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Tian M, Ye L, Liang B, Chen Y, Mei J, Zhao Z, Guo X, Xu M, Zhang J, Yang S. Pharmacokinetics and Bioequivalence of 2 Oral Formulations of Vildagliptin in Healthy Chinese Subjects. Clin Pharmacol Drug Dev 2025; 14:154-160. [PMID: 39444294 DOI: 10.1002/cpdd.1482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 10/07/2024] [Indexed: 10/25/2024]
Abstract
A randomized, open-label, 2-period, 2-sequence crossover study was conducted to evaluate the pharmacokinetics and bioequivalence of 2 oral formulations of vildagliptin tablets under both fasting and fed conditions in healthy Chinese subjects. A total of 56 healthy subjects were randomized to receive a single 50-mg dose of either a generic vildagliptin tablet (T) or the reference formulation (R). The washout period was 3 days. Blood samples were collected up to 24 hours postdosing during each period and analyzed for vildagliptin using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The 90% confidence intervals for the geometric mean ratios (T:R) of maximum serum concentration, area under the serum concentration-time curve from time 0 to the last measurable concentration, and area under the serum concentration-time curve from time 0 to infinity were all within the predefined bioequivalence range of 80%-125%. This indicates that the generic and reference formulations are bioequivalent under both fasting and fed states. All adverse events reported were mild and transient. High-fat meals delayed absorption and reduced the maximum peak concentration of both formulations; however, they did not affect the overall exposure. Therefore, vildagliptin can be taken without regard to meals.
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Affiliation(s)
- Mengli Tian
- Department of Pharmacy, Clinical Trial Center, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, China
| | - Libing Ye
- Department of Pharmacy, Clinical Trial Center, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, China
| | - Binhong Liang
- Zhejiang Huahai Pharmaceutical Co., Ltd., Linhai, Zhejiang, China
| | - Yingrong Chen
- Department of Pharmacy, Clinical Trial Center, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, China
| | - Jue Mei
- Department of Pharmacy, Clinical Trial Center, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, China
| | - Zhouming Zhao
- Zhejiang Huahai Pharmaceutical Co., Ltd., Linhai, Zhejiang, China
| | - Xiaodi Guo
- Zhejiang Huahai Pharmaceutical Co., Ltd., Linhai, Zhejiang, China
| | - Min Xu
- Department of Pharmacy, Clinical Trial Center, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, China
| | - Jingyao Zhang
- Chengdu Finelyse Pharmaceutical Technology Co., Ltd., Sichuan, China
| | - Shuixin Yang
- Department of Pharmacy, Clinical Trial Center, Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang, China
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Хамнуева ЛЮ, Андреева ЛС. [Efficacy of treatment with glucagon-like peptide receptor agonists-1 in Asian patients with type 2 diabetes mellitus]. PROBLEMY ENDOKRINOLOGII 2023; 69:38-46. [PMID: 37448270 PMCID: PMC10204790 DOI: 10.14341/probl13245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/17/2023] [Accepted: 02/19/2023] [Indexed: 07/15/2023]
Abstract
BACKGROUND The projected 68% increase in patients with type 2 diabetes mellitus (T2D) in the upcoming decades and the specific pathophysiological course of the disease are critical factors for the development of optimal disease management tactics in the Asian population. It is now known that β-cell dysfunction is dominant in the pathogenesis of T2D in Asians. In a number of Asian countries, incretin therapy is the leading therapy. AIM To review literature on glucagon-like peptide-1 (GLP-1) secretion and clinical trial results of GLP-1 receptor agonist class (GLP-1RA) drugs as well as to evaluate their effectiveness in Asian population with T2D. MATERIALS AND METHODS A review of studies on pathophysiological aspects of GLP-1 secretion and evaluation of the efficacy of therapy with GLP-1RA preparations registered and used in clinical practice in Asian regions. RESULTS Several studies in Asian countries have shown that intact GLP-1 levels were significantly lower in both T2D patients and healthy Japanese volunteers; as well as in patients with impaired glucose tolerance. It is suggested that either impaired secretion of GLP-1 in the gut, accelerated processing by dipeptidyl peptidase-4, or a combination of both are responsible for the decrease in GLP-1. The greater efficacy of GLP-1RA treatment in achieving glycemic control in Asian T2D patients was presented by Kim Y.G. et al. in a meta-analysis of 15 randomised controlled trials, the reduction in HbA1c on GLP-1RA treatment averaged -1.16% in Asian-dominated studies and -0.83% in non-Asian-dominated studies. In the PIONEER 9 clinical programme, similar results were obtained, with oral semaglutide having a more pronounced effect on glycaemic control in Japanese patients. Thus, the mean change in HbA 1c was -1.1%, 7 mg -1.5%, and 14 mg -1.7% at the 3 mg dose; whereas in the PIONEER 1 study in the global population, the mean change in HbA1c was -0.6%, -0.9% and -1.1% for 3, 7, 14 mg semaglutide, respectively. The PIONEER 10 study concluded that oral semaglutide was well tolerated by Japanese patients with T2D. Oral semaglutide reduced HbA1c (14 mg dose) and body weight (7 and 14 mg doses) more significantly compared to dulaglutide at 0.75 mg dose. Results of a pooled analysis of long-acting GLP-1RA showed a more significant reduction in cardiovascular event risk in the Asian subpopulation. CONCLUSION The presented review describes benefits in glycemic control as well as in the reduction of relative cardiovascular event risks with GLP-1RA treatment in the Asian population, which requires further in-depth research and implies optimal management tactics in patients with T2DM.
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Chawla M, Chawla P, Jethwani P, Shah K, Reddy S. Metformin Sustained-Release and Vildagliptin Fixed-Dose Combination for Optimizing Glycemic Control: A Review with Real-World Case Reports. Clin Pract 2023. [DOI: 10.3390/clinpract13020045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/30/2023] Open
Abstract
(1) Background: There is a high burden of poor glycemic control in the Indian population with type 2 diabetes mellitus (T2DM). Currently, the use of metformin sustained-release (SR)–vildagliptin fixed-dose combination (FDC) is very low as compared to metformin immediate-release (IR)–vildagliptin FDC which is associated with higher adverse events (AEs). Here, we present real-world effectiveness of metformin SR–vildagliptin FDC treatment in patients with T2DM; (2) Methods: This retrospective analysis was carried out from the medical records of adult T2DM patients visiting a single study center in India (December 2020–February 2021). A total of 10 patients (aged ≥20 years) were treated with vildagliptin 50 mg and metformin SR 500 mg FDC for 15 days. The treatment response was assessed by the percentage of time spent in the target glucose range (TIR at baseline and 15 days after treatment); (3) Results: The glycated hemoglobin (HbA1c) levels at baseline varied between 6.5% to 12%. The glycemic control improved in 70% of patients (mean increase in TIR: 18.9%). Treatment adherence was 100%. No gastrointestinal symptoms or AEs were reported; (4) Conclusions: Early intervention with metformin SR–vildagliptin FDC in patients with T2DM can ensure therapy compliance in terms of superior efficacy along with safety and tolerability. Key summary points: Early initiation of combination therapy helps in early achievement of glycemic goals; Early initiation of metformin and vildagliptin FDC results in significant glycemic control with good tolerability and compliance; Metformin SR–vildagliptin FDC has lower adverse events, compared to metformin IR–vildagliptin FDC; A case series of ten patients with T2DM treated with metformin SR–vildagliptin FDC is presented to assess the real-world effectiveness of this combination.
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Development, validation and application of a liquid chromatography-tandem mass spectrometry method for the activity and inhibition of DPP-4. Bioanalysis 2022; 14:369-378. [PMID: 35249375 DOI: 10.4155/bio-2022-0004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background: Inhibition of the enzyme dipeptidyl peptidase 4 (DPP-4) is a pharmaceutical treatment for type 2 diabetes. To demonstrate bioequivalence of enzyme inhibition of a new dosage form of the inhibitor vildagliptin, a method for enzyme activity was developed, validated and applied using liquid chromatography and tandem mass spectrometry (LC-MS/MS). Results: The method was validated fit for purpose, including accuracy, precision as well as the stability of the activity and the inhibition of DPP-4 in human plasma. Conclusion: A method for the determination of the activity and inhibition of DPP-4 was developed using LC-MS/MS readout; the characteristics and performance of the method met predefined acceptance criteria and were fit for the purpose of a bioequivalence clinical trial.
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Nishimura R, Taniguchi M, Takeshima T, Iwasaki K. Efficacy and Safety of Metformin Versus the Other Oral Antidiabetic Drugs in Japanese Type 2 Diabetes Patients: A Network Meta-analysis. Adv Ther 2022; 39:632-654. [PMID: 34846709 PMCID: PMC8799586 DOI: 10.1007/s12325-021-01979-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 10/21/2021] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Although metformin is recommended as a first-line treatment for patients with type 2 diabetes (T2D) in Western countries, no specific treatment is recommended in Japan, and various agents are used. Metformin has long been used at low doses in Japan, and information regarding its effect at the maximum maintenance dose is lacking. Here, we compared the efficacy and safety of metformin at 1500 mg/day with those of the other oral anti-diabetic drugs (OADs) approved in Japan. METHODS Randomized controlled trials comparing a change in hemoglobin A1c (HbA1c) from baseline at 12 weeks or later (ΔHbA1c) among OADs (including placebo) as a first-line treatment in adult patients with T2D were selected by systematic review with comprehensive searching of CENTRAL, MEDLINE, Ichushi Web, and EMBASE and manual searching of clinical trial registries. The ΔHbA1c and incidence of hypoglycemia were compared among OAD treatments using Bayesian network meta-analysis (NMA). The relative risk (RR) of the incidence of hypoglycemia was determined relative to that of placebo. RESULTS Forty-six randomized controlled trials were identified in the systematic review, and 37 studies, comprising 38 different types of treatments, including placebos, were selected for the NMA of ΔHbA1c. Compared with metformin 1500 mg/day, 20 OAD treatments were significantly less effective in reducing HbA1c from baseline (differences from metformin 1500 mg/day: 0.40-0.96%). Two treatments (glimepiride 2 mg/day and pioglitazone 45 mg/day) showed greater mean reductions in HbA1c from baseline than metformin 1500 mg/day (- 0.38% and - 0.03%), although these differences were not significant. Regarding the incidence of hypoglycemia, only pioglitazone 30 mg/day among 31 treatments showed a lower RR (< - 0.01), whereas 23 treatments showed a significantly higher RR (1.02-66.71) than metformin 1500 mg/day. CONCLUSION The NMA suggested a preferable efficacy and safety profile of metformin 1500 mg/day compared with the other OADs approved in Japan.
