Type 2 diabetes (T2D) is a progressive disease in which it is challenging to achieve long-term durable glycemic control. However, intensive glycemic control is crucial for preventing diabetes-related complications. Previous studies showed that monotherapy with a stepwise add-on approach was seldom effective for long-term durable glycemic control. Combination therapy, which refers to the use of two or more drugs to control hyperglycemia, has multiple benefits, including the ability to target a variety of pathophysiological processes underlying hyperglycemia. In clinical trials, initial combination therapy showed better glycemic control than monotherapy or a stepwise approach. Emerging evidence indicates that initial combination therapy is associated with preserved β-cell function and fewer complications in T2D. However, cost-effectiveness and adverse events with combination therapy are issues that should be considered. Therefore, initial combination therapy is an important option for patients with T2D that clinicians should consider with a view toward balancing benefits and potential harms. In this review, we summarize the literature addressing initial combination therapy in T2D, and we suggest optimal strategies based on clinical situations and patient characteristics.
Citations
Citations to this article as recorded by
Glycemia Risk Index is Associated With Risk of Albuminuria Among Individuals With Type 1 Diabetes Ji Yoon Kim, Jee Hee Yoo, Nam Hoon Kim, Jae Hyeon Kim Journal of Diabetes Science and Technology.2026; 20(3): 775. CrossRef
Sodium‐glucose cotransporter 2 inhibitor ameliorates thiazolidinedione‐induced fluid retention through vascular leakage reduction in white adipose tissue Ji Yoon Kim, Hye‐Min Jang, Hye‐Jin Lee, Ah Hyeon Lee, Dong‐Hoon Kim, Sin Gon Kim, Nam Hoon Kim Diabetes, Obesity and Metabolism.2026; 28(3): 1764. CrossRef
Development and Validation of a High‐Performance Liquid Chromatography Coupled With Photodiode Array Detection Method for the Simultaneous Analysis of Metformin, Cyanoguanidine, and Antidiabetic Agents in Fixed‐Dose Combinations Gökhan Bayrak, Selen Al, Aykut Kul, Armağan Önal SEPARATION SCIENCE PLUS.2026;[Epub] CrossRef
Ethnic Disparities in Glycemic Control among Malaysian Adults with Type 2 Diabetes: A Retrospective Multivariable Analysis Fikry Ahmad, Suhaili Abubakar, Sharifah Sakinah Syed Alwi, Ng Ooi Chuan, Hasni Idayu Saidi Journal of Racial and Ethnic Health Disparities.2026;[Epub] CrossRef
GLIMSI: A real-world, multicenter study assessing the effectiveness and safety of Sitagliptin + Glimepiride + Metformin FDC in Indian patients with Type 2 diabetes Kunal Zaveri, Girish Kulkarni, Rathish Nair, Govarthanan Shanmugan, Shubhada Amol Dharmadhikari, R. P. S. Makkar, Rahul Jalgaonkar, B. D. Chatterjee, Krishnaprasad Korukonda, Natural Hoi Sing Chu PLOS One.2026; 21(2): e0337107. CrossRef
A Randomized, Multicenter Study Evaluating the Efficacy, Safety and Tolerability of Dapagliflozin + Gliclazide Fixed Dose Combination Over Dapagliflozin Monotherapy in Type 2 Diabetes Mellitus Patients Inadequately Controlled on Metformin Monotherapy Suhas G Erande, Amar Raykantiwar, Vivek Shejole, Rashmi GR, Animesh Maiti, A.S. Veeramani Kartheek, Mohamed Hanifah, Richa Giri, Sharvil Gadve, Arindam Ray, Kunal Thakkar, Balram Sharma, Saket Kant, Abhyudaya Verma , Yogesh Yadav, Hiren Prajapati, Honey D Cureus.2026;[Epub] CrossRef
Comparative Analysis of Clinical Outcomes in Patients With Type 2 Diabetes Mellitus on Monotherapy Versus Combination Therapy Hariballav Mahapatra, Piyush Kumar Gupta, Ajo Paul, Amit Nampalliwar, Manju Bansal, Baijnath Das, K. Parameswaran Namboothiri Cureus.2026;[Epub] CrossRef
Clinical Experience and Outcomes with Triple-drug Fixed-dose Combination Therapy (Sitagliptin + Dapagliflozin + Metformin Sustained-Release Tablets) in Type 2 Diabetes Mellitus Management: A Real-world Observational Survey of Clinician Perspectives Manoj Arajanbhai Suva Archives of Medicine and Health Sciences.2026; 14(1): 61. CrossRef
Circulating GDF15 levels reflect metabolic and inflammatory burden in early dysglycemia: findings from the ADIOS cohort Ji Yoon Kim, Ah Hyeon Lee, Jiyoon Lee, Hye-Min Jang, Sin Gon Kim, Dong-Hoon Kim, Nam Hoon Kim Diabetes Research and Clinical Practice.2026; 239: 113461. CrossRef
