Diabetes & Metabolism Journal

Original Articles

Drug/Regimen
Efficacy and Safety of Treatment with Quadruple Oral Hypoglycemic Agents in Uncontrolled Type 2 Diabetes Mellitus: A Multi-Center, Retrospective, Observational Study: Jun Sung Moon, Sunghwan Suh, Sang Soo Kim, Heung Yong Jin, Jeong Mi Kim, Min Hee Jang, Kyung Ae Lee, Ju Hyung Lee, Seung Min Chung, Young Sang Lyu, Jin Hwa Kim, Sang Yong Kim, Jung Eun Jang, Tae Nyun Kim, Sung Woo Kim, Eonju Jeon, Nan Hee Cho, Mi-Kyung Kim, Hye Soon Kim, Il Seong Nam-Goong, Eun Sook Kim, Jin Ook Chung, Dong-Hyeok Cho, Chang Won Lee, Young Il Kim, Dong Jin Chung, Kyu Chang Won, In Joo Kim, Tae Sun Park, Duk Kyu Kim, Hosang Shon; Diabetes Metab J. 2021;45(5):675-683. Published online August 12, 2020; DOI: https://doi.org/10.4093/dmj.2020.0107

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Background

Only few studies have shown the efficacy and safety of glucose-control strategies using the quadruple drug combination. Therefore, the aim of the present study was to investigate the usefulness of the quadruple combination therapy with oral hypoglycemic agents (OHAs) in patients with uncontrolled type 2 diabetes mellitus (T2DM).

Methods

From March 2014 to December 2018, data of patients with T2DM, who were treated with quadruple hypoglycemic medications for over 12 months in 11 hospitals in South Korea, were reviewed retrospectively. We compared glycosylated hemoglobin (HbA1c) levels before and 12 months after quadruple treatment with OHAs. The safety, maintenance rate, and therapeutic patterns after failure of the quadruple therapy were also evaluated.

Results

In total, 357 patients were enrolled for quadruple OHA therapy, and the baseline HbA1c level was 9.0%±1.3% (74.9±14.1 mmol/mol). After 12 months, 270 patients (75.6%) adhered to the quadruple therapy and HbA1c was significantly reduced from 8.9%±1.2% to 7.8%±1.3% (mean change, −1.1%±1.2%; P<0.001). The number of patients with HbA1c <7% increased significantly from 5 to 68 (P<0.005). In addition, lipid profiles and liver enzyme levels were also improved whereas no changes in body weight. There was no significant safety issue in patients treated with quadruple OHA therapy.

Conclusion

This study shows the therapeutic efficacy of the quadruple OHA regimen T2DM and demonstrates that it can be an option for the management of T2DM patients who cannot use insulin or reject injectable therapy.