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Affiliation(s)
- Rimei Nishimura
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo, Japan
| | - Mayumi Taniguchi
- Medical Affairs, Sumitomo Dainippon Pharma Co., Ltd., 1-13-1, Kyobashi, Chuo-ku, Tokyo, Japan.
| | - Tomomi Takeshima
- Milliman Inc., 8F, Kojimachi 1-chome Building, 1-6-2 Kojimachi, Chiyoda-ku, Tokyo, Japan
| | - Kosuke Iwasaki
- Milliman Inc., 8F, Kojimachi 1-chome Building, 1-6-2 Kojimachi, Chiyoda-ku, Tokyo, Japan
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Chai S, Zhang R, Zhang Y, Carr RD, Zheng Y, Rajpathak S, Ji L. Effect of dipeptidyl peptidase-4 inhibitors on postprandial glucagon level in patients with type 2 diabetes mellitus: A systemic review and meta-analysis. Front Endocrinol (Lausanne) 2022; 13:994944. [PMID: 36313782 PMCID: PMC9597445 DOI: 10.3389/fendo.2022.994944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 09/21/2022] [Indexed: 11/13/2022] Open
Abstract
AIMS Hyperglucagonemia occurs in the pathogenesis of type 2 diabetes mellitus (T2DM). In this meta-analysis, we summarized the effects of DPP4 inhibitors on glucagon levels in patients with T2DM. MATERIALS AND METHODS Randomized controlled trials (RCTs) comparing the influence of DPP4 inhibitors on circulating glucagon levels with placebo or other oral antidiabetic drugs (OADs) in patients with T2DM were identified by searches of Medline (PubMed), Embase (Ovid), and CENTER (Cochrane Library). Only studies reporting changes in glucagon level presented as total area under the curve (AUCglucagon) using a meal or oral glucose tolerance test were included. Results were combined using a random-effects model that incorporated potential heterogeneity among the included studies. RESULTS A total of 36 RCTs with moderate to high quality were included. Overall, the numbers of T2DM patients included for the meta-analyses comparing DPP4 inhibitors with placebo and other OADs were 4266 and 1652, respectively. Compared to placebo, DPP4 inhibitors significantly reduced circulating glucagon levels (standard mean difference [SMD]: -0.32, 95% CI: -0.40 to -0.24, P<0.001; I2 = 28%). Analysis of subgroups revealed that study characteristics had no significant effect on results, such as study design (parallel group or crossover), number of patients, mean patient age, proportion of men, baseline HbA1c, duration of diabetes, background therapy, treatment duration, or methods for glucagon measurement (all P for subgroup differences >0.05). Moreover, DPP4 inhibitors significantly reduced glucagon levels compared to other OADs (SMD: -0.35, 95% CI: -0.53 to -0.16, P<0.001; I2 = 66%), and the reduction in glucagon was greater in comparison with insulin secretagogues than in comparison with non-insulin secretagogues (P for subgroup difference =0.03). SYSTEMATIC REVIEW REGISTRATION https://inplasy.com/, identifier INPLASY202280104. CONCLUSIONS DPP4 inhibitors are effective at reducing the circulating postprandial glucagon level in T2DM patients.
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Affiliation(s)
- Shangyu Chai
- Merck Research Laboratories (MRL) Global Medical Affairs, Merck Sharp & Dohme (MSD) China, Shanghai, China
| | - Ruya Zhang
- Merck Research Laboratories (MRL) Global Medical Affairs, Merck Sharp & Dohme (MSD) China, Shanghai, China
| | - Ye Zhang
- Merck Research Laboratories (MRL) Global Medical Affairs, Merck Sharp & Dohme (MSD) China, Shanghai, China
| | - Richard David Carr
- Hatter Cardiovascular Institute, University College London, UK and Ulster University, Coleraine, United Kingdom
| | - Yiman Zheng
- Merck Research Laboratories (MRL) Global Medical Affairs, Merck Sharp & Dohme (MSD) China, Shanghai, China
| | - Swapnil Rajpathak
- Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ, United States
| | - Linong Ji
- Department of Endocrinology, People’s Hospital of Peking University, Beijing, China
- *Correspondence: Linong Ji,
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Yang W, Cai X, Zhang S, Han X, Ji L. Dipeptidyl peptidase-4 inhibitor treatment and the risk of bullous pemphigoid and skin-related adverse events: A systematic review and meta-analysis of randomized controlled trials. Diabetes Metab Res Rev 2021; 37:e3391. [PMID: 32741073 DOI: 10.1002/dmrr.3391] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 07/16/2020] [Accepted: 07/17/2020] [Indexed: 12/24/2022]
Abstract
AIMS This meta-analysis aimed to evaluate the risk of developing bullous pemphigoid (BP) and other skin-related adverse events (AEs) in patients with type 2 diabetes (T2DM) undergoing dipeptidyl peptidase-4 inhibitor (DPP-4i) treatment in randomized controlled trials (RCTs). METHODS In this meta-analysis, the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases were searched for RCTs, which involve patients with T2DM reporting skin-related AEs. RCTs that comparatively evaluated the effects of DPP-4i treatment and placebo on patients with T2DM and reported skin-related AEs were included in the analysis. The odds ratio (OR) and 95% confidence interval (CI) were calculated using the Peto's methods. The GRADE approach was used to rate the quality of evidence. RESULTS A total of 46 randomized placebo-controlled trials, including 3 trials with reports of BP (n = 38 011), that reported skin-related AEs were included (n = 59 332). Compared to the placebo group, the risk of developing BP was significantly higher in the DPP-4i treatment group (OR = 7.38, 95% CI 2.00-27.25, I2 = 0%, P = .003; quality rating: very low). Additionally, DPP-4i treatment was associated with an increased overall risk of developing skin-related AEs (OR = 1.22, 95% CI 1.02-1.46, I2 = 32%, P = .03; quality rating: moderate). CONCLUSIONS This meta-analysis suggested that treatment with DPP-4is, including sitagliptin, saxagliptin, and linagliptin, was associated with an increased risk of developing BP. Additionally, the risk of developing skin-related AEs increased when all DPP-4is were combined. Skin lesion, especially BP, should be monitored in patients with diabetes undergoing DPP-4i treatment. Future studies should evaluate the susceptible population and develop strategies for early detection of skin-related AEs.
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Affiliation(s)
- Wenjia Yang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Simin Zhang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xueyao Han
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
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Lin C, Cai X, Yang W, Lv F, Nie L, Ji L. Age, sex, disease severity, and disease duration difference in placebo response: implications from a meta-analysis of diabetes mellitus. BMC Med 2020; 18:322. [PMID: 33190640 PMCID: PMC7667845 DOI: 10.1186/s12916-020-01787-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 09/17/2020] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND The placebo response in patients with diabetes mellitus is very common. A systematic evaluation needs to be updated with the current evidence about the placebo response in diabetes mellitus and the associated factors in clinical trials of anti-diabetic medicine. METHODS Literature research was conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for studies published between the date of inception and June 2019. Randomized placebo-controlled trials conducted in type 1and type 2 diabetes mellitus (T1DM/T2DM) were included. Random-effects model and meta-regression analysis were accordingly used. This meta-analysis was registered in PROSPERO as CRD42014009373. RESULTS Significantly weight elevation (effect size (ES) = 0.33 kg, 95% CI, 0.03 to 0.61 kg) was observed in patients with placebo treatments in T1DM subgroup while significantly HbA1c reduction (ES = - 0.12%, 95% CI, - 0.16 to - 0.07%) and weight reduction (ES = - 0.40 kg, 95% CI, - 0.50 to - 0.29 kg) were observed in patients with placebo treatments in T2DM subgroup. Greater HbA1c reduction was observed in patients with injectable placebo treatments (ES = - 0.22%, 95% CI, - 0.32 to - 0.11%) versus oral types (ES = - 0.09%, 95% CI, - 0.14 to - 0.04%) in T2DM (P = 0.03). Older age (β = - 0.01, 95% CI, - 0.02 to - 0.01, P < 0.01) and longer diabetes duration (β = - 0.02, 95% CI, - 0.03 to - 0.21 × 10-2, P = 0.03) was significantly associated with more HbA1c reduction by placebo in T1DM. However, younger age (β = 0.02, 95% CI, 0.01 to 0.03, P = 0.01), lower male percentage (β = 0.01, 95% CI, 0.22 × 10-2, 0.01, P < 0.01), higher baseline BMI (β = - 0.02, 95% CI, - 0.04 to - 0.26 × 10-2, P = 0.02), and higher baseline HbA1c (β = - 0.09, 95% CI, - 0.16 to - 0.01, P = 0.02) were significantly associated with more HbA1c reduction by placebo in T2DM. Shorter diabetes duration (β = 0.06, 95% CI, 0.06 to 0.10, P < 0.01) was significantly associated with more weight reduction by placebo in T2DM. However, the associations between baseline BMI, baseline HbA1c, and placebo response were insignificant after the adjusted analyses. CONCLUSION The placebo response in diabetes mellitus was systematically outlined. Age, sex, disease severity (indirectly reflected by baseline BMI and baseline HbA1c), and disease duration were associated with placebo response in diabetes mellitus. The association between baseline BMI, baseline HbA1c, and placebo response may be the result of regression to the mean.
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Affiliation(s)
- Chu Lin
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
| | - Wenjia Yang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Fang Lv
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Lin Nie
- Department of Endocrinology and Metabolism, Beijing Airport Hospital, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
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Ishida Y, Murayama H, Shinfuku Y, Taniguchi T, Sasajima T, Oyama N. Cardiovascular safety and effectiveness of vildagliptin in patients with type 2 diabetes mellitus: a 3-year, large-scale post-marketing surveillance in Japan. Expert Opin Drug Saf 2020; 19:625-631. [DOI: 10.1080/14740338.2020.1740679] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
| | | | - Yohei Shinfuku
- Regulatory Office Japan, Novartis Pharma K.K., Tokyo, Japan
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Kamalinia S, Josse RG, Donio PJ, Leduc L, Shah BR, Tobe SW. Risk of any hypoglycaemia with newer antihyperglycaemic agents in patients with type 2 diabetes: A systematic review and meta-analysis. Endocrinol Diabetes Metab 2020; 3:e00100. [PMID: 31922027 PMCID: PMC6947712 DOI: 10.1002/edm2.100] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 10/11/2019] [Accepted: 10/13/2019] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES For patients with type 2 diabetes, newer antihyperglycaemic agents (AHA), including the dipeptidyl peptidase IV inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium glucose co-transporter 2 inhibitors (SGLT2i) offer a lower risk of hypoglycaemia relative to sulfonylurea or insulin. However, it is not clear how AHA compare to placebo on risk of any hypoglycaemia. This study evaluates the risk of any and severe hypoglycaemia with AHA and metformin relative to placebo. DESIGN A systematic review and meta-analysis was conducted of randomized, placebo-controlled trials ≥12 weeks in duration. MEDLINE, Embase and the Cochrane Library were searched up to April 16, 2019. Studies allowing use of other diabetes medications were excluded. Mantel-Haenszel risk ratio with 95% confidence intervals were used to pool estimates based on class of AHA and number of concomitant therapies used. PATIENTS Eligible studies enrolled patients with type 2 diabetes ≥18 years of age. RESULTS 144 studies met our inclusion criteria. Any hypoglycaemia was not increased with AHA when used as monotherapy (DPP4i (RR 1.12; 95% CI 0.81-1.56), GLP1RA (1.77; 0.91-3.46), SGLT2i (1.34; 0.83-2.15)), or as add-on to metformin (DPP4i (0.95; 0.67-1.35), GLP1RA (1.24; 0.80-1.91), SGLT2i (1.29; 0.91-1.83)) or as triple therapy (1.13; 0.67-1.91). However, metformin monotherapy (1.73; 1.02-2.94) and dual therapy initiation (3.56; 1.79-7.10) was associated with an increased risk of any hypoglycaemia. Severe hypoglycaemia was rare not increased for any comparisons. CONCLUSIONS Metformin and the simultaneous initiation of dual therapy, but not AHA used alone or as single add-on combination therapy, was associated with an increased risk of any hypoglycaemia relative to placebo.
