Diabetes & Metabolism Journal

Original Article

Cardiovascular Risk/Epidemiology
Comparative Efficacy of Initial Statin and Ezetimibe Combination versus Statin Monotherapy on Cardiovascular Outcomes in Diabetes Mellitus: A Nationwide Cohort Study: Minji Sohn, Young-Hwan Park, Soo Lim; Diabetes Metab J. 2025;49(6):1318-1330. Published online June 5, 2025; DOI: https://doi.org/10.4093/dmj.2024.0482

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Background
This study aimed to assess the efficacy of an initial combination therapy of statin and ezetimibe compared with statin monotherapy on major cardiovascular outcomes in individuals with diabetes.
Methods
In this population-based cohort study using National Health Insurance Service data (2010–2020), we included adults with diabetes who had not previously used any lipid-lowering medications. Those initiating statin monotherapy were matched 1:1 using propensity scores with patients starting combination therapy with a lower-potency statin and ezetimibe. This matching process resulted in 21,458 individuals in the primary prevention cohort and 10,094 in the secondary prevention cohort, respectively. The primary endpoint was a composite of myocardial infarction, stroke, and cardiovascular death. Hospitalizations for heart failure, angina, and all-cause mortality were analyzed. The impact of ezetimibe maintenance on the primary endpoint was analyzed, and other hospitalizations were categorized as adverse events.
Results
Compared with statin monotherapy, statin-ezetimibe combination significantly reduced the incidence of the primary endpoint (4.85 vs. 3.25 per 1,000 person-years: hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.56 to 0.81 in the primary cohort; and 19.5 vs. 15.7 per 1,000 person-years: HR, 0.80; 95% CI, 0.70 to 0.91 in the secondary cohort) and myocardial infarction (HR, 0.64; 95% CI, 0.46 to 0.82 in the primary cohort; and HR, 0.73; 95% CI, 0.60 to 0.89 in the secondary cohort). A longer maintenance period of ezetimibe was significantly related to better efficacy in the composite cardiovascular outcomes. High-intensity statin monotherapy was associated with an elevated risk of liver, muscle, and diabetes-related hospitalization in the primary prevention cohort.
Conclusion
Initial therapy with a statin-ezetimibe combination is associated with a reduced risk of cardiovascular events and fewer adverse events compared to statin monotherapy in individuals with diabetes, over a mean follow-up of 5.5 years (up to 9 years).

Citations

Citations to this article as recorded by

Cardiovascular outcomes and adverse drug reactions associated with the use of ezetimibe in combination with a statin in diabetes mellitus patients with higher risk for myocardial infarction: a meta-analysis
Yan Zhou, Ji Jin
BMC Cardiovascular Disorders.2026;[Epub] CrossRef
Sirtuins and regulatory miRNAs as epigenetic determinants of empagliflozin-mediated recovery after acute myocardial infarction
Anna Nowak-Szwed, Ceren Eyileten, Zofia Wicik, Sara Ahmadova, Jeff Palatini, Jolanta Siller-Matula, Dirk von Lewinski, Harald Sourij, Marek Postula
Cardiovascular Diabetology.2025;[Epub] CrossRef

Response

Two-Year Therapeutic Efficacy and Safety of Initial Triple Combination of Metformin, Sitagliptin, and Empagliflozin in Drug-Naïve Type 2 Diabetes Mellitus Patients (Diabetes Metab J 2024;48:253-64): Young-Hwan Park, Minji Sohn, Soo Lim; Diabetes Metab J. 2024;48(5):1012-1013. Published online September 1, 2024; DOI: https://doi.org/10.4093/dmj.2024.0485

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Citations

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Comparative effectiveness of metformin and alogliptin combination therapy versus metformin monotherapy in patients with type 2 diabetes: an emulated target trial
Jaehyeong Cho, Yerin Hwang, Selin Woo, Tae Hyeon Kim, Kyeongmin Lee, Yejun Son, Seoyoung Park, Hyunjee Kim, Ju-Young Shin, YongHyun Cho, Dahye Shin, Dosang Cho, Kyung-Jae Lee, Chang Hyun Kim, Sang Youl Rhee, Dong Keon Yon
BMC Endocrine Disorders.2025;[Epub] CrossRef

Original Article

Drug/Regimen
Two-Year Therapeutic Efficacy and Safety of Initial Triple Combination of Metformin, Sitagliptin, and Empagliflozin in Drug-Naïve Type 2 Diabetes Mellitus Patients: Young-Hwan Park, Minji Sohn, So Yeon Lee, Soo Lim; Diabetes Metab J. 2024;48(2):253-264. Published online January 26, 2024; DOI: https://doi.org/10.4093/dmj.2023.0128

