emoto M, Shoji T, et al. Linagliptin monotherapy compared with voglibose monotherapy in patients with type 2 diabetes undergoing hemodialysis: a 12-week randomized trial. BMJ open diabetes Res care. 2016;4(1). doi:10.1136/BMJDRC-2016-000265
19. Hong JH, Kim MJ, Min KW. Efficacy and safety of a fixed dose combination of dapagliflozin and linagliptin in patients with type 2 diabetes mellitus: a multicentre, randomized, double blind, parallel group, placebo controlled phase III study. Diabetes, Obes Metab. 2025;27(1):81-91. doi:10.1111/dom.15985
20. Deacon CF. Physiology and pharmacology of DPP 4 in glucose homeostasis and the treatment of type 2 diabetes. Front Endocrinol (Lausanne). 2019;10:80. doi:10.3389/fendo.2019.00080
21. Vithian K, Hurel S. Microvascular complications: pathophysiology and management. Clin Med (Northfield Il). 2010;10(5):505-509. doi:10.7861/clinmedicine.10-5-505
22. Willison A, Tully V, Davey P. All Patients with Diabetes Should Have Annual UACR Tests. Why is That So Hard? BMJ Open Qual. 2016;5(1):u209185.w3747. doi:10.1136/BMJQUALITY.U209185.W3747
23. Yamin M, Putra HA, Yamin M, Putra HA. Sindrom Kardiovaskular-Ginjal-Metabolik: Konsep Terkini untuk Klinisi. J Penyakit Dalam Indones. 2024;11(2):9. doi:10.7454/jpdi.v11i2.1597
24. Kim YG, Kim S, Han SJ, Kim DJ, Lee KW, Kim HJ. Dipeptidyl peptidase 4 inhibitors and the risk of pancreatitis in patients with type 2 diabetes mellitus: a population based cohort study. J Diabetes Res. 2018;2018:5246976. doi:10.1155/2018/5246976
25. Padda IS, Mahtani AU, Parmar M. Sodium-Glucose Transport 2 (SGLT2) Inhibitors. StatPearls. Published online September 15, 2025. https://www.ncbi.nlm.nih.gov/books/NBK576405/
26. Mudaliar S, Henry RR. Thiazolidinediones. In: Type 2 Diabetes: Principles and Practice. 2nd ed. 2023:137-158. doi:10.3109/9780849379581-14
27. Shuldiner AR, Barbetti F, Raben N, Scavo L, Serrano J. Insulin. In: Insulin and Growth Factors: Molecular and Cellular Aspects. 2023:181-219. doi:10.1201/9781003574583-7
28. Bellido V, Suarez L, Rodriguez MG, et al. Comparison of Basal-Bolus and Premixed Insulin Regimens in Hospitalized Patients With Type 2 Diabetes. Diabetes Care. 2015;38(12):2211-2216. doi:10.2337/DC15-0160
29. Trerattanavong K, Tadi P. Glimepiride. In: XPharm: The Comprehensive Pharmacology Reference. 2023:1-4. doi:10.1016/B978-008055232-3.61828-8
30. Cerillo JL, Parmar M. Liraglutide. StatPearls. Preprint posted online 2024.
31. Kassie Netere A, Kibret Sendekie A. Time to doubling of serum creatinine in patients with diabetes in Ethiopian University Hospital: retrospective follow up study. PLoS One. 2022;17(9):e0274495. doi:10.1371/journal.pone.0274495
32. Akmal M, Patel P, Wadhwa R. Alpha Glucosidase Inhibitors. StatPearls. Published online February 28, 2024. Accessed September 30, 2025. https://www.ncbi.nlm.nih.gov/books/NBK557848/
33. Abe M, Kalantar-Zadeh K. Haemodialysis-induced hypoglycaemia and glycaemic disarrays. Nat Rev Nephrol 2015 115. 2015;11(5):302-313. doi:10.1038/nrneph.2015.38
34. Goto H, Mita T, Fujitani Y. Effects of linagliptin versus voglibose on treatment related quality of life in patients with type 2 diabetes: subanalysis of the L STEP study. Endocr J. 2018;65(6):657-668. doi:10.1507/endocrj.EJ18-0088
35. Yonata A, Islamy N. The relationship between diabetes and hypertension and mortality in chronic kidney disease patients in Indonesia. Heal Tadulako J. 2025;11(4):517-526. doi:10.22487/htj.v11i4.1534
36. Kusuma AA, Purwanti OS. The relationship between the role of nurses as educators and the level of adherence to taking medication in diabetes mellitus patients at RSUD Dr. Moewardi Surakarta. Heal Tadulako J (Jurnal Kesehat Tadulako). 2025;11(4):548-555. doi:10.22487/htj.v11i4.1760
37. Sari I. Effect of diabetes exercise on reduction of blood glucose levels in patients with type II diabetes mellitus. Heal Tadulako J (Jurnal Kesehat Tadulako). 2025;11(4):620-627. doi:10.22487/htj.v11i4.1785
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