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Affiliation(s)
- Sanaz Kamalinia
- Institute of Medical SciencesUniversity of TorontoTorontoONCanada
| | - Robert G. Josse
- St. Michael's HospitalTorontoONCanada
- Department of MedicineUniversity of TorontoTorontoONCanada
| | | | | | - Baiju R. Shah
- Department of MedicineUniversity of TorontoTorontoONCanada
- Sunnybrook Research InstituteTorontoONCanada
| | - Sheldon W. Tobe
- Institute of Medical SciencesUniversity of TorontoTorontoONCanada
- Department of MedicineUniversity of TorontoTorontoONCanada
- Northern Ontario School of MedicineSudburyONCanada
- Sunnybrook Research InstituteTorontoONCanada
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Nakagawa T, Nagai Y, Yamamoto Y, Miyachi A, Hamajima H, Mieno E, Takahashi M, Inoue E, Tanaka Y. Effects of anagliptin on plasma glucagon levels and gastric emptying in patients with type 2 diabetes: An exploratory randomized controlled trial versus metformin. Diabetes Res Clin Pract 2019; 158:107892. [PMID: 31669625 DOI: 10.1016/j.diabres.2019.107892] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Revised: 08/24/2019] [Accepted: 10/22/2019] [Indexed: 02/03/2023]
Abstract
AIMS Glucagon has an important role in glucose homeostasis. Recently, a new plasma glucagon assay based on liquid chromatography-high resolution mass spectrometry was developed. We evaluated the influence of a dipeptidyl peptidase-4 inhibitor (anagliptin) on plasma glucagon levels in Japanese patients with type 2 diabetes by using this new assay. METHODS Twenty-four patients with type 2 diabetes were enrolled in a prospective, single-center, randomized, open-label study and were randomly allocated to 4 weeks of treatment with metformin (1000 mg/day) or anagliptin (200 mg/day). A liquid test meal labeled with sodium [13C] acetate was ingested before and after the treatment period. Samples of blood and expired air were collected over 3 h. Plasma levels of glucose, glucagon, C-peptide, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) were measured, and gastric emptying was also evaluated. RESULTS Twenty-two patients completed the study (metformin group: n = 10; anagliptin group: n = 12). Glycemic control showed similar improvement in both groups. In the anagliptin group, there was a slight decrease of the incremental area under the plasma concentration versus time curve for glucagon after the test meal (P = 0.048). In addition, the plasma level of active GLP-1 and GIP was increased, and plasma C-peptide was also increased versus baseline. Neither anagliptin nor metformin delayed gastric emptying. CONCLUSIONS In patients with type 2 diabetes maintained endogenous insulin secretion, anagliptin increased the plasma level of active GLP-1 and GIP in association with a slight stimulation of insulin secretion and slight inhibition of glucagon secretion, but did not delay gastric emptying. Clinical Trial Registry: University hospital Medical Information Network UMIN000028293.
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Affiliation(s)
- Tomoko Nakagawa
- Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
| | - Yoshio Nagai
- Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
| | - Yutaro Yamamoto
- Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
| | - Atsushi Miyachi
- Radioisotope and Chemical Analysis Center, Sanwa Kagaku Kenkyusho Co., Ltd., 363 Shisaki, Hokusei-cho, Inabe, Mie 511-0406, Japan.
| | - Hitoshi Hamajima
- Radioisotope and Chemical Analysis Center, Sanwa Kagaku Kenkyusho Co., Ltd., 363 Shisaki, Hokusei-cho, Inabe, Mie 511-0406, Japan.
| | - Eri Mieno
- Radioisotope and Chemical Analysis Center, Sanwa Kagaku Kenkyusho Co., Ltd., 363 Shisaki, Hokusei-cho, Inabe, Mie 511-0406, Japan.
| | - Masaki Takahashi
- Medical Informatics, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
| | - Eisuke Inoue
- Medical Informatics, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
| | - Yasushi Tanaka
- Division of Metabolism and Endocrinology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
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12
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Hayashi T, Murayama H, Shinfuku Y, Taniguchi T, Tsumiyama I, Oyama N. Safety and efficacy of vildagliptin: 52-week post-marketing surveillance of Japanese patients with type 2 diabetes in combination with other oral antidiabetics and insulin. Expert Opin Pharmacother 2019; 21:121-130. [PMID: 31689132 DOI: 10.1080/14656566.2019.1685500] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Background: Vildagliptin is a dipeptidyl peptidase-4 inhibitor that reduces glycemia in patients with type 2 diabetes mellitus (T2DM). When approved in 2013, data on vildagliptin combined with >750 mg/day metformin in Japanese patients were limited. There is a need to confirm the safety and efficacy of vildagliptin in combination with oral antidiabetic drugs (OADs).Research design and methods: This 52-week post-marketing surveillance (PMS) observational study in Japanese T2DM patients evaluated the safety and efficacy of vildagliptin in combination with OADs including high-dose metformin or insulin but excluding combination with sulfonylureas alone.Results: During this survey of 3006 Japanese T2DM patients, 13.61% of patients experienced adverse events (AEs) and 2.20% reported a serious AE (SAE). The frequency of AEs/SAEs was similar when in combination with biguanides (12.93%/1.46%), metformin ≥1000 mg/day (12.92%/1.22%), metformin <1000 mg/day (12.62%/1.54%), thiazolidine derivatives (16.71%/2.86%), α-glucosidase inhibitors (13.18%/1.90%), rapid-acting insulin secretagogues (glinides) (20.41%/5.71%), or insulin (15.87%/2.47%). The mean ± SD changes from baseline at endpoint in glycated hemoglobin and fasting blood glucose were -0.76 ± 1.27% and -23.3 ± 57.3 mg/dL, respectively, and these changes were consistent, regardless of concomitant OAD.Conclusions: Long-term vildagliptin combination therapy is safe and effective in Japanese T2DM patients in real-world settings.
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Affiliation(s)
| | | | - Yohei Shinfuku
- Regulatory Office Japan, Novartis Pharma K.K., Tokyo, Japan
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13
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Mucoadhesive Particles: A Novel, Prolonged-Release Nanocarrier of Sitagliptin for the Treatment of Diabetics. BIOMED RESEARCH INTERNATIONAL 2019; 2019:3950942. [PMID: 31815135 PMCID: PMC6878770 DOI: 10.1155/2019/3950942] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 08/21/2019] [Accepted: 09/19/2019] [Indexed: 12/23/2022]
Abstract
Sitagliptin (MK–0431) is a widely and commonly used oral hypoglycemic drug in the treatment of type 2 diabetes mellitus; patients typically take higher doses of this drug (50 mg, twice daily). One drawback is that only 38% of the drug is bound reversibly to plasma proteins and 79% is excreted in urine without being metabolized. To overcome this issue, there is a need for a better drug-delivery method to improve its efficacy in patients. It has been found that in existing formulations, the drug content is 72.5% ± 5% and the percentage yield is 84.9% ± 3%. In this study, sitagliptin nanoparticles (sizes ranging from 210 to 618 nm) were developed. The bioadhesion properties of the nanoparticles, as well as the swelling of the nanoparticles on the mucus membrane aided in sustained drug release. The pattern of drug release was in accordance with the Peppas model. Fourier-transform infrared (FTIR) spectroscopy demonstrated that there were no significant interactions between sitagliptin and chitosan. Differential scanning calorimetry (DSC) results showed an absence of drug peaks due to the fact that the drug was present in an amorphous state. Mucoadhesive nanoparticles were formulated using sitagliptin and were effective for about 12 hours in the gastrointestinal tract. When compared to conventional sitagliptin administration, use of a nanoparticle delivery system demonstrated greater benefits for use in oral delivery applications. This is the first time that a drug-delivery method based on the mucoadhesive properties of nanoparticles could prolong the drug-release time of sitagliptin.
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14
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Murayama H, Toda M, Tsumiyama I, Shinfuku Y, Taniguchi T, Tanaka Y, Oyama N. Relationship of patient background with macro- and microvascular complications: a 2-year post-marketing surveillance of vildagliptin in nearly 20,000 Japanese diabetic patients. Expert Opin Pharmacother 2019; 20:1037-1047. [PMID: 30831038 DOI: 10.1080/14656566.2019.1585802] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Vildagliptin is indicated for type 2 diabetes mellitus (T2DM); however, the onset and exacerbation of diabetic complications in Japanese T2DM patients treated with vildagliptin is unknown. RESEARCH DESIGN AND METHODS This 2-year post-marketing surveillance (PMS) assessed the real-world safety and efficacy of vildagliptin therapy in 19,218 Japanese T2DM patients. The relationship between the incidence of macro- and microvascular complications with patient characteristics and changes in glycemic control (HbA1c) were evaluated. RESULTS The incidences of macro- and microvascular diseases were 1.14% and 3.09%, respectively. Patients with HbA1c ≥8.4% had a higher odds ratio (OR) for micro- and macrovascular disease (OR: 2.02 and 1.90) compared with patients with HbA1c <6.9%. Patient characteristics (OR, 95% CI) associated with macrovascular disease were age (1.04, 1.01-1.07) and a history of macrovascular disease (3.38, 1.98-5.75). Microvascular disease was associated with a final HbA1c level ≥7.0% (1.48, 1.11-1.98) and previous diabetic nephropathy (1.42, 1.05-1.93). The mean (SD) HbA1c decreased from 7.89% (1.46%) to 7.05% (0.99%) after 24 months. CONCLUSIONS Vildagliptin elicited no increases/exacerbations of diabetic complications; this PMS suggested that the incidence of diabetic complications tends to be low in subjects with good HbA1c control.