Citations

Citations to this article as recorded by

Estimating Type 2 Diabetes Prevalence: A Model of Drug Consumption Data
Rita Oliveira, Matilde Monteiro-Soares, José Pedro Guerreiro, Rúben Pereira, António Teixeira-Rodrigues
Pharmacy.2024; 12(1): 18. CrossRef
Disease burden and symptom management in type 2 diabetic patients: A phenomenological study
Sevgi Demir Çam, Sevda Uzun
Public Health Nursing.2024; 41(6): 1291. CrossRef
Comparing dual oral agents plus insulin vs. Triple oral agents in uncontrolled type II diabetes: A pilot study
Nadia Gul, Inayat Ur Rehman, Yasar shah, Arbab Muhammad Ali, Zahid Ali, Omer Shehzad, Khang Wen Goh, Long Chiau Ming, Amal K. Suleiman, Nimesh Lageju
PLOS ONE.2024; 19(11): e0311435. CrossRef
Efficacy and safety of enavogliflozin versus dapagliflozin added to metformin plus gemigliptin treatment in patients with type 2 diabetes: A double-blind, randomized, comparator-active study: ENHANCE-D study
Kyung-Soo Kim, Kyung Ah Han, Tae Nyun Kim, Cheol-Young Park, Jung Hwan Park, Sang Yong Kim, Yong Hyun Kim, Kee Ho Song, Eun Seok Kang, Chul Sik Kim, Gwanpyo Koh, Jun Goo Kang, Mi Kyung Kim, Ji Min Han, Nan Hee Kim, Ji Oh Mok, Jae Hyuk Lee, Soo Lim, Sang S
Diabetes & Metabolism.2023; 49(4): 101440. CrossRef
Effectiveness and safety of teneligliptin added to patients with type 2 diabetes inadequately controlled by oral triple combination therapy: A multicentre, randomized, double‐blind, and placebo‐controlled study
Minyoung Lee, Woo‐je Lee, Jae Hyeon Kim, Byung‐Wan Lee
Diabetes, Obesity and Metabolism.2022; 24(6): 1105. CrossRef
A double‐blind, Randomized controlled trial on glucose‐lowering EFfects and safety of adding 0.25 or 0.5 mg lobeglitazone in type 2 diabetes patients with INadequate control on metformin and dipeptidyl peptidase‐4 inhibitor therapy: REFIND study
Soree Ryang, Sang Soo Kim, Ji Cheol Bae, Ji Min Han, Su Kyoung Kwon, Young Il Kim, Il Seong Nam‐Goong, Eun Sook Kim, Mi‐kyung Kim, Chang Won Lee, Soyeon Yoo, Gwanpyo Koh, Min Jeong Kwon, Jeong Hyun Park, In Joo Kim
Diabetes, Obesity and Metabolism.2022; 24(9): 1800. CrossRef
Glycaemic control with add‐on thiazolidinedione or a sodium‐glucose co‐transporter‐2 inhibitor in patients with type 2 diabetes after the failure of an oral triple antidiabetic regimen: A 24‐week, randomized controlled trial
Jaehyun Bae, Ji Hye Huh, Minyoung Lee, Yong‐Ho Lee, Byung‐Wan Lee
Diabetes, Obesity and Metabolism.2021; 23(2): 609. CrossRef

Drug/Regimen
Efficacy and Safety of Pioglitazone versus Glimepiride after Metformin and Alogliptin Combination Therapy: A Randomized, Open-Label, Multicenter, Parallel-Controlled Study: Jeong Mi Kim, Sang Soo Kim, Jong Ho Kim, Mi Kyung Kim, Tae Nyun Kim, Soon Hee Lee, Chang Won Lee, Ja Young Park, Eun Sook Kim, Kwang Jae Lee, Young Sik Choi, Duk Kyu Kim, In Joo Kim; Diabetes Metab J. 2020;44(1):67-77. Published online July 11, 2019; DOI: https://doi.org/10.4093/dmj.2018.0274

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Background

There is limited information regarding the optimal third-line therapy for managing type 2 diabetes mellitus (T2DM) that is inadequately controlled using dual combination therapy. This study assessed the efficacy and safety of pioglitazone or glimepiride when added to metformin plus alogliptin treatment for T2DM.

Methods

This multicenter, randomized, active-controlled trial (ClinicalTrials.gov: NCT02426294) recruited 135 Korean patients with T2DM that was inadequately controlled using metformin plus alogliptin. The patients were then randomized to also receive pioglitazone (15 mg/day) or glimepiride (2 mg/day) for a 26-week period, with dose titration was permitted based on the investigator's judgement.

Results

Glycosylated hemoglobin levels exhibited similar significant decreases in both groups during the treatment period (pioglitazone: −0.81%, P<0.001; glimepiride: −1.05%, P<0.001). However, the pioglitazone-treated group exhibited significantly higher high density lipoprotein cholesterol levels (P<0.001) and significantly lower homeostatic model assessment of insulin resistance values (P<0.001). Relative to pioglitazone, adding glimepiride to metformin plus alogliptin markedly increased the risk of hypoglycemia (pioglitazone: 1/69 cases [1.45%], glimepiride: 14/66 cases [21.21%]; P<0.001).

Conclusion

Among patients with T2DM inadequately controlled using metformin plus alogliptin, the addition of pioglitazone provided comparable glycemic control and various benefits (improvements in lipid profiles, insulin resistance, and hypoglycemia risk) relative to the addition of glimepiride.

