Diabetes & Metabolism Journal

Original Articles

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

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

Clinical Diabetes & Therapeutics
Additional Effect of Dietary Fiber in Patients with Type 2 Diabetes Mellitus Using Metformin and Sulfonylurea: An Open-Label, Pilot Trial: Seung-Eun Lee, Yongbin Choi, Ji Eun Jun, You-Bin Lee, Sang-Man Jin, Kyu Yeon Hur, Gwang Pyo Ko, Moon-Kyu Lee; Diabetes Metab J. 2019;43(4):422-431. Published online April 23, 2019; DOI: https://doi.org/10.4093/dmj.2018.0090

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Abstract PDF PubReader

Background

Metformin, sulfonylurea, and dietary fiber are known to affect gut microbiota in patients with type 2 diabetes mellitus (T2DM). This open and single-arm pilot trial investigated the effects of the additional use of fiber on glycemic parameters, insulin, incretins, and microbiota in patients with T2DM who had been treated with metformin and sulfonylurea.

Methods

Participants took fiber for 4 weeks and stopped for the next 4 weeks. Glycemic parameters, insulin, incretins during mixed-meal tolerance test (MMTT), lipopolysaccharide (LPS) level, and fecal microbiota were analyzed at weeks 0, 4, and 8. The first tertile of difference in glucose area under the curve during MMTT between weeks 0 and 4 was defined as ‘responders’ and the third as ‘nonresponders,’ respectively.

Results

In all 10 participants, the peak incretin levels during MMTT were higher and LPS were lower at week 4 as compared with at baseline. While the insulin sensitivity of the ‘responders’ increased at week 4, that of the ‘nonresponders’ showed opposite results. However, the results were not statistically significant. In all participants, metabolically unfavorable microbiota decreased at week 4 and were restored at week 8. At baseline, metabolically hostile bacteria were more abundant in the ‘nonresponders.’ In ‘responders,’ Roseburia intestinalis increased at week 4.

Conclusion

While dietary fiber did not induce additional changes in glycemic parameters, it showed a trend of improvement in insulin sensitivity in ‘responders.’ Even if patients are already receiving diabetes treatment, the additional administration of fiber can lead to additional benefits in the treatment of diabetes.

Citations

Citations to this article as recorded by

The effects of prebiotics on gastrointestinal side effects of metformin in youth: A pilot randomized control trial in youth-onset type 2 diabetes
Sydney A. Dixon, Sidharth Mishra, Katrina B. Dietsche, Shalini Jain, Lilian Mabundo, Michael Stagliano, Andrea Krenek, Amber Courville, Shanna Yang, Sara A. Turner, Abby G. Meyers, Doris E. Estrada, Hariom Yadav, Stephanie T. Chung
Frontiers in Endocrinology.2023;[Epub] CrossRef
The impact of dietary, surgical, and pharmacological interventions on gut microbiota in individuals with diabetes mellitus: A systematic review
Patricia M. Bock, Andreza F. Martins, Rafaela Ramalho, Gabriela H. Telo, Gabriel Leivas, Clara K. Maraschin, Beatriz D. Schaan
Diabetes Research and Clinical Practice.2022; 189: 109944. CrossRef
Assessment of the safety and probiotic properties of Roseburia intestinalis: A potential “Next Generation Probiotic”
Chao Zhang, Kejia Ma, Kai Nie, Minzi Deng, Weiwei Luo, Xing Wu, Yujun Huang, Xiaoyan Wang
Frontiers in Microbiology.2022;[Epub] CrossRef
The Effect of Prebiotics and Oral Anti-Diabetic Agents on Gut Microbiome in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis of Randomised Controlled Trials
Omorogieva Ojo, Xiaohua Wang, Osarhumwese Osaretin Ojo, Joanne Brooke, Yiqing Jiang, Qingqing Dong, Trevor Thompson
Nutrients.2022; 14(23): 5139. CrossRef
The Effect of Dietary Interventions on Chronic Inflammatory Diseases in Relation to the Microbiome: A Systematic Review
Carlijn A. Wagenaar, Marieke van de Put, Michelle Bisschops, Wendy Walrabenstein, Catharina S. de Jonge, Hilde Herrema, Dirkjan van Schaardenburg
Nutrients.2021; 13(9): 3208. CrossRef
The Role of Dietary Fibre in Modulating Gut Microbiota Dysbiosis in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomised Controlled Trials
Omorogieva Ojo, Qian-Qian Feng, Osarhumwese Osaretin Ojo, Xiao-Hua Wang
Nutrients.2020; 12(11): 3239. CrossRef
High Fiber and Beta Carotene from Sweet Potatoes and Pumpkin Improve Insulin Resistance by Inhibition of Sterol Regulatory Binding Protein 1c in Liver of Hypertriglyceridemic Rats
Sunarti Sunarti, Umar Santoso, Abrory Agus Cahya Pramana, Emy Huriyati, Dianandha Septiana Rubi
Open Access Macedonian Journal of Medical Sciences.2020; 8(A): 898. CrossRef

Clinical Care/Education
Clinical Characteristics and Metabolic Predictors of Rapid Responders to Dipeptidyl Peptidase-4 Inhibitor as an Add-on Therapy to Sulfonylurea and Metformin: Ye An Kim, Won Sang Yoo, Eun Shil Hong, Eu Jeong Ku, Kyeong Seon Park, Soo Lim, Young Min Cho, Kyong Soo Park, Hak Chul Jang, Sung Hee Choi; Diabetes Metab J. 2015;39(6):489-497. Published online November 27, 2015; DOI: https://doi.org/10.4093/dmj.2015.39.6.489

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Abstract PDF PubReader

Background

Dipeptidyl peptidase-4 (DPP-4) inhibitor add-on therapy is a new option for patients with inadequately controlled type 2 diabetes who are taking combined metformin and sulfonylurea (SU). We evaluated the efficacy and safety of this triple therapy and the characteristics of rapid responders and hypoglycemia-prone patients.

