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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, the Practical Evidence of Antidiabetic Combination Therapy in Korea (PEAK) study investigators
Diabetes Metab J. 2024;48(5):915-928.   Published online April 23, 2024
DOI: https://doi.org/10.4093/dmj.2023.0259
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Guidelines for switching to triple combination therapy directly after monotherapy failure are limited. This study investigated the efficacy, long-term sustainability, and safety of either mono or dual add-on therapy using alogliptin and pioglitazone for patients with type 2 diabetes mellitus (T2DM) who did not achieve their target glycemic range with metformin monotherapy.
Methods
The Practical Evidence of Antidiabetic Combination Therapy in Korea (PEAK) was a multicenter, placebo-controlled, double-blind, randomized trial. A total of 214 participants were randomized to receive alogliptin+pioglitazone (Alo+Pio group, n=70), alogliptin (Alo group, n=75), or pioglitazone (Pio group, n=69). The primary outcome was the difference in glycosylated hemoglobin (HbA1c) levels between the three groups at baseline to 24 weeks. For durability, the achievement of HbA1c levels <7% and <6.5% was compared in each group. The number of adverse events was investigated for safety.
Results
After 24 weeks of treatment, the change of HbA1c in the Alo+Pio, Alo, and Pio groups were –1.38%±0.08%, –1.03%±0.08%, and –0.84%±0.08%, respectively. The Alo+Pio group had significantly lower HbA1c levels than the other groups (P=0.0063, P<0.0001) and had a higher proportion of patients with target HbA1c achievement. In addition, insulin sensitivity and β-cell function, lipid profiles, and other metabolic indicators were also improved. There were no significant safety issues in patients treated with triple combination therapy.
Conclusion
Early combination triple therapy showed better efficacy and durability than the single add-on (dual) therapy. Therefore, combination therapy with metformin, alogliptin, and pioglitazone is a valuable early treatment option for T2DM poorly controlled with metformin monotherapy.
Drug/Regimen
Comparison of Efficacy of Glimepiride, Alogliptin, and Alogliptin-Pioglitazone as the Initial Periods of Therapy in Patients with Poorly Controlled Type 2 Diabetes Mellitus: An Open-Label, Multicenter, Randomized, Controlled Study
Hae Jin Kim, In Kyung Jeong, Kyu Yeon Hur, Soo-Kyung Kim, Jung Hyun Noh, Sung Wan Chun, Eun Seok Kang, Eun-Jung Rhee, Sung Hee Choi
Diabetes Metab J. 2022;46(5):689-700.   Published online March 17, 2022
DOI: https://doi.org/10.4093/dmj.2021.0183
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  • 397 Download
  • 2 Web of Science
  • 2 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
The choice of an optimal oral hypoglycemic agent in the initial treatment periods for type 2 diabetes mellitus (T2DM) patients remains difficult and deliberate. We compared the efficacy and safety of glimepiride (GLIM), alogliptin (ALO), and alogliptin-pioglitazone (ALO-PIO) in poorly controlled T2DM patients with drug-naïve or metformin failure.
Methods
In this three-arm, multicenter, open-label, randomized, controlled trial, poorly controlled T2DM patients were randomized to receive GLIM (n=35), ALO (n=31), or ALO-PIO (n=33) therapy for 24 weeks. The primary endpoint was change in the mean glycosylated hemoglobin (HbA1c) levels at week 24 from baseline. Secondary endpoints were changes in HbA1c level at week 12 from baseline, fasting plasma glucose (FPG) levels, lipid profiles at weeks 12 and 24, and parameters of glycemic variability, assessed by continuous glucose monitoring for 24 weeks.
Results
At weeks 12 and 24, the ALO-PIO group showed significant reduction in HbA1c levels compared to the ALO group (–0.96%±0.17% vs. –0.37%±0.17% at week 12; –1.13%±0.19% vs. –0.18%±0.2% at week 24). The ALO-PIO therapy caused greater reduction in FPG levels and significant increase in high-density lipoprotein cholesterol levels at weeks 12 and 24 than the ALO therapy. Compared to low-dose GLIM therapy, ALO-PIO therapy showed greater improvement in glycemic variability. The adverse events were similar among the three arms.
Conclusion
ALO-PIO combination therapy during the early period exerts better glycemic control than ALO monotherapy and excellency in glycemic variability than low-dose sulfonylurea therapy in uncontrolled, drug-naïve or metformin failed T2DM patients.