Citations

Citations to this article as recorded by

Efficacy and Safety of Alogliptin-Pioglitazone Combination for Type 2 Diabetes Mellitus Poorly Controlled with Metformin: A Multicenter, Double-Blind Randomized Trial
Ji-Yeon Park, Joonyub Lee, Yoon-Hee Choi, Kyung Wan Min, Kyung Ah Han, Kyu Jeung Ahn, Soo Lim, Young-Hyun Kim, Chul Woo Ahn, Kyung Mook Choi, Kun-Ho Yoon
Diabetes & Metabolism Journal.2024; 48(5): 915. CrossRef
Efficacy and Safety of Pioglitazone Add-on in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Metformin and Dapagliflozin: A Multicenter, Randomized, Double-blind, and Placebo-controlled Study
Yun Kyung Cho, Kyung-Soo Kim, Byung-Wan Lee, Jun Hwa Hong, Jae Myung Yu, Soo Lim, Ye An Kim, Chang Beom Lee, Sang Soo Kim, Soo Heon Kwak, Woo Je Lee
Clinical Therapeutics.2024; 46(9): 662. CrossRef
Pioglitazone as Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Dapagliflozin and Metformin: Double-Blind, Randomized, Placebo-Controlled Trial
Ji Hye Heo, Kyung Ah Han, Jun Hwa Hong, Hyun-Ae Seo, Eun-Gyoung Hong, Jae Myung Yu, Hye Seung Jung, Bong-Soo Cha
Diabetes & Metabolism Journal.2024; 48(5): 937. CrossRef
A Green Approach: Optimization of the UPLC Method Using DoE Software for Concurrent Quantification of Pioglitazone and Dapagliflozin in a SNEDDS Formulation for the Treatment of Diabetes
Ehab M. Elzayat, Abdelrahman Y. Sherif, Mohamed W. Attwa, Mohammad A. Altamimi
ACS Omega.2024; 9(45): 45011. CrossRef
Cost-effectiveness and budget impact analysis of fixed combination of alogliptin and pioglitazone in the treatment of type 2 diabetes mellitus
Yu.V. Strunina, N.A. Petunina
Medical Technologies. Assessment and Choice.2023; (3): 70. CrossRef
Pioglitazone-Enhanced Brown Fat Whitening Contributes to Weight Gain in Diet-Induced Obese Mice
Piaojian Yu, Wei Wang, Wanrong Guo, Lidan Cheng, Zhiping Wan, Yanglei Cheng, Yunfeng Shen, Fen Xu
Experimental and Clinical Endocrinology & Diabetes.2023; 131(11): 595. CrossRef
Compliance with Cardiovascular Prevention Guidelines in Type 2 Diabetes Individuals in a Middle-Income Region: A Cross-Sectional Analysis
Joaquim Barreto, Beatriz Luchiari, Vaneza L. W. Wolf, Isabella Bonilha, Ticiane G. Bovi, Barbara S. Assato, Ikaro Breder, Sheila T. Kimura-Medorima, Daniel B. Munhoz, Thiago Quinaglia, Otavio R. Coelho-Filho, Luiz Sergio F. Carvalho, Wilson Nadruz, Andrei
Diagnostics.2022; 12(4): 814. CrossRef
Effects of Glimepiride Combined with Recombinant Human Insulin Injection on Serum IGF-1, VEGF and TRACP-5b Oxidative Stress Levels in Patients with Type 2 Diabetes Mellitus
Xue Chen, Sheng Kang, Zeqing Bao, Ciara Hughes
Evidence-Based Complementary and Alternative Medicine.2022; 2022: 1. CrossRef
Glycaemic control with add‐on thiazolidinedione or a sodium‐glucose co‐transporter‐2 inhibitor in patients with type 2 diabetes after the failure of an oral triple antidiabetic regimen: A 24‐week, randomized controlled trial
Jaehyun Bae, Ji Hye Huh, Minyoung Lee, Yong‐Ho Lee, Byung‐Wan Lee
Diabetes, Obesity and Metabolism.2021; 23(2): 609. CrossRef
Development and validation of a sensitive LC-MS/MS method for pioglitazone: application towards pharmacokinetic and tissue distribution study in rats
Kusuma Kumari G., Praveen Thaggikuppe Krishnamurthy, Ravi Kiran Ammu V. V. V., Kurawattimath Vishwanath, S. T. Narenderan, B. Babu, Nagappan Krishnaveni
RSC Advances.2021; 11(19): 11437. CrossRef
Compliance with Cardiovascular Prevention Guidelines in Individuals with Type 2 Diabetes in a Middle-Income Region: Cross-Sectional Analysis
Joaquim Barreto, Beatriz Luchiari, Vaneza Lira W. Wolf, Isabella Bonilha, Ticiane G. Bovi, Barbara S. Assato, Ikaro Breder, Sheila T. Kimura-Medorima, Daniel B. Munhoz, Thiago Quinaglia, Otavio R. Coelho-Filho, Luiz Sérgio Fernandes de Carvalho, Wilson Na
SSRN Electronic Journal .2021;[Epub] CrossRef