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Affiliation(s)
| | | | - Isao Tsumiyama
- b Japan Development , Novartis Pharma K.K ., Tokyo , Japan
| | - Yohei Shinfuku
- c Regulatory Office Japan , Novartis Pharma K.K ., Tokyo , Japan
| | - Tomoko Taniguchi
- c Regulatory Office Japan , Novartis Pharma K.K ., Tokyo , Japan
| | - Yoshio Tanaka
- a Medical Division , Novartis Pharma K.K ., Tokyo , Japan
| | - Naotsugu Oyama
- a Medical Division , Novartis Pharma K.K ., Tokyo , Japan
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15
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Overbeek JA, Bakker M, van der Heijden AAWA, van Herk-Sukel MPP, Herings RMC, Nijpels G. Risk of dipeptidyl peptidase-4 (DPP-4) inhibitors on site-specific cancer: A systematic review and meta-analysis. Diabetes Metab Res Rev 2018; 34:e3004. [PMID: 29573125 DOI: 10.1002/dmrr.3004] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 01/03/2018] [Accepted: 03/12/2018] [Indexed: 12/19/2022]
Abstract
The long-term impact of dipeptidyl peptidase-4 (DPP-4) inhibition is unknown, and there are concerns about the influence of DPP-4 inhibition on carcinogenesis of the pancreas and thyroid. As DPP-4 is a rather unselective enzyme present in many tissues, we focused on all specific cancer types. PubMed and EMBASE were searched between January 2005 and April 2017 to identify studies comparing DPP-4 inhibitors with either placebo or active drugs on cancer risk. Studies were included if they reported on at least one specific cancer outcome and had a follow-up of at least 1 year after start of drug use. Methodological quality of the studies was assessed by the Cochrane Collaboration's tool and the Newcastle-Ottawa Scale. Twenty-five studies met the inclusion criteria (12 randomized controlled trials and 13 observational studies). Sample sizes of the DPP-4 inhibitor groups ranged from 29 to 8212 patients for randomized controlled trials and from 2422 to 71 137 patients for observational studies. Mean age ranged from 51 to 76 years, and mean follow-up was 1.5 years. None of the pooled (sensitivity) analyses, except the observational studies studying breast cancer (hazard ratio [95% CI]: 0.76 [0.60-0.96]), showed evidence for an association between DPP-4 inhibitors and site-specific cancer. Also for pancreatic and thyroid cancer, no statistically significant risk was found. Based on the current literature, it is not possible to conclude whether DPP-4 inhibitors were associated with an increased risk of site-specific cancer. Future studies should address the methodological limitations and follow patients for a longer period to determine the long-term cancer risk of DPP-4 inhibitors.
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Affiliation(s)
- Jetty A Overbeek
- Department of General Practice and Elderly Care Medicine, Amsterdam Public Health Research Institute, VU University Medical Centre, Amsterdam, Netherlands
- PHARMO Institute for Drug Outcomes Research, Utrecht, Netherlands
| | - Marina Bakker
- PHARMO Institute for Drug Outcomes Research, Utrecht, Netherlands
| | - Amber A W A van der Heijden
- Department of General Practice and Elderly Care Medicine, Amsterdam Public Health Research Institute, VU University Medical Centre, Amsterdam, Netherlands
| | - Myrthe P P van Herk-Sukel
- Department of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Ron M C Herings
- PHARMO Institute for Drug Outcomes Research, Utrecht, Netherlands
- Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, Netherlands
| | - Giel Nijpels
- Department of General Practice and Elderly Care Medicine, Amsterdam Public Health Research Institute, VU University Medical Centre, Amsterdam, Netherlands
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16
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An Effective Delivery System of Sitagliptin Using Optimized Mucoadhesive Nanoparticles. APPLIED SCIENCES-BASEL 2018. [DOI: 10.3390/app8060861] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
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17
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Hædersdal S, Lund A, Knop FK, Vilsbøll T. The Role of Glucagon in the Pathophysiology and Treatment of Type 2 Diabetes. Mayo Clin Proc 2018; 93:217-239. [PMID: 29307553 DOI: 10.1016/j.mayocp.2017.12.003] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 12/04/2017] [Accepted: 12/07/2017] [Indexed: 12/19/2022]
Abstract
Type 2 diabetes is a disease involving both inadequate insulin levels and increased glucagon levels. While glucagon and insulin work together to achieve optimal plasma glucose concentrations in healthy individuals, the usual regulatory balance between these 2 critical pancreatic hormones is awry in patients with diabetes. Although clinical discussion often focuses on the role of insulin, glucagon is equally important in understanding type 2 diabetes. Furthermore, an awareness of the role of glucagon is essential to appreciate differences in the mechanisms of action of various classes of glucose-lowering therapies. Newer drug classes such as dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists improve glycemic control, in part, by affecting glucagon levels. This review provides an overview of the effect of glucose-lowering therapies on glucagon on the basis of an extensive PubMed literature search to identify clinical studies of glucose-lowering therapies in type 2 diabetes that included assessment of glucagon. Clinical practice currently benefits from available therapies that impact the glucagon regulatory pathway. As clinicians look to the future, improved treatment strategies are likely to emerge that will either use currently available therapies whose mechanisms of action complement each other or take advantage of new therapies based on an improved understanding of glucagon pathophysiology.
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Affiliation(s)
- Sofie Hædersdal
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Asger Lund
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Filip K Knop
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Steno Diabetes Center Copenhagen, University of Copenhagen, Gentofte, Denmark; Faculty of Health and Medical Sciences, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
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18
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Suzuki L, Kanazawa A, Uzawa H, Osonoi Y, Masuyama A, Azuma K, Takeno K, Takayanagi N, Sato J, Someya Y, Komiya K, Goto H, Mita T, Ikeda F, Ogihara T, Shimizu T, Ohmura C, Saito M, Osonoi T, Watada H. Safety and efficacy of metformin up-titration in Japanese patients with type 2 diabetes mellitus treated with vildagliptin and low-dose metformin. Expert Opin Pharmacother 2017; 18:1921-1928. [DOI: 10.1080/14656566.2017.1404576] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Luka Suzuki
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Akio Kanazawa
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hirotsugu Uzawa
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yusuke Osonoi
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Atushi Masuyama
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kosuke Azuma
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Kageumi Takeno
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Naoko Takayanagi
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Junko Sato
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yuki Someya
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Koji Komiya
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hiromasa Goto
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Tomoya Mita
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Fuki Ikeda
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takeshi Ogihara
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Tomoaki Shimizu
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Chie Ohmura
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | | | | | - Hirotaka Watada
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Center for Identification of Diabetic Therapeutic Targets, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
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19
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Ayers D, Kanters S, Goldgrub R, Hughes M, Kato R, Kragh N. Network meta-analysis of liraglutide versus dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes in Japanese patients. Curr Med Res Opin 2017. [PMID: 28635331 DOI: 10.1080/03007995.2017.1345730] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
AIMS To determine the comparative efficacy and safety of liraglutide and dipeptidyl peptidase-4 (DPP-4) inhibitors as antidiabetics for Japanese patients with uncontrolled type 2 diabetes (T2DM). METHODS AND MATERIALS We searched for randomized controlled trials (RCTs) evaluating outcomes among Japanese adults with uncontrolled T2DM and including liraglutide or DPP-4 inhibitors up to August 2016. We extracted data on trial and patient characteristics, and the following outcomes: HbA1c, weight, patients meeting HbA1c <7%, patients experiencing hypoglycemic events, microalbuminuria, estimated glomerular filtration rate (eGFR) and creatinine. We synthesized data using network meta-analyses (NMA) using a Bayesian framework. Continuous outcomes were modeled using normal likelihoods and an identity link, while dichotomous outcomes were modeled using a binomial likelihood and a logit link. RESULTS The systematic literature review yielded 39 publications pertaining to 38 trials. A total of 27 trials (5032 patients) reported change in HbA1c at 12 weeks and at 24 weeks 9 trials (2091 patients). All treatments showed statistically significant reductions in HbA1c relative to placebo at 12 and 24 weeks. Liraglutide 0.9 mg was statistically superior to all DPP-4 interventions (vildagliptin, sitagliptin, linagliptin, alogliptin, teneligliptin, trelagliptin and omarigliptin) at 12 weeks and 24 weeks among those reporting. Treatments were not statistically differentiable with respect to weight change and risk of hypoglycemia. Finally, no comparisons of eGFR and microalbuminuria were conducted, as this data was reported in too few trials to conduct analyses. LIMITATIONS Some important outcomes were limited by poor reporting (eGFR and microalbuminuria) or low event rates (hypoglycemia). The follow-up time was relatively short. Clinically, the 24 week time point is more important as it demonstrates more sustained results. CONCLUSIONS Our research suggests that liraglutide 0.9 mg offers a more efficacious treatment option for T2DM than the DPP-4 inhibitors among adult Japanese patients and that it is a viable option for this population.
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Affiliation(s)
- Dieter Ayers
- a Precision Health Economics , Vancouver , BC , Canada
| | - Steve Kanters
- a Precision Health Economics , Vancouver , BC , Canada
- b School of Population and Public Health , University of British Columbia , Vancouver , Canada
| | | | - Monica Hughes
- a Precision Health Economics , Vancouver , BC , Canada
| | - Ryo Kato
- c Novo Nordisk Pharma Ltd , Japan
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20
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Elgendy IY, Mahmoud AN, Barakat AF, Elgendy AY, Saad M, Abuzaid A, Wayangankar SA, Bavry AA. Cardiovascular Safety of Dipeptidyl-Peptidase IV Inhibitors: A Meta-Analysis of Placebo-Controlled Randomized Trials. Am J Cardiovasc Drugs 2017; 17:143-155. [PMID: 27873238 DOI: 10.1007/s40256-016-0208-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Large randomized trials have shown conflicting evidence regarding the cardiovascular safety of dipeptidyl-peptidase 4 (DPP-4) inhibitors. Systematic reviews have been limited by incomplete data and inclusion of observational studies. This study aimed to systematically evaluate the cardiovascular safety of DPP-4 inhibitors in patients with type 2 diabetes. METHODS Electronic databases were searched for randomized trials that compared DPP-4 inhibitors versus placebo and reported cardiovascular outcomes. The main outcome assessed in this analysis was heart failure. Other outcomes included all-cause mortality, cardiovascular mortality, myocardial infarction, and ischemic stroke. Summary odds ratios (ORs) were primarily constructed using Peto's model. RESULTS A total of 90 trials with 66,730 patients were included. Compared with placebo, DPP-4 inhibitors were associated with a non-significant increased risk of heart failure [OR 1.11, 95% confidence interval (CI) 0.99-1.25, P = 0.07] at a mean of 108 weeks. The risk of all-cause mortality (OR 1.03, 95% CI 0.94-1.12, P = 0.53), cardiovascular mortality (OR 1.02, 95% CI 0.92-1.14, P = 0.72), myocardial infarction (OR 0.98, 95% CI 0.88-1.09, P = 0.69), and ischemic stroke (OR 0.99, 95% CI 0.85-1.15, P = 0.92) was similar between both groups. CONCLUSION In patients with type 2 diabetes, the safety profile of DPP-4 inhibitors is similar to placebo. As a class, there is only weak evidence for an increased risk of heart failure.