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  • A Comprehensive Review on Weight Loss Associated with Anti-Diabetic Medications
    Fatma Haddad, Ghadeer Dokmak, Maryam Bader, Rafik Karaman
    Life.2023; 13(4): 1012.     CrossRef
  • Role of Dipeptidyl Peptidase 4 Inhibitors in Antidiabetic Treatment
    Ruili Yin, Yongsong Xu, Xin Wang, Longyan Yang, Dong Zhao
    Molecules.2022; 27(10): 3055.     CrossRef
Increased Risk of Hospitalization for Heart Failure with Newly Prescribed Dipeptidyl Peptidase-4 Inhibitors and Pioglitazone Using the Korean Health Insurance Claims Database
Sunghwan Suh, Gi Hyeon Seo, Chang Hee Jung, Mee-Kyoung Kim, Sang-Man Jin, You-Cheol Hwang, Byung-Wan Lee, Jae Hyeon Kim
Diabetes Metab J. 2015;39(3):247-252.   Published online April 22, 2015
DOI: https://doi.org/10.4093/dmj.2015.39.3.247
  • 4,615 View
  • 37 Download
  • 20 Web of Science
  • 18 Crossref
AbstractAbstract PDFPubReader   
Background

We assessed the association of dipeptidyl peptidase 4 inhibitors (DPP4i) with hospitalization for heart failure (HF) using the Korean Health Insurance claims database.

Methods

We collected data on newly prescribed sitagliptin, vildagliptin, and pioglitazone between January 1, 2009 and December 31, 2012 (mean follow-up of 336.8 days) to 935,519 patients with diabetes (518,614 males and 416,905 females) aged 40 to 79 years (mean age of 59.4 years).

Results

During the study, 998 patients were hospitalized for primary HF (115.7 per 100,000 patient-years). The incidence rate of hospitalization for HF was 117.7 per 100,000 per patient-years among patients on pioglitazone, 105.7 for sitagliptin, and 135.8 for vildagliptin. The hospitalization rate for HF was greatest in the first 30 days after starting the medication, which corresponded to a significantly higher incidence at days 0 to 30 compared with days 31 to 360 for all three drugs. The hazard ratios were 1.85 (pioglitazone), 2.00 (sitagliptin), and 1.79 (vildagliptin). The incidence of hospitalization for HF did not differ between the drugs for any time period.

Conclusion

This study showed an increase in hospitalization for HF in the initial 30 days of the DPP4i and pioglitazone compared with the subsequent follow-up period. However, the differences between the drugs were not significant.

Citations

Citations to this article as recorded by  
  • Cardioprotective effects of dipeptidyl peptidase-4 inhibitors versus sulfonylureas in addition to metformin: A nationwide cohort study of patients with type 2 diabetes
    Jui Wang, Hon-Yen Wu, Kuo-Liong Chien
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    Korean Circulation Journal.2018; 48(5): 395.     CrossRef
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    Milton Packer
    JACC: Heart Failure.2018; 6(6): 445.     CrossRef
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    Milton Packer
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    Hyouk-Jun Chin, Jin Hyun Nam, Eui-Kyung Lee, Ju-Young Shin
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    Nattayaporn Apaijai, Tharnwimol Inthachai, Suree Lekawanvijit, Siriporn C Chattipakorn, Nipon Chattipakorn
    Journal of Endocrinology.2016; 229(3): 245.     CrossRef
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    Christos V. Rizos, Anastazia Kei, Moses S. Elisaf
    Archives of Toxicology.2016; 90(8): 1861.     CrossRef
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    Dae Ho Lee
    Diabetes & Metabolism Journal.2015; 39(4): 348.     CrossRef
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    Sunghwan Suh, Gi Hyeon Seo, Chang Hee Jung, Mee-Kyoung Kim, Sang-Man Jin, You-Cheol Hwang, Byung-Wan Lee, Jae Hyeon Kim
    Diabetes & Metabolism Journal.2015; 39(4): 350.     CrossRef
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Glycemic Effectiveness of Metformin-Based Dual-Combination Therapies with Sulphonylurea, Pioglitazone, or DPP4-Inhibitor in Drug-Naïve Korean Type 2 Diabetic Patients
Young Ki Lee, Sun Ok Song, Kwang Joon Kim, Yongin Cho, Younjeong Choi, Yujung Yun, Byung-Wan Lee, Eun-Seok Kang, Bong Soo Cha, Hyun Chul Lee
Diabetes Metab J. 2013;37(6):465-474.   Published online December 12, 2013
DOI: https://doi.org/10.4093/dmj.2013.37.6.465
  • 5,991 View
  • 79 Download
  • 18 Crossref
AbstractAbstract PDFPubReader   
Background

This study compared the glycemic effectiveness of three metformin-based dual therapies according to baseline hemoglobin A1c (HbA1c) to evaluate the appropriateness of the guideline enforced by the National Health Insurance Corporation of Korea for initial medication of type 2 diabetes (T2D).