Methods

We included 807 patients with type 2 diabetes who were prescribed a newly added DPP-4 inhibitor to ongoing metformin and SU in 2009 to 2011. Glycemia and other metabolic parameters at baseline, 12, 24, and 52 weeks, as well as episodes of hypoglycemia were analyzed. Rapid responders were defined as patients with ≥25% reduction in glycosylated hemoglobin (HbA1c) within 12 weeks.

Results

At baseline, while on the submaximal metformin and SU combination, the mean HbA1c level was 8.4%. Twelve weeks after initiation of DPP-4 inhibitor add-on, 269 patients (34.4%) achieved an HbA1c level ≤7%. Sixty-six patients (8.2%, 47 men) were rapid responders. The duration of diabetes was shorter in rapid responders, and their baseline fasting plasma glucose (FPG), HbA1c, C-peptide, and homeostasis model assessment of insulin resistance were significantly higher. Patients who experienced hypoglycemia after taking DPP-4 inhibitor add-on were more likely to be female, to have a lower body weight and lower triglyceride and FPG levels, and to have higher homeostasis model assessment of β-cells.

Conclusion

An oral hypoglycemic triple agent combination including a DPP-4 inhibitor was effective in patients with uncontrolled diabetes. Proactive dose reduction of SU should be considered when a DPP-4 inhibitor is added for rapid responders and hypoglycemia-prone patients.

Citations

Citations to this article as recorded by

A genetic variant in GLP1R is associated with response to DPP-4 inhibitors in patients with type 2 diabetes
Eugene Han, Hye Sun Park, Obin Kwon, Eun Yeong Choe, Hye Jin Wang, Yong-ho Lee, Sang-Hak Lee, Chul Hoon Kim, Lee-Kyung Kim, Soo Heon Kwak, Kyong Soo Park, Chul Sik Kim, Eun Seok Kang
Medicine.2016; 95(44): e5155. CrossRef

Effects of Sulfonylureas on Peroxisome Proliferator-Activated Receptor γ Activity and on Glucose Uptake by Thiazolidinediones: Kyeong Won Lee, Yun Hyi Ku, Min Kim, Byung Yong Ahn, Sung Soo Chung, Kyong Soo Park; Diabetes Metab J. 2011;35(4):340-347. Published online August 31, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.4.340

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20 Crossref

Abstract PDF PubReader

Background

Sulfonylurea primarily stimulates insulin secretion by binding to its receptor on the pancreatic β-cells. Recent studies have suggested that sulfonylureas induce insulin sensitivity through peroxisome proliferator-activated receptor γ (PPARγ), one of the nuclear receptors. In this study, we investigated the effects of sulfonylurea on PPARγ transcriptional activity and on the glucose uptake via PPARγ.

Methods

Transcription reporter assays using Cos7 cells were performed to determine if specific sulfonylureas stimulate PPARγ transactivation. Glimepiride, gliquidone, and glipizide (1 to 500 µM) were used as treatment, and rosiglitazone at 1 and 10 µM was used as a control. The effects of sulfonylurea and rosiglitazone treatments on the transcriptional activity of endogenous PPARγ were observed. In addition, 3T3-L1 adipocytes were treated with rosiglitazone (10 µM), glimepiride (100 µM) or both to verify the effect of glimepiride on rosiglitazone-induced glucose uptake.

Results

Sulfonylureas, including glimepiride, gliquidone and glipizide, increased PPARγ transcriptional activity, gliquidone being the most potent PPARγ agonist. However, no additive effects were observed in the presence of rosiglitazone. When rosiglitazone was co-treated with glimepiride, PPARγ transcriptional activity and glucose uptake were reduced compared to those after treatment with rosiglitazone alone. This competitive effect of glimepiride was observed only at high concentrations that are not achieved with clinical doses.

Conclusion

Sulfonylureas like glimepiride, gliquidone and glipizide increased the transcriptional activity of PPARγ. Also, glimepiride was able to reduce the effect of rosiglitazone on PPARγ agonistic activity and glucose uptake. However, the competitive effect does not seem to occur at clinically feasible concentrations.

Citations

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Ayesha Fauzi, Ewen Se Thoe, Tang Yin Quan, Adeline Chia Yoke Yin
Journal of Diabetes and its Complications.2023; 37(11): 108629. CrossRef
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Mika E. A. Berg, Jette-Britt Naams, Laura C. Hautala, Tuomas A. Tolvanen, Jari P. Ahonen, Sanna Lehtonen, Kristiina Wähälä
ACS Omega.2020; 5(3): 1430. CrossRef
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