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Affiliation(s)
- Islam Y Elgendy
- Division of Cardiovascular Medicine, Department of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL, 32610, USA.
| | - Ahmed N Mahmoud
- Division of Cardiovascular Medicine, Department of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL, 32610, USA
| | - Amr F Barakat
- Department of Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Akram Y Elgendy
- Division of Cardiovascular Medicine, Department of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL, 32610, USA
| | - Marwan Saad
- Department of Medicine, University of Arkansas, Little Rock, AR, USA
| | - Ahmed Abuzaid
- Division of Cardiovascular Medicine, Jefferson University Hospital/Christiana Care Health System, Newark, DE, USA
| | - Siddarth A Wayangankar
- Division of Cardiovascular Medicine, Department of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL, 32610, USA
| | - Anthony A Bavry
- Division of Cardiovascular Medicine, Department of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL, 32610, USA
- North Florida/South Georgia Veterans Health System, Gainesville, FL, USA
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21
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Kozlovski P, Fonseca M, Mohan V, Lukashevich V, Odawara M, Paldánius PM, Kothny W. Effect of race and ethnicity on vildagliptin efficacy: A pooled analysis of phase II and III studies. Diabetes Obes Metab 2017; 19:429-435. [PMID: 27943546 PMCID: PMC5516163 DOI: 10.1111/dom.12844] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 12/05/2016] [Accepted: 12/05/2016] [Indexed: 01/02/2023]
Abstract
AIMS To determine the impact of race and ethnicity on the efficacy, body weight and hypoglycaemia incidence with vildagliptin treatment in patients with type 2 diabetes mellitus using patient-level data from the vildagliptin clinical trial programme. METHODS Data from 22 randomized, placebo-controlled global and local (Japan, China) registration studies of vildagliptin (50 mg once-daily or twice-daily) of ≥12-week duration were analysed by race (Caucasian [n = 2764] and Asian [n = 2232]) and by ethnicity (Japanese, Chinese, and Indian). The placebo-subtracted differences in the change in glycated haemoglobin (HbA1c) and body weight from baseline to week 12 or week 24 were evaluated by race or ethnicity using repeated measure analysis of unstructured covariance. Hypoglycaemia incidences were summarized using descriptive statistics. RESULTS The HbA1c reduction from baseline with vildagliptin was similar across the racial/ethnic subgroups (-0.83% ± 0.02% to -1.01% ± 0.05%). Placebo-corrected HbA1c reduction was similar between Caucasian (-0.68% ± 0.03%) and Asian (-0.80% ± 0.03%) patients ( P value for interaction = .56); analysis by race and ethnicity showed better efficacy ( P < .02) in Japanese patients. Japanese patients were drug-naïve and treated with a single oral anti-diabetes drug only; they showed no response to placebo. Weight neutrality of vildagliptin was demonstrated in all groups (0.47 ± 0.11 kg to -0.29 ± 0.08 kg). Hypoglycaemic events (≥1) were infrequent in all ethnic subgroups. CONCLUSIONS The glycaemic efficacy of vildagliptin was similar in Caucasian and Asian patients. The slightly better efficacy observed in Japanese patients was driven by the absence of placebo effect and might be explained by their earlier stage of diabetes compared to other subgroups.
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Affiliation(s)
| | - Marilia Fonseca
- School of Public HealthUniversity of São PauloSão PauloBrazil
| | | | | | - Masato Odawara
- The Department of Diabetes, Endocrinology, Metabolism and RheumatologyTokyo Medical UniversityTokyoJapan
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Tanaka K, Okada Y, Mori H, Miyazaki M, Kuno F, Sonoda S, Sugai K, Hajime M, Kurozumi A, Narisawa M, Torimoto K, Arao T, Mine S, Tanaka Y. Comparative analysis of the effects of alogliptin and vildagliptin on glucose metabolism in type 2 diabetes mellitus. Endocr J 2017; 64:179-189. [PMID: 27840383 DOI: 10.1507/endocrj.ej16-0341] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The aim of this 24-week, prospective randomized open-label study was to compare the effects of alogliptin and vildagliptin on glucose control, renal function, and lipid metabolism. In Study 1, DPP-4 inhibitor-naive type 2 diabetes (T2DM) were randomly assigned to alogliptin 25 mg/day or vildagliptin 50 mg twice daily. In Study 2, T2DM on treatment with 50 mg/day sitagliptin were switched to either 25 mg/day alogliptin or 50 mg twice daily vildagliptin. The primary endpoint was change in glycosylated hemoglobin (HbA1c) level at 24 weeks, while the secondary endpoints were changes in urinary albumin excretion and low-density lipoprotein cholesterol (LDL-C) levels at 24 weeks. In Study 1, HbA1c levels changed at 24-week by -0.5±0.7% in the alogliptin group (p=0.002, relative to baseline) and -0.7±0.9% in the vildagliptin group (p=0.001, relative to baseline), and the extent of these changes were comparable between the two groups (p=0.219). The decrease in log urinary albumin excretion was more significant in the vildagliptin group (p=0.008). In Study 2, HbA1c levels at 24-week changed by 0.2±0.7% in the switch-to-alogliptin group (p=0.007) and 0.0±0.6% in the switch-to-vildagliptin group (p=0.188), indicating a significant difference between the groups (p=0.003). In both studies, the changes in LDL-C levels were comparable between the two groups. The two drugs had comparable glucose-lowering effects in DPP-4 inhibitor-naive patients but the effect was more pronounced for vildagliptin in patients switched from sitagliptin. The results may point to subtle yet important differences between the two DPP-4 inhibitors. This trial was registered with UMIN (no. #000019022).
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Affiliation(s)
- Kenichi Tanaka
- First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu 807-8555, Japan
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Sakura H, Hashimoto N, Sasamoto K, Ohashi H, Hasumi S, Ujihara N, Kasahara T, Tomonaga O, Nunome H, Honda M, Iwamoto Y, for the JAMP Study Investigators SatoAkikoYamashitaAkinoriMiyashitaAkiraKokuboAsakoTsuchiyaAtsuroHiroharaDaiKogureDaijiKasaharaDaijoTanakaHidekiTanakaHidekiTezukaHideoKurokiHiroyukiOginoJunKinKanuKinKanuMutoKazukoSuzukiKazuoIsekiKeikoWatanabeKeitaHigamiKenshiMatsumuraKenzoNakajimaKiyotakaShinKokiKoizumiKuniyaSaneshigeMakiSekineMakioYaidaMakotoKiuchiMariMugishimaMariOsawaMariBannoMasaeYamamotoMasahiroHiratsukaMasatakeHosoyaMasumiAtsutaMichikaKatoMitsutoshiMoritaMiwaMiyamaeMunehiroIijimaMutsumiOkuyamaNaomiHisanoNobuoTsuchiyaNorihiroWadaRieWadaRieMomoseRyujiOtakeSachikoMaruyamaSatokoTakadaSatoruDanShigekiNishizawaShigekiYamashitaShigeoSaneshigeShingoTenoShinichiTsurutaShinjiKumakuraShinobuKijimaSumikoKondoTakashiOnishiTakeoKudoTakuSugiuraTatsushiIshiguroToshihikoSuzukiYasueTomitaYasuhiroTakanoYasukoAkimotoYoshihisaOdanakaYoshikoTasakaYoshimasaAisoYoshitakaInoueYukikoKobayashiYukinobu. Effect of sitagliptin on blood glucose control in patients with type 2 diabetes mellitus who are treatment naive or poorly responsive to existing antidiabetic drugs: the JAMP study. BMC Endocr Disord 2016; 16:70. [PMID: 27905912 PMCID: PMC5133763 DOI: 10.1186/s12902-016-0149-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 11/18/2016] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND To investigate the ameliorating effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood glucose control in patients with type 2 diabetes mellitus who were previously untreated with or who have a poor responsive to existing antidiabetic drugs. METHODS Sitagliptin (50 mg/day) was added on to the pre-existing therapy for type 2 diabetes and changes in the glycated hemoglobin (HbA1c) level after 3 months of treatment were compared with the baseline and performed exploratory analysis. RESULTS HbA1c levels were significantly decreased after 1 month of treatment compared to baseline, with a mean change in HbA1c level from baseline of -0.73% (range, -0.80 to -0.67) in the entire study population at 3 months. Patients who received a medium dose of glimepiride showed the least improvement in HbA1c levels. The percentage of patients who achieved an HbA1c level of <7.0% significantly increased after 1 month of treatment, reaching 53.1% at 3 months. The percentage of patients who achieved a fasting blood glucose level of <130 mg/dL significantly increased after 1 month of treatment, reaching 50.9% at 3 months. CONCLUSIONS Sitagliptin improved the HbA1c level and rate of achieving the target control levels in patients with type 2 diabetes mellitus who were previously untreated with, or poorly responsive to, existing antidiabetic drugs. Thus, sitagliptin is expected to be useful in this patient group. However, the additional administration of sitagliptin in patients treated with medium-dose glimepiride only slightly improved blood glucose control when corrected for baseline HbA1c level.