Methods

This prospective observational study was conducted across 24 weeks for drug-naïve Korean T2D patients with HbA1c greater than 7.5%. Subjects were first divided into three groups based on the agent combined with metformin (group 1, gliclazide-modified release or glimepiride; group 2, pioglitazone; group 3, sitagliptin). Subjects were also classified into three categories according to baseline HbA1c (category I, 7.5%≤HbA1c<9.0%; category II, 9.0%≤HbA1c<11.0%; category III, 11.0%≤HbA1c).

Results

Among 116 subjects, 99 subjects completed the study, with 88 subjects maintaining the initial medication. While each of the metformin-based dual therapies showed a significant decrease in HbA1c (group 1, 8.9% to 6.4%; group 2, 9.0% to 6.6%; group 3, 9.3% to 6.3%; P<0.001 for each), there was no significant difference in the magnitude of HbA1c change among the groups. While the three HbA1c categories showed significantly different baseline HbA1c levels (8.2% vs. 9.9% vs. 11.9%; P<0.001), endpoint HbA1c was not different (6.4% vs. 6.6% vs. 6.0%; P=0.051).

Conclusion

The three dual therapies using a combination of metformin and either sulfonylurea, pioglitazone, or sitagliptin showed similar glycemic effectiveness among drug-naïve Korean T2D patients. In addition, these regimens were similarly effective across a wide range of baseline HbA1c levels.

Citations

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    Elena Filipova, Katya Uzunova, Krassimir Kalinov, Toni Vekov
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The Risk of Bladder Cancer in Korean Diabetic Subjects Treated with Pioglitazone
Sun Ok Song, Kwang Joon Kim, Byung-Wan Lee, Eun Seok Kang, Bong Soo Cha, Hyun Chul Lee
Diabetes Metab J. 2012;36(5):371-378.   Published online October 18, 2012
DOI: https://doi.org/10.4093/dmj.2012.36.5.371
  • 4,993 View
  • 34 Download
  • 30 Crossref
AbstractAbstract PDFPubReader   
Background

There is growing concern regarding the increased incidence of bladder cancer in diabetic patients using pioglitazone. This study aimed to investigate the association between bladder cancer and the use of pioglitazone in Korean diabetics.

Methods

This retrospective, matched case-control study included a case group (n=329) of diabetic patients with bladder cancer who presented at the Severance Hospital from November 2005 to June 2011. The control group consisted of patients without bladder cancer (1:2 ratio matching for sex and age, n=658) who were listed on the Severance Hospital diabetes registry.

Results

The percentage of subjects who had ever used pioglitazone was significantly lower in the case group than in the control group (6.4% vs. 15.0%, P<0.001). Multivariate conditional logistic analysis revealed that independent factors affecting bladder cancer were smoking (odds ratio [OR], 11.64; 95% confidence interval [CI], 6.56 to 20.66; P<0.001), coexisting cancer (OR, 6.11; 95% CI, 2.25 to 16.63; P<0.001), and hemoglobin levels (OR, 0.78; 95% CI, 0.69 to 0.88; P<0.001). The OR of the history of pioglitazone use was 2.09 and was not significantly different between the two groups (95% CI, 0.26 to 16.81; P=0.488).

Conclusion

A relationship between pioglitazone use and incidence of bladder cancer was not observed in Korean diabetic patients. This suggests that the risk for bladder cancer in Korean diabetic subjects treated with pioglitazone might be different from that of Caucasian populations. Large-scale, well-designed and multi-center studies are needed to further evaluate this relationship.