Others
Repeated Glucose Deprivation/Reperfusion Induced PC-12 Cell Death through the Involvement of FOXO Transcription Factor: Na Han, You Jeong Kim, Su Min Park, Seung Man Kim, Ji Suk Lee, Hye Sook Jung, Eun Ju Lee, Tae Kyoon Kim, Tae Nyun Kim, Min Jeong Kwon, Soon Hee Lee, Mi-kyung Kim, Byoung Doo Rhee, Jeong Hyun Park; Diabetes Metab J. 2016;40(5):396-405. Published online September 1, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.5.396

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Background

Cognitive impairment and brain damage in diabetes is suggested to be associated with hypoglycemia. The mechanisms of hypoglycemia-induced neural death and apoptosis are not clear and reperfusion injury may be involved. Recent studies show that glucose deprivation/reperfusion induced more neuronal cell death than glucose deprivation itself. The forkhead box O (FOXO) transcription factors are implicated in the regulation of cell apoptosis and survival, but their role in neuronal cells remains unclear. We examined the role of FOXO transcription factors and the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt and apoptosis-related signaling pathways in PC-12 cells exposed to repeated glucose deprivation/reperfusion.

Methods

PC-12 cells were exposed to control (Dulbecco's Modified Eagle Medium [DMEM] containing 25 mM glucose) or glucose deprivation/reperfusion (DMEM with 0 mM glucose for 6 hours and then DMEM with 25 mM glucose for 18 hours) for 5 days. MTT assay and Western blot analysis were performed for cell viability, apoptosis, and the expression of survival signaling pathways. FOXO3/4',6-diamidino-2-phenylindole staining was done to ascertain the involvement of FOXO transcription factors in glucose deprivation/reperfusion conditions.

Results

Compared to PC-12 cells not exposed to hypoglycemia, cells exposed to glucose deprivation/reperfusion showed a reduction of cell viability, decreased expression of phosphorylated Akt and Bcl-2, and an increase of cleaved caspase-3 expression. Of note, FOXO3 protein was localized in the nuclei of glucose deprivation/reperfusion cells but not in the control cells.

Conclusion

Repeated glucose deprivation/reperfusion caused the neuronal cell death. Activated FOXO3 via the PI3K/Akt pathway in repeated glucose deprivation/reperfusion was involved in genes related to apoptosis.

Citations

Citations to this article as recorded by

Banxia Xiexin Decoction Prevents HT22 Cells from High Glucose-induced Neurotoxicity via JNK/SIRT1/Foxo3a Signaling Pathway
Yinli Shi, Pei Sheng, Ming Guo, Kai Chen, Yun Zhao, Xu Wang, Mianhua Wu, Bo Li
Current Computer-Aided Drug Design.2024; 20(6): 911. CrossRef
Predictive factors for the development of diabetes in cancer patients treated with phosphatidylinositol 3-kinase inhibitors
Gyuri Kim, Myungeun Yoo, Min Hee Hong, Byung-Wan Lee, Eun Seok Kang, Bong-Soo Cha, Hye Ryun Kim, Yong-ho Lee, Byoung Chul Cho
Cancer Chemotherapy and Pharmacology.2019; 84(2): 405. CrossRef

Risk Factors Associated with Left Ventricular Diastolic Dysfunction in Type 2 Diabetic Patients without Hypertension: Jung Hyun Noh, Joon Hyung Doh, Sung Yun Lee, Tae Nyun Kim, Hyuk Lee, Hwa Young Song, Jeong Hyun Park, Kyung Soo Ko, Byoung Doo Rhee, Dong Jun Kim; Korean Diabetes J. 2010;34(1):40-46. Published online February 28, 2010; DOI: https://doi.org/10.4093/kdj.2010.34.1.40

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Abstract PDF PubReader

Background

Hypertension and age are recognized as important risk factors for left ventricular (LV) diastolic dysfunction. Some studies have shown that diabetes itself may also be an independent risk factor for LV diastolic dysfunction, although this is controversial. The aim of this study was to determine the factors associated with LV diastolic dysfunction in patients with type 2 diabetes in the absence of hypertension or ischemic heart disease (IHD).