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Affiliation(s)
- Hiroshi Sakura
- Department of Medicine, Medical Center East, Tokyo Women’s Medical University School of Medicine , 2-1-10 Nishiogu, Arakawa-ku, Tokyo 116-8567 Japan
| | - Naotake Hashimoto
- Department of Diabetes, Endocrine and Metabolic Diseases, Tokyo Women’s Medical University Yachiyo Medical Center, 477-96, Owada-shinden, Yachiyo-shi, Chiba 276-8524 Japan
| | - Kazuo Sasamoto
- Internal Medicine, Suzuki Clinic, 2-10-14, Koyasu-machi, Hachioji-shi, Tokyo 192-0904 Japan
| | - Hiroshi Ohashi
- Internal Medicine, Oyama East Clinic, 1-32-1, Ekihigashi-dori, Oyama-shi, Tochigi 323-0022 Japan
| | - Sumiko Hasumi
- Internal Medicine, Nishiyamado-Keiwa Hospital, 3247-1, Kounosu, Naka-shi, Ibaraki 311-0133 Japan
| | - Noriko Ujihara
- Department of Medicine, Diabetes Center, Institute of Geriatrics, Tokyo Women’s Medical University, Shibuya Cross Tower 22F, 2-15-1, Shibuya, Shibuya-ku, Tokyo 150-0002 Japan
| | - Tadasu Kasahara
- Josai Hospital, 2-42-11, Kamiogi, Suginami-ku, Tokyo 167-0043 Japan
| | - Osamu Tomonaga
- Diabetes and Lifestyle Center, Tomonaga Clinic, Shinyon curumu Building 9F, 4-2-23, Shinjuku, Shinjuku-ku, Tokyo 160-0022 Japan
| | - Hideo Nunome
- Diabetes Center, Edogawa Hospital, Medical Plaza Shinozaki, SK Building, 7-15-12, Shinozaki-machi, Edogawa-ku, Tokyo 133-0057 Japan
| | - Masashi Honda
- Nishikawa Clinic, 2-16-3, Towa, Adachi-ku, Tokyo 120-0003 Japan
| | - Yasuhiko Iwamoto
- The Institute for Adult Diseases, Asahi Life Foundation, Asahiseimeisunaga building, 2-2-6, Nihonbashi Bakuro-cho, Chuo-ku, Tokyo 103-0002 Japan
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Fujita K, Kaneko M, Narukawa M. Factors Related to the Glucose-Lowering Efficacy of Dipeptidyl Peptidase-4 Inhibitors: A Systematic Review and Meta-Analysis Focusing on Ethnicity and Study Regions. Clin Drug Investig 2016; 37:219-232. [DOI: 10.1007/s40261-016-0478-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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He L, Liu S, Shan C, Tu Y, Li Z, Zhang XD. Differential HbA1c response in the placebo arm of DPP-4 inhibitor clinical trials conducted in China compared to other countries: a systematic review and meta-analysis. BMC Pharmacol Toxicol 2016; 17:40. [PMID: 27600598 PMCID: PMC5013632 DOI: 10.1186/s40360-016-0084-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Accepted: 08/03/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND It has been observed that the efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors as compared to the placebo groups in some clinical trials conducted in China is weaker than that in trials conducted outside China, leading to the suspicion that this may be caused by differential Glycosylated Hemoglobin (HbA1c) response in the placebo arm of DPP-4 inhibitor clinical trials conducted in China compared to other countries. METHODS We searched published articles and other documents related to phase III placebo-control trials of DPP-4 inhibitors in Type 2 diabetes mellitus (T2DM). We included studies from different countries and compared those conducted in China to those conducted in other countries. Meta-regression analysis was used to analyze the HbA1c response in the placebo arms. RESULTS A total of 66 studies met the inclusion criteria and 10 were conducted within China. There were a total of 8303 participants (mean age 56, male 57 %) in placebo groups. The pooled change in HbA1c for the placebo groups of 10 trials conducted in patients with T2DM in China was 0.26 % (95 % CI [-0.36 %, -0.16 %], p-value < 0.001), compared to 0.015 % (95 % CI [-0.05 %, 0.08 %], p-value is 0.637) for 56 trials conducted outside of China. The difference of placebo effect between trials conducted in and outside China is -0.273 % (95 % CI [-0.42 %, -0.13 %], p-value is less than 0.001) while after excluding trials conducted in Japan, the difference is -0.203 % (95 % CI [-0.35 %, -0.06 %], p-value is 0.005). They are both statistically significant. CONCLUSIONS The meta-analysis in the article demonstrates that there is statistically significant difference in the HbA1c response in the placebo arm of DPP-4 inhibitor clinical trials conducted in China compared to other countries. This differential HbA1c response in the placebo arm should be taken into consideration by both experimenters and medical decision makers when future DPP-4 studies are conducted in China.
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Affiliation(s)
- Lingyu He
- Research School of Finance, Actuarial Studies & Statistics, The Australian National University, Canberra, ACT 2601, Australia
| | - Shu Liu
- Clinical Research, MSD China R&D Center, Beijing, 100015, China
| | - Chun Shan
- National Institutes for Food and Drug Control, Beijing, 100050, China
| | - Yingmei Tu
- Clinical Research, MSD China R&D Center, Beijing, 100015, China
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Sekar R, Singh K, Arokiaraj AWR, Chow BKC. Pharmacological Actions of Glucagon-Like Peptide-1, Gastric Inhibitory Polypeptide, and Glucagon. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2016; 326:279-341. [PMID: 27572131 DOI: 10.1016/bs.ircmb.2016.05.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Glucagon family of peptide hormones is a group of structurally related brain-gut peptides that exert their pleiotropic actions through interactions with unique members of class B1 G protein-coupled receptors (GPCRs). They are key regulators of hormonal homeostasis and are important drug targets for metabolic disorders such as type-2 diabetes mellitus (T2DM), obesity, and dysregulations of the nervous systems such as migraine, anxiety, depression, neurodegeneration, psychiatric disorders, and cardiovascular diseases. The current review aims to provide a detailed overview of the current understanding of the pharmacological actions and therapeutic advances of three members within this family including glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), and glucagon.
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Affiliation(s)
- R Sekar
- School of Biological Sciences, University of Hong Kong, Hong Kong, China
| | - K Singh
- School of Biological Sciences, University of Hong Kong, Hong Kong, China
| | - A W R Arokiaraj
- School of Biological Sciences, University of Hong Kong, Hong Kong, China
| | - B K C Chow
- School of Biological Sciences, University of Hong Kong, Hong Kong, China.
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Bekiari E, Rizava C, Athanasiadou E, Papatheodorou K, Liakos A, Karagiannis T, Mainou M, Rika M, Boura P, Tsapas A. Systematic review and meta-analysis of vildagliptin for treatment of type 2 diabetes. Endocrine 2016; 52:458-80. [PMID: 26714458 DOI: 10.1007/s12020-015-0841-1] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2015] [Accepted: 12/19/2015] [Indexed: 02/08/2023]
Abstract
This systematic review and meta-analysis provides an update on the efficacy and safety of vildagliptin for treatment of type 2 diabetes mellitus (T2DM). We searched MEDLINE, COCHRANE, EMBASE and the drug manufacturer's website for randomised controlled trials of vildagliptin in patients with T2DM. Sixty-nine studies (28,006 patients) were included in the meta-analysis. Compared with placebo vildagliptin reduced HbA1c (weighted mean difference WMD -0.69 %; 95 % CI -0.83 to -0.56 %; I (2) = 82 %), and it was as effective as other antidiabetic agents (WMD -0.01 %; 95 % CI -0.16 to 0.14 %; I (2) = 93 %), without increasing the risk for hypoglycemia (OR 0.83; 95 % CI 0.59 to 1.16; I (2) = 0 % vs. placebo, and OR 0.19; 95 % CI 0.15 to 0.24; I (2) = 78 % versus active comparators). However, it was associated with an increase in the incidence of arthralgia compared with other comparators (OR 1.23; 95 % CI 1.02 to 1.48; I (2) = 0 %). On the contrary, vildagliptin did not increase the incidence of pancreatitis (OR 0.97; 95 % CI 0.37 to 2.53; I (2) = 0 %), serious adverse events (OR 0.98; 95 % CI 0.88 to 1.09; I (2) = 0 %) or death (OR 1.10, 95 % CI 0.75 to 1.61; I (2) = 0 %). Finally, odds ratio (OR) for heart failure, and overall cardiovascular and cerebrovascular events was 0.77 (95 % CI 0.46 to 1.30; I (2) = 0 %) and 0.91 (95 % CI 0.73 to 1.14; I (2) = 0 %), respectively. Vildagliptin is an effective and safe therapeutic option for patients with T2DM, both as monotherapy and as add-on treatment.
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Affiliation(s)
- Eleni Bekiari
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University Thessaloniki, Hippokratio General Hospital, 49 Konstantinoupoleos Street, 54642, Thessaloníki, Greece
- Diabetes Centre, Second Medical Department, Aristotle University Thessaloniki, Thessaloníki, Greece
| | - Chrysoula Rizava
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University Thessaloniki, Hippokratio General Hospital, 49 Konstantinoupoleos Street, 54642, Thessaloníki, Greece
| | - Eleni Athanasiadou
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University Thessaloniki, Hippokratio General Hospital, 49 Konstantinoupoleos Street, 54642, Thessaloníki, Greece
| | - Konstantinos Papatheodorou
- Diabetes Centre, Second Medical Department, Aristotle University Thessaloniki, Thessaloníki, Greece
- Second Medical Department, Democritus University Thrace, Alexandroupoli, Greece
| | - Aris Liakos
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University Thessaloniki, Hippokratio General Hospital, 49 Konstantinoupoleos Street, 54642, Thessaloníki, Greece
| | - Thomas Karagiannis
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University Thessaloniki, Hippokratio General Hospital, 49 Konstantinoupoleos Street, 54642, Thessaloníki, Greece
| | - Maria Mainou
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University Thessaloniki, Hippokratio General Hospital, 49 Konstantinoupoleos Street, 54642, Thessaloníki, Greece
| | - Maria Rika
- Diabetes Centre, Second Medical Department, Aristotle University Thessaloniki, Thessaloníki, Greece
| | - Panagiota Boura
- Second Medical Department, Aristotle University Thessaloniki, Thessaloníki, Greece
| | - Apostolos Tsapas
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University Thessaloniki, Hippokratio General Hospital, 49 Konstantinoupoleos Street, 54642, Thessaloníki, Greece.
- Diabetes Centre, Second Medical Department, Aristotle University Thessaloniki, Thessaloníki, Greece.
- Harris Manchester College, University of Oxford, Oxford, UK.
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Yang W, Cai X, Han X, Ji L. DPP-4 inhibitors and risk of infections: a meta-analysis of randomized controlled trials. Diabetes Metab Res Rev 2016; 32:391-404. [PMID: 26417956 DOI: 10.1002/dmrr.2723] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Accepted: 08/25/2015] [Indexed: 12/16/2022]
Abstract
BACKGROUND To evaluate the risk of infections in the treatment of type 2 diabetes patients with dipeptidyl-peptidase 4 (DPP-4) inhibitors. METHODS A literature search was conducted through electronic databases. The inclusion criteria included study duration of no less than 12 weeks developed in type 2 diabetes patients, the use of a randomized control group receiving a DPP-4 inhibitor and the availability of outcome data for infections. Out of 2181 studies, 74 studies were finally included. RESULTS The risk of overall infection for DPP-4 inhibitors treatment was comparable to placebo (odds ratio (OR) = 0.97, 95% confidence interval (CI), 0.91 to 1.04, p = 0.40), metformin treatment (OR = 1.22, 95% CI, 0.95 to 1.56, p = 0.12), sulphonylurea treatment (OR = 1.09, 0.93 to 1.29, p = 0.29), thiazolidinedione treatment (OR = 0.86, 95% CI, 0.65 to 1.14, p = 0.29) and alpha glucosidase inhibitor treatment (OR = 1.03, 95% CI, 0.33 to 3.22, p = 0.96). When compared different DPP-4 inhibitors with placebo treatment, risks of infections were comparable for alogliptin, linagliptin, sitagliptin, saxagliptin and vildagliptin. Compared with placebo or active comparator treatment, risks of infection in different systems for DPP-4 inhibitors were all comparable. CONCLUSIONS The overall risk of infections of DPP-4 inhibitor was not increased compared with control groups.