A Phase III, Randomized, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of a Fixed Dose Combination of Dapagliflozin and Pioglitazone in Type 2 Diabetes Mellitus Patients Inadequately Controlled on Metformin Monotherapy Nilakshi Deka, Sambit Das, Kirtikumar D. Modi, Arundhati Das Gupta, Mukulesh Gupta, Ajay Chhabra, Niroj Kumar Mishra, Manjunath Goroshi, Hemi Soneja, Sameer Agarwal, Biplab Mandal, Amarkant Amar, Santosh Saklecha, Hiren Prajapati, Sachin Negi International Journal of Diabetes and Technology.2026; 5(3): 146. CrossRef
Safety outcomes of antidiabetic medications: A comprehensive review of the EU summaries of product characteristics and international clinical practice guidelines David Liang, Daniala L. Weir, Safana Thevasahayam, Vera H. M. Deneer, Arno Siebes, Helga Gardarsdottir British Journal of Clinical Pharmacology.2026;[Epub] CrossRef
Early combination therapy in type 2 diabetes: Rethinking initial treatment strategies Andrej Janez, Tanja Smid, Manfredi Rizzo, Tsvetalina Tankova Journal of Diabetes and its Complications.2026; 40(10): 109392. CrossRef
GDD, a first-in-class APPL1 activator, restores mitochondrial homeostasis and insulin sensitivity with regulation of LKB1-AMPK axis Hao Zheng, Ya-Ru Zhao, Xian-Yan Deng, Dan-Yu Huang, Fang-Qiong Qiu, Chang Yan, Shu-Ying Li, Jing Chen, Wan-Bin Song, Hui-Qing Lv, Ri-Hui Wu, Ligen Lin, Li-She Gan Phytomedicine.2026; 161: 158712. CrossRef
Beyond Fat Loss: Addressing the Sarcopenia Challenge of Incretin-Based Therapies Ji Yoon Kim, Nam Hoon Kim Diabetes & Metabolism Journal.2026; 50(5): 844. CrossRef
Ginsenoside Rb1 and berberine synergistically protect against type 2 diabetes mellitus via GDF15/HAMP pathway throughout the liver lobules: Insights from spatial transcriptomics analysis Rongfang Guo, Shuying Zhang, Anyao Li, Ping Zhang, Xin Peng, Xiaoyan Lu, Xiaohui Fan Pharmacological Research.2025; 215: 107711. CrossRef
Factors associated with prescription of modern antidiabetics in newly diagnosed patients with type 2 diabetes. a real-world data study in a Spanish region Irantzu Bengoa-Urrengoechea, Isabel Aguilar-Palacio, María José Rabanaque, María Jesús Lallana, Adriana Gamba Cabezas, Sara Malo Frontiers in Pharmacology.2025;[Epub] CrossRef
Fenofibrate therapy and risk of heart failure outcomes in patients with Type 2 diabetes: a propensity-matched cohort study Ji Yoon Kim, Nam Hoon Kim, Jiyoon Lee, Dong-Hoon Kim, Sin Gon Kim European Heart Journal - Cardiovascular Pharmacotherapy.2025; 11(7): 620. CrossRef
High-performance liquid chromatography method for simultaneous determination of the degradation products of metformin hydrochloride and vildagliptin Amra Demirović, Alija Uzunović, Anisa Veledar-Hamalukić European Journal of Pharmaceutical Sciences.2025; 214: 107268. CrossRef
Cyclic amines-modified metformin derivatives with enhanced glucose uptake activity Muhammad Fathiy Mutalabisin, Nor Akmalyati Sulong, Nader Ghaffari Khaligh, Vannajan Sanghiran Lee, Nurshamimi Nor Rashid, Mohd Rafie Johan, Chin Fei Chee Results in Chemistry.2025; 18: 102830. CrossRef
Beta-Cell Function, Insulin Sensitivity, and Metabolic Characteristics in Young-Onset Type 2 Diabetes Mellitus: Findings from Anam Diabetes Observational Study Ji Yoon Kim, Jiyoon Lee, Sin Gon Kim, Nam Hoon Kim Diabetes & Metabolism Journal.2025; 49(6): 1287. CrossRef
Anti-Senescence Effect of Inhibiting Sodium-Glucose Cotransporter 2 and α-Glucosidase in a Type 2 Diabetes Mellitus Animal Model Serin Hong, Byung Soo Kong, Hyunsuk Lee, Young Min Cho Diabetes & Metabolism Journal.2025; 49(6): 1229. CrossRef
Targeting adipose remodeling: Synergistic mechanisms of drugs and adipose-derived stem cells in obese type 2 diabetes mellitus Cheng Luo, Xian-Mei Yu, Liang-Yan Hua, Mei-Qi Zeng, Hui Xu, Cheng-Zheng Duan, Shi-Yu Xu, Da Sun, Li-Ya Ye, Dong-Juan He World Journal of Stem Cells.2025;[Epub] CrossRef
Balancing Bleeding and Ischemic Risks: A Systematic Review of Dual Versus Triple Therapy After Percutaneous Coronary Intervention in Patients With Atrial Fibrillation Abubakar Gapizov, Ahmad Mohammad, Shivam Singla, Bhavna Singla, Saifullah Syed, Sunita Kumawat, Zulqurnain Ali Cureus.2025;[Epub] CrossRef
GLYCEMIC CONTROL AND COMORBIDITIES IN PATIENTS WITH TYPE 2 DIABETES MELLITUS: A GENDER-BASED STUDY IN HEALTH FACILITIES OF DUHOK, IRAQ Hozan Qasim Hussein, Hileen Mustafa Haji, Milat Hussein Mustafa Health Problems of Civilization.2025;[Epub] CrossRef
Vector of glycated hemoglobin in the formation of dysglycemia in postmenopause: Emphasis on early diagnosis and therapy L. A. Ruyatkina, D. S. Ruyatkin, L. V. Shcherbakova, I. S. Iskhakova Meditsinskiy sovet = Medical Council.2024; (16): 135. CrossRef