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809 Download
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Background
We investigated the long-term efficacy and safety of initial triple therapy using metformin, a dipeptidyl peptidase-4 inhibitor, and a sodium-glucose cotransporter-2 inhibitor, in patients with type 2 diabetes mellitus.
Methods
We enrolled 170 drug-naïve patients with glycosylated hemoglobin (HbA1c) level >7.5% who had started triple therapy (metformin, sitagliptin, and empagliflozin). Glycemic, metabolic, and urinary parameters were measured for 24 months.
Results
After 24 months, HbA1c level decreased significantly from 11.0%±1.8% to 7.0%±1.7%. At 12 and 24 months, the rates of achievement of the glycemic target goal (HbA1c <7.0%) were 72.5% and 61.7%, respectively, and homeostasis model assessment of β-cell function and insulin resistance indices improved. Whole-body fat percentage decreased by 1.08%, and whole-body muscle percentage increased by 0.97% after 24 months. Fatty liver indices and albuminuria improved significantly. The concentration of ketone bodies was elevated at the baseline but decreased after 24 months. There were no serious adverse events, including ketoacidosis.
Conclusion
Initial triple combination therapy with metformin, sitagliptin, and empagliflozin led to achievement of the glycemic target goal, which was maintained for 24 months without severe hypoglycemia but with improved metabolic function and albuminuria. This combination therapy may be a good strategy for drug-naïve patients with type 2 diabetes mellitus.

Citations

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Antidiabetic prescribing patterns, quality, and economic influence in resource-limited settings: evidence from a Pakistani tertiary care hospital using WHO/INRUD indicators
Amna Saeed, Iltaf Hussain, Ali Hassan Gillani, Farhan Ullah, Muhammad Ali, Muhammad Shafiq Khan, Ifra Maqbool, Asif Nawaz Khan, Yu Fang
BMC Health Services Research.2026;[Epub] CrossRef
Patterns and Clinical Outcomes of Sitagliptin/Metformin Extended-Release in Internal Medicine: A Real-World Multicenter Italian Study
Mariarosaria De Luca, Michele Arcopinto, Giosiana Bosco, Sebastiano Cicco, Francesco Di Giacomo Barbagallo, Chiara Giacinti, Marialuisa Sveva Marozzi, Maristella Salvatora Masala, Miriam Pinna, Giacomo Pucci, Andrea Salzano, Roberto Scicali, Alberto Maria
Journal of Clinical Medicine.2026; 15(3): 927. CrossRef
Long-term effectiveness on glycemic control of insulin compared to combined oral antidiabetic drugs for initial intensive treatment in newly diagnosed type 2 diabetes: A duplicated target trial
Tae Hyeon Kim, Yerin Hwang, Selin Woo, Kyeongmin Lee, Yejun Son, Seoyoung Park, Hyunjee Kim, Ju-Young Shin, YongHyun Cho, Dahye Shin, Dosang Cho, Kyung-Jae Lee, Sang Youl Rhee, Dong Keon Yon
Medicine.2026; 105(5): e47235. CrossRef
Successful portosystemic shunt embolization resolves hepatic encephalopathy and enhances hepatic function and glycemic control in MASH-related cirrhosis: a case report
Yoshiaki Kobayashi, Takanobu Iwadare, Hiroyuki Kobayashi, Takefumi Kimura, Yoshiki Ozawa, Ryo Kodama, Masahiro Kurozumi, Yayoi Yamazaki, Yuki Yamashita, Takeji Umemura
Clinical Journal of Gastroenterology.2025; 18(1): 137. CrossRef
Efficacy and Safety of Triple Fixed Dose Combination of Dapagliflozin + Sitagliptin + Metformin IR in Indian Patients with Type 2 Diabetes Mellitus: A Randomized, Phase 3 Study in Comparison with Dual FDC Sitagliptin + Metformin IR
Mahendra Pal Singh, Sandeep Gupta, Manish Singh, C. Ambrish, Prakash Kurmi, Dinesh Kumar Gangwani, J. Naganna, Ravikumar Sethuraman, Vrindavani Dhumal, Sapan Behera, Piyush M. Patel, Dipak M. Patil, Lalit K. Lakhwani, Pravin S. Ghadge, Suyog C. Mehta, Sad
Advances in Therapy.2025; 42(10): 5187. CrossRef
Triple oral therapy with metformin, DPP‐4 inhibitor, and SGLT2 inhibitor for adults with type 2 diabetes: Consensus recommendations of a Chinese expert panel (version 2025)
Miao Yu, Tong Wang, Chun Xu, Yan Bi, Ling Gao, Guang Wang, Guangda Xiang, Yaoming Xue, Tao Yang, Deying Kang, Zhiguang Zhou, Lixin Guo, Xinhua Xiao
Diabetes, Obesity and Metabolism.2025; 27(S9): 3. CrossRef
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Sachin Dhiman, Sanchit Dhankhar, Anjali Garg, Manni Rohilla, Monika Saini, Thakur Gurjeet Singh, Samrat Chauhan, Samy Selim, Soad K. Al Jaouni, Sabina Yasmin, Naseem Begum, Aziza Alshahrani, Mohammad Yousuf Ansari
Heliyon.2024; 10(21): e39996. CrossRef

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