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    Elena Filipova, Katya Uzunova, Krassimir Kalinov, Toni Vekov
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    E. Erdmann, S. Harding, H. Lam, A. Perez
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Long-term Effect of Pioglitazone Treatment in Patients with Type 2 Diabetes.
Jae Hoon Moon, Hye Jin Kim, Soo Kyung Kim, Wan Sub Shim, Eun Seuk Kang, Yumie Rhee, Chul Woo Ahn, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee, Bong Soo Cha
Korean Diabetes J. 2006;30(4):264-276.   Published online July 1, 2006
DOI: https://doi.org/10.4093/jkda.2006.30.4.264
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AbstractAbstract PDF
BACKGROUND
Type 2 diabetes is characterized by impaired insulin secretion and/or insulin resistance. Thiazolidinediones have been shown to ameliorate insulin resistance. The purpose of the present study was to evaluate the long term serial effect of pioglitazone on anthropometrics and metabolic parameters in Korean type 2 diabetes patients. METHODS: One hundred thirteen type 2 diabetes patients (male, 67; female, 46; mean age, 49.1+/-10.8 years) were evaluated before and after 3 months, 6 months and 12 months of treatment with pioglitazone (Actos(TM), 15 mg/day). Anthropometric parameters and metabolic variables were measured. RESULTS: Body weight and body mass index (BMI) were increased in 3 months after pioglitazone treatment (body weight, 68.8+/-12.2 vs 69.8+/-11.9 kg, P < 0.01) without further increase. In women, body weight and BMI tended to increase more (body weight change after 3 months, 0.6+/-1.7 kg vs 1.6+/-1.7 kg, P < 0.01) and longer (3 months vs 6 months) than in men. Fasting plasma glucose (FPG) and HbA1c were decreased in 3 months after pioglitazone treatment (FPG, 7.97+/-2.29 vs 6.94+/-2.01 mmol/L, P < 0.01; HbA1c, 7.7+/-1.5 vs 7.0+/-1.1%, P < 0.01). Hypoglycemic effect of pioglitazone was prominent in women than in men (FPG change after 12 months, -1.80+/-2.54 vs -0.09+/-1.72 mmol/L, P < 0.001; HbA1c change after 12 months, -0.9+/-1.3 vs -0.4+/-1.1%, P < 0.05). Serum high-density lipoprotein cholesterol was increased after 3 months of pioglitazone treatment (1.16+/-0.24 vs 1.31+/-0.28 mmol/L, P < 0.01) without return until the end of this study. Serum triglycerides level decreased at 3 months (basal vs 3 months, 2.29+/-1.86 vs 1.88+/-1.21 mmol/L, P < 0.01) and 6 months (basal vs 6 months, 2.29+/-1.86 vs 1.97+/-1.40 mmol/L, P < 0.05) of pioglitazone treatment, but returned to basal level at 12 months. Liver enzyme, especially serum alanine transferase level decreased after 3 months of pioglitazone treatment (30.8+/-23.7 vs 24.5+/-18.5 IU/L, P < 0.01) without return until the end of this study. Hypoglycemic effect of pioglitazone was associated with basal BMI, fat contents and serum leptin level. CONCLUSION: Korean type 2 diabetes patients with pioglitazone use showed favorable metabolic effect for glycemic control, lipid metabolism and liverfunction, but pioglitazone induced body weight increase may be limited.

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  • Therapeutic Effect of Quadruple Oral Hypoglycemic Agents in Patients with Type 2 Diabetes Mellitus Who Have Insulin Limitations
    Won Sang Yoo, Do Hee Kim, Hee Jin Kim, Hyun Kyung Chung
    The Journal of Korean Diabetes.2019; 20(2): 117.     CrossRef
Effects of Pioglitazone on Cerebral Hemodynamics in Patients of Type 2 Diabetes.
Jong Suk Park, You Jung Lee, Chul Sik Kim, Hai Jin Kim, Jina Park, Chul Woo Ahn, Kyung Yul Lee, Hyeong Jin Kim, Young Jun Won, Hun Ju Ha, Hae Sun Kwak, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee
Korean Diabetes J. 2006;30(2):96-103.   Published online March 1, 2006
DOI: https://doi.org/10.4093/jkda.2006.30.2.96
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AbstractAbstract PDF
BACKGROUND
Atherosclerosis is one of the major causes of morbidity and mortality in patients with type 2 diabetes and pioglitazone has been reported to have antiatherogenic effect. The aim of this study was to investigate whether pioglitazone affects carotid intima-media thickness (IMT) and pulsatility index (PI) in type 2 diabetic patients. METHODS: A total of 40 type 2 diabetic patients were included and divided into two groups: the pioglitazone-treated group (pioglitazone 15 mg/day with gliclazide 80~320 mg/day for 12 weeks) (n = 20) and control group (gliclazide 80~320 mg/day for 12 weeks) (n = 20). The changes in lipid profile, insulin resistance, IMT, and PI were monitored to determine that pioglitazone improves cerebrovascular blood flow. RESULTS: The pioglitazone treatment significantly increased HDL-C, reduced triglyceride, insulin resistance and PI. IMT tended to decrease but the change was not significant. This study revealed that treatment with pioglitazone was associated with the improvement of cerebrovascular blood flow. CONCLUSIONS: Pioglitazone appears to be effective for the improvement of cerebrovascular blood flow in type 2 diabetic patients

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