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Affiliation(s)
- Wenjia Yang
- Endocrinology and Metabolism Department, Peking University People's Hospital, Beijing, China
| | - Xiaoling Cai
- Endocrinology and Metabolism Department, Peking University People's Hospital, Beijing, China
| | - Xueyao Han
- Endocrinology and Metabolism Department, Peking University People's Hospital, Beijing, China
| | - Linong Ji
- Endocrinology and Metabolism Department, Peking University People's Hospital, Beijing, China
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Okamoto A, Yokokawa H, Sanada H. Dipeptidyl peptidase-4 inhibitor (vildagliptin) improves glycemic control after meal tolerance test by suppressing glucagon release. Drugs R D 2016; 14:227-32. [PMID: 25204760 PMCID: PMC4269812 DOI: 10.1007/s40268-014-0062-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Aim We aimed to evaluate changes in insulin and glucagon secretion, as well as glucose levels, with a meal tolerance test (MTT) before and after 6 months of treatment with vildagliptin in a clinical setting. Materials and Methods Participants were 15 patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA1c] over 6.9 % for more than 3 months). MTTs were conducted before and 6 months after addition of vildagliptin (50 mg twice daily [bid]). Blood samples were collected immediately before, and 1 and 2 h after the test meal for measurement of blood glucose concentration, immune-reactive insulin (IRI), and glucagon. HbA1c was measured at 6 months. Results Mean age of participants was 55.5 ± 2.8 years, and ten (66.7 %) were male. Mean HbA1c significantly improved from 7.6 to 6.8 % at 6 months after addition of vildagliptin. Blood glucose at 1 and 2 h after the test meal was significantly reduced after addition of vildagliptin, while the reduction in glucagon showed borderline significance and IRI showed no difference. In a comparison of blood glucose-related parameters between subgroups based on median glucose change in area under the curve during MTT (ΔAUC0–2h), glucagon ΔAUC0–2h was significantly lower in the group with more improved glucose levels (ΔAUC0–2h ≥65 mg/dL), but that of IRI did not differ. Conclusion Suppression of glucagon release by vildagliptin may improve glycemic control without increasing insulin levels in patients with type 2 diabetes.
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Affiliation(s)
| | - Hirohide Yokokawa
- Department of General Medicine, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Hironobu Sanada
- Division of Health Science Research, Fukushima Welfare Federation of Agricultural Cooperatives, Fukushima, Japan
- Department of Tumor and Host Bioscience, Fukushima Medical University School of Medicine, Fukushima, Japan
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Takatori S, Hamada Y, Tanaka A, Akiyama S, Namba H, Tanaka M, Kawasaki H, Araki H. Factors Contributing to the Clinical Effectiveness of the DPP-4 Inhibitor Sitagliptin in Patients With Type 2 Diabetes. Clin Ther 2016; 38:398-403. [DOI: 10.1016/j.clinthera.2015.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 11/06/2015] [Accepted: 12/29/2015] [Indexed: 11/24/2022]
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McInnes G, Evans M, Del Prato S, Stumvoll M, Schweizer A, Lukashevich V, Shao Q, Kothny W. Cardiovascular and heart failure safety profile of vildagliptin: a meta-analysis of 17 000 patients. Diabetes Obes Metab 2015; 17:1085-92. [PMID: 26250051 DOI: 10.1111/dom.12548] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Revised: 07/13/2015] [Accepted: 07/31/2015] [Indexed: 12/26/2022]
Abstract
AIMS To report the cardiovascular (CV) safety profile and heart failure (HF) risk of vildagliptin from a large pool of studies, including trials in high-risk patients with type 2 diabetes mellitus (T2DM), such as those with congestive HF and/or moderate/severe renal impairment. METHODS We conducted a retrospective meta-analysis of prospectively adjudicated CV events. Patient-level data were pooled from 40 double-blind, randomized controlled phase III and IV vildagliptin studies. The primary endpoint was occurrence of major adverse CV events (MACEs; myocardial infarction, stroke and CV death). Assessments of the individual MACE components and HF events (requiring hospitalization or new onset) were secondary endpoints. The risk ratio (RR) of vildagliptin (50 mg once- and twice-daily combined) versus comparators (placebo and all non-vildagliptin treatments) was calculated using the Mantel-Haenszel (M-H) method. RESULTS Of the 17 446 patients, 9599 received vildagliptin (9251.4 subject-years of exposure) and 7847 received comparators (7317.0 subject-years of exposure). The mean age of the patients was 57 years, body mass index 30.5 kg/m(2) (nearly 50% obese), glycated haemoglobin concentration 8.1% and T2DM duration 5.5 years. A MACE occurred in 83 (0.86%) vildagliptin-treated patients and 85 (1.20%) comparator-treated patients, with an M-H RR of 0.82 [95% confidence interval (CI) 0.61-1.11]. Similar RRs were observed for the individual events. Confirmed HF events were reported in 41 (0.43%) vildagliptin-treated patients and 32 (0.45%) comparator-treated patients, with an M-H RR 1.08 (95% CI 0.68-1.70). CONCLUSIONS This large meta-analysis indicates that vildagliptin is not associated with an increased risk of adjudicated MACEs relative to comparators. Moreover, this analysis did not find a significant increased risk of HF in vildagliptin-treated patients.
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Affiliation(s)
- G McInnes
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - M Evans
- University Hospital Llandough, Cardiff, UK
| | - S Del Prato
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - M Stumvoll
- Division of Endocrinology, University Hospital Leipzig, Leipzig, Germany
| | | | - V Lukashevich
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
| | - Q Shao
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
| | - W Kothny
- Novartis Pharma AG, Basel, Switzerland
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Nakamura Y, Hasegawa H, Tsuji M, Udaka Y, Mihara M, Shimizu T, Inoue M, Goto Y, Gotoh H, Inagaki M, Oguchi K. Diabetes therapies in hemodialysis patients: Dipeptidase-4 inhibitors. World J Diabetes 2015; 6:840-9. [PMID: 26131325 PMCID: PMC4478579 DOI: 10.4239/wjd.v6.i6.840] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 03/16/2015] [Accepted: 04/01/2015] [Indexed: 02/05/2023] Open
Abstract
Although several previous studies have been published on the effects of dipeptidase-4 (DPP-4) inhibitors in diabetic hemodialysis (HD) patients, the findings have yet to be reviewed comprehensively. Eyesight failure caused by diabetic retinopathy and aging-related dementia make multiple daily insulin injections difficult for HD patients. Therefore, we reviewed the effects of DPP-4 inhibitors with a focus on oral antidiabetic drugs as a new treatment strategy in HD patients with diabetes. The following 7 DPP-4 inhibitors are available worldwide: sitagliptin, vildagliptin, alogliptin, linagliptin, teneligliptin, anagliptin, and saxagliptin. All of these are administered once daily with dose adjustments in HD patients. Four types of oral antidiabetic drugs can be administered for combination oral therapy with DPP-4 inhibitors, including sulfonylureas, meglitinide, thiazolidinediones, and alpha-glucosidase inhibitor. Nine studies examined the antidiabetic effects in HD patients. Treatments decreased hemoglobin A1c and glycated albumin levels by 0.3% to 1.3% and 1.7% to 4.9%, respectively. The efficacy of DPP-4 inhibitor treatment is high among HD patients, and no patients exhibited significant severe adverse effects such as hypoglycemia and liver dysfunction. DPP-4 inhibitors are key drugs in new treatment strategies for HD patients with diabetes and with limited choices for diabetes treatment.
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Godinho R, Mega C, Teixeira-de-Lemos E, Carvalho E, Teixeira F, Fernandes R, Reis F. The Place of Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes Therapeutics: A "Me Too" or "the Special One" Antidiabetic Class? J Diabetes Res 2015; 2015:806979. [PMID: 26075286 PMCID: PMC4449938 DOI: 10.1155/2015/806979] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2015] [Revised: 04/09/2015] [Accepted: 04/11/2015] [Indexed: 12/12/2022] Open
Abstract
Incretin-based therapies, the most recent therapeutic options for type 2 diabetes mellitus (T2DM) management, can modify various elements of the disease, including hypersecretion of glucagon, abnormal gastric emptying, postprandial hyperglycaemia, and, possibly, pancreatic β cell dysfunction. Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) increase glucagon-like peptide-1 (GLP-1) availability and correct the "incretin defect" seen in T2DM patients. Clinical studies have shown good glycaemic control with minimal risk of hypoglycaemia or any other adverse effects, despite the reports of pancreatitis, whose association remains to be proved. Recent studies have been focusing on the putative ability of DPP-4 inhibitors to preserve pancreas function, in particular due to the inhibition of apoptotic pathways and stimulation of β cell proliferation. In addition, other cytoprotective effects on other organs/tissues that are involved in serious T2DM complications, including the heart, kidney, and retina, have been increasingly reported. This review outlines the therapeutic potential of DPP-4 inhibitors for the treatment of T2DM, focusing on their main features, clinical applications, and risks, and discusses the major challenges for the future, in particular the possibility of becoming the preferred therapy for T2DM due to their ability to modify the natural history of the disease and ameliorate nephropathy, retinopathy, and cardiovascular complications.