Methods

Participants in this study consisted of 65 type 2 diabetes patients (M : F = 45 : 20; mean age 51 [26 to 76] years; mean body mass index [BMI] 25.0 ± 2.5 kg/m²) without hypertension, heart disease, or renal disease. Individuals with ischemic electrocardiographic changes were excluded. LV diastolic function was evaluated by Doppler echocardiographic studies.

Results

Fifteen patients (23.1%) showed LV diastolic dysfunction on Doppler echocardiographic studies. Patients with LV diastolic dysfunction were older than those without diastolic dysfunction (60.0 ± 2.5 vs. 50.5 ± 1.9 years; P < 0.01). After adjusting for age and sex, BMI was higher (26.6 ± 0.7 vs. 24.6 ± 0.3 kg/m²; P < 0.01) and diabetes duration was longer (9.65 ± 1.48 vs. 4.71 ± 0.78 years; P < 0.01) in patients with LV diastolic dysfunction than in those without diastolic dysfunction. There were no differences in sex, smoking, blood pressure, lipid profiles, hemoglobin A₁C, fasting glucose, fasting insulin, or diabetic microvascular complications between the LV diastolic dysfunction group and the normal diastolic function group. After adjusting for age, sex, and BMI, diabetes duration was found to be independently associated with LV diastolic dysfunction (odds ratio 1.38; confidence interval 1.12 to 1.72; P = 0.003).

Conclusion

These results suggest that diabetes duration may be a risk factor for LV diastolic dysfunction in type 2 diabetic patients without hypertension or IHD.

Citations

Citations to this article as recorded by

Reducing Cardiac Steatosis: Interventions to Improve Diastolic Function: A Narrative Review
Kiyan Heshmat-Ghahdarijani, Roya Modaresi, Sobhan Pourmasjedi, Setayesh Sotoudehnia Korani, Ali Rezazadeh Roudkoli, Razieh Ziaei, Armita Farid, Mehrnaz Salehi, Afshin Heidari, Sina Neshat
Current Problems in Cardiology.2023; 48(8): 101739. CrossRef
Glycemic variability is associated with diastolic dysfunction in patients with type 2 diabetes
Yana Dzhun, Georgy Mankovsky, Nadiya Rudenko, Yevgen Marushko, Yanina Saienko, Borys Mankovsky
Journal of Diabetes and its Complications.2023; 37(11): 108519. CrossRef
Lipids and diastolic dysfunction: Recent evidence and findings
Padideh Daneii, Sina Neshat, Monir Sadat Mirnasiry, Zahra Moghimi, Fatemeh Dehghan Niri, Armita Farid, Setayesh Sotoudehnia Korani, Masood Shekarchizadeh, Kiyan Heshmat-Ghahdarijani
Nutrition, Metabolism and Cardiovascular Diseases.2022; 32(6): 1343. CrossRef
Does diabetes increase the risk of cardiovascular events in patients with negative treadmill stress echocardiography?
So Young Yang, Hui-Jeong Hwang
Endocrine Journal.2022; 69(7): 785. CrossRef
Factors associated with left ventricular diastolic dysfunction in patients with septic shock
Wei-Dong Ge, Feng-Zhi Li, Bang-Chuan Hu, Li-Hong Wang, Ding-Yuan Ren
European Journal of Medical Research.2022;[Epub] CrossRef
An in-depth analysis of glycosylated haemoglobin level, body mass index and left ventricular diastolic dysfunction in patients with type 2 diabetes
Xin Zuo, Xueting Liu, Runtian Chen, Huiting Ou, Jiabao Lai, Youming Zhang, Dewen Yan
BMC Endocrine Disorders.2019;[Epub] CrossRef
Early detection of left ventricular diastolic dysfunction using conventional and speckle tracking echocardiography in a large animal model of metabolic dysfunction
Mark M. P. van den Dorpel, Ilkka Heinonen, Sanne M. Snelder, Hendrik J. Vos, Oana Sorop, Ron T. van Domburg, Daphne Merkus, Dirk J. Duncker, Bas M. van Dalen
The International Journal of Cardiovascular Imaging.2017;[Epub] CrossRef
Risk Factors Associated with Left Ventricular Diastolic Dysfunction in Type 2 Diabetic Patients without Hypertension (Korean Diabetes J 2010;34:40-6)
Dong-Lim Kim
Korean Diabetes Journal.2010; 34(2): 135. CrossRef

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