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Affiliation(s)
- Ricardo Godinho
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, Coimbra University, 3000-548 Coimbra, Portugal
| | - Cristina Mega
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, Coimbra University, 3000-548 Coimbra, Portugal
- ESAV, Polytechnic Institute of Viseu, 3504-510 Viseu, Portugal
| | - Edite Teixeira-de-Lemos
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, Coimbra University, 3000-548 Coimbra, Portugal
- ESAV, Polytechnic Institute of Viseu, 3504-510 Viseu, Portugal
| | - Eugénia Carvalho
- Center for Neuroscience and Cell Biology-Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Research Unit, University of Coimbra, 3000-548 Coimbra, Portugal
- The Portuguese Diabetes Association (APDP), 1250-189 Lisbon, Portugal
| | - Frederico Teixeira
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, Coimbra University, 3000-548 Coimbra, Portugal
| | - Rosa Fernandes
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, Coimbra University, 3000-548 Coimbra, Portugal
- Center for Neuroscience and Cell Biology-Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Research Unit, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Flávio Reis
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, Coimbra University, 3000-548 Coimbra, Portugal
- Center for Neuroscience and Cell Biology-Institute for Biomedical Imaging and Life Sciences (CNC.IBILI) Research Unit, University of Coimbra, 3000-548 Coimbra, Portugal
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Cai X, Han X, Luo Y, Ji L. Efficacy of dipeptidyl-peptidase-4 inhibitors and impact on β-cell function in Asian and Caucasian type 2 diabetes mellitus patients: A meta-analysis. J Diabetes 2015; 7:347-59. [PMID: 25043156 DOI: 10.1111/1753-0407.12196] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Accepted: 06/21/2014] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND This work aimed to compare the efficacy of dipeptidyl peptidase-IV (DPP-4) inhibitors and their impact on β-cell function in Asian and Caucasian patients with type 2 diabetes mellitus. METHODS Databases were systematically searched and qualifying studies that compared DPP-4 inhibitors with other antidiabetic medications in type 2 diabetes were included. RESULTS A total of 68 studies were included in the meta-analysis. Comparison of DPP-4 inhibitors with placebo in Asian patients showed a decrease in glycosylated hemoglobin (HbA1c ) favoring DPP-4 inhibitors (weighted mean difference [WMD], -0.81%; 95% confidence interval [CI], -0.95% to -0.68%; P < 0.001). Comparison of HbA1c changes between Asian and Caucasian patients showed a significant between-group difference of -0.18% (95% CI, -0.32% to -0.04%; P = 0.011) when compared with placebo. In Asian patients, the homeostatic model assessment for β-cell function (HOMA-β) was increased with DPP-4 inhibitors compared with placebo (WMD, 7.90; 95% CI, 4.29 to 11.51; P < 0.001), although to a lesser extent in Caucasian patients. Comparisons between Asian and Caucasian patients showed a significant between-group difference of -4.97 (95% CI, -9.86 to -0.09; P = 0.046) compared with placebo. Body weight increase with DPP-4 inhibitors compared with placebo was comparable in Asian and Caucasian studies (WMD, 0.37 kg and 0.45 kg and 95% CI, 0.04-0.69 and 0.27-0.62, respectively). CONCLUSIONS The glucose-lowering efficacy of DPP-4 inhibitors was greater in Asian patients than in Caucasian patients, although the effect on β-cell function was inferior in Asian patients. The effect of DPP-4 inhibitors on insulin resistance and body weight in Asian patients was comparable with that observed in Caucasian patients.
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Affiliation(s)
- Xiaoling Cai
- Endocrinology and Metabolism Department, Peking University People's Hospital, Beijing, China
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Odawara M, Yoshiki M, Sano M, Hamada I, Lukashevich V, Kothny W. Efficacy and safety of a single-pill combination of vildagliptin and metformin in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled trial. Diabetes Ther 2015; 6:17-27. [PMID: 25691359 PMCID: PMC4374075 DOI: 10.1007/s13300-015-0099-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Indexed: 11/08/2022] Open
Abstract
INTRODUCTION The use of dipeptidyl peptidase-4 inhibitors in combination with metformin is increasing in Japanese patients with type 2 diabetes mellitus (T2DM), but no single-pill combination (SPC) is currently available in Japan. The objective of this study was to assess the efficacy and safety of vildagliptin/metformin SPC in Japanese patients with T2DM inadequately controlled with vildagliptin monotherapy. METHODS This was a 14-week, randomized, double-blind, parallel-group, placebo-controlled trial. 171 patients with T2DM inadequately controlled [HbA1c (glycosylated hemoglobin) 7.0-10.0%] with vildagliptin 50 mg twice daily (bid) were randomized (2:1) to receive either a vildagliptin/metformin SPC (n = 115) or matching vildagliptin/placebo SPC (n = 56). RESULTS Baseline demographics and background characteristics were generally comparable between the treatment groups. The change in HbA1c [mean ± standard error (SE)] was -0.8 ± 0.1% in the vildagliptin/metformin SPC (baseline HbA1c, 7.9 ± 0.1%) group and 0.1 ± 0.1% in the vildagliptin/placebo SPC (baseline HbA1c, 8.0 ± 0.1%) group, with a between-treatment difference of -1.0 ± 0.1% (P <0.001) in favor of the vildagliptin/metformin SPC group. The proportion of patients achieving target HbA1c <7.0% was significantly higher with vildagliptin/metformin SPC compared with vildagliptin/placebo SPC (45.8% vs. 13.5%, P <0.001). The overall incidences of adverse events (AEs) were 43.5% in the vildagliptin/metformin SPC and 67.9% in the vildagliptin/placebo SPC group. The incidences of serious AEs were low in both the treatment groups (0.9% vs. 3.6%, respectively). Body weight remained constant throughout the study in both the treatment groups. There were no deaths or hypoglycemic events during the study. CONCLUSIONS Switching Japanese patients with T2DM requiring treatment intensification, from vildagliptin monotherapy to a vildagliptin/metformin SPC (50/250 or 50/500 mg) was efficacious and safe, eliciting significant reduction in HbA1c without increased risk of hypoglycemia and weight gain.
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Affiliation(s)
- Masato Odawara
- The Department of Diabetes, Endocrinology, Metabolism and Rheumatology, Tokyo Medical University, Tokyo, Japan,
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Harsha SN, Aldhubiab BE, Nair AB, Alhaider IA, Attimarad M, Venugopala KN, Srinivasan S, Gangadhar N, Asif AH. Nanoparticle formulation by Büchi B-90 Nano Spray Dryer for oral mucoadhesion. DRUG DESIGN DEVELOPMENT AND THERAPY 2015; 9:273-82. [PMID: 25670882 PMCID: PMC4315564 DOI: 10.2147/dddt.s66654] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Diabetes is considered one of the main threats to global public health in this era. It is increasing rapidly in every part of the world; the prevalence of the disease will grow to the point where 366 million people will be affected by 2030. The prevalence of diabetes mellitus (DM) in the Saudi population is high, and the majority of patients suffer from type 2 DM. Marketed oral antidiabetic drugs have indicated poor tolerability during chronic treatments, and this contributes to the moderately large proportion of type 2 DM patients that remain inadequately managed. Vildagliptin nanospheres were prepared with aminated gelatin using a spray-drying method; narrow particle-size distribution was seen at 445 nm. The angle of repose was found to be θ <33.5°. The nanospheres appeared to be spherical with a smooth surface. The drug content and percentage yield of the nanospheres were found to be 76.2%±4.6% and 83%±2%, respectively. The nanosphere-swell profile was found to be 165%±7%. The pure drug was 100% dissolved in 30 minutes, and the nanosphere formulation took 12 hours to dissolve (97.5%±2%), and followed a Korsmeyer-Peppas kinetic model with an R (2) of 0.9838. The wash-off test of nanospheres found that they exhibited an excellent mucoadhesive property at 86.7% for 8 hours. The stability-study data showed no changes in the physicochemical properties of the nanospheres, and suggested that the nanospheres be stored below room temperature. The amount of vildagliptin retained was 1.6% within 3 hours, and in comparison with the gelatin vildagliptin nanoparticles formulation, the percentage that was retained was much higher (98.2% in 12 hours).
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Affiliation(s)
- Sree N Harsha
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Bander E Aldhubiab
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Anroop B Nair
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Ibrahim Abdulrahman Alhaider
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Mahesh Attimarad
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia
| | - Katharigatta N Venugopala
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia
| | | | - Nagesh Gangadhar
- Department of Pharmaceutics, East Point College of Pharmacy, Bangalore, India
| | - Afzal Haq Asif
- Department of Pharmacy Practice, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia
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Aziz KMA. Fasting during Ramadan: efficacy, safety, and patient acceptability of vildagliptin in diabetic patients. Diabetes Metab Syndr Obes 2015; 8:207-11. [PMID: 25931826 PMCID: PMC4404947 DOI: 10.2147/dmso.s54683] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Diabetes management during Ramadan fasting is challenging to the physician in terms of minimizing the risk of hypoglycemia. As compared to oral hypoglycemic agents (OHAs) and sulfonylureas (SUs), which carry a higher and significant risk of hypoglycemia, newer antidiabetic agents such as dipeptidyl peptidase-4 (DPP-4) inhibitors have demonstrated lower risk of hypoglycemia during Ramadan fasting, with better patient compliance. In addition to diabetes education and pre-Ramadan assessments, the physician should also consider use of DPP-4 inhibitors (such as vildagliptin) during Ramadan fasting to minimize the risk of hypoglycemia in type 2 diabetic subjects. Severe episodes of hypoglycemia have been demonstrated in recent research and clinical trials with OHAs/SUs. Conversely, these research observations have also demonstrated comparative safety and efficacy with lower risk of hypoglycemia associated with vildagliptin. Current research review has collected evidence-based clinical trials and observations for the drug vildagliptin to minimize the risk of hypoglycemia during Ramadan fasting, while at the same time focusing the role of diabetes self-management education (DSME), pre-Ramadan assessments, and patient care.
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Affiliation(s)
- Kamran MA Aziz
- Aseer Diabetes Center, Aseer Central Hospital, Ministry of Health, Abha, Saudi Arabia
- Correspondence: Kamran MA Aziz, Aseer Diabetes Center, Aseer Central Hospital, Ministry of Health, PO Box 34, Abha, Saudi Arabia, Tel +966 5 6836 1040, Email
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Raimond V, Josselin JM, Rochaix L. HTA agencies facing model biases: the case of type 2 diabetes. PHARMACOECONOMICS 2014; 32:825-839. [PMID: 24862533 DOI: 10.1007/s40273-014-0172-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
When evaluating new drugs or treatments eligible for reimbursement, health technology assessment (HTA) agencies are repeatedly faced with cost-effectiveness analyses that evidence lack of adequate data and modeling biases. The case of type 2 diabetes illustrates this difficulty. In spite of its high disease burden, type 2 diabetes is poorly documented through existing cost-effectiveness analyses. We support this statement by an exhaustive literature review that enables us to precisely pinpoint the limitations of models used for the assessment of newly marketed (and expensive) drugs. We find that models are mostly restricted to surrogate endpoints and based on non-inferiority clinical trial data; they also show biases in the choice of comparators and inclusion criteria. Such limitations undermine the scope and applicability of HTA practice guidelines based on cost-effectiveness evidence. Nevertheless, cost-effectiveness models remain an opportunity to better inform decision makers and to reduce the uncertainty surrounding their decisions. HTA agencies are best placed to provide incentives for companies to improve the quality of the cost-effectiveness studies submitted for pricing and reimbursement decisions. One such incentive is to include stages of discussion between the company and the health authority during the evaluation process.
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Affiliation(s)
- Véronique Raimond
- Health Economics and Public Health Department, Haute Autorité de Santé, 2, avenue du Stade de France, 93218, Saint-Denis La Plaine Cedex, France,
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Abstract
Gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are the two primary incretin hormones secreted from the intestine on ingestion of glucose or nutrients to stimulate insulin secretion from pancreatic β cells. GIP and GLP‐1 exert their effects by binding to their specific receptors, the GIP receptor (GIPR) and the GLP‐1 receptor (GLP‐1R), which belong to the G‐protein coupled receptor family. Receptor binding activates and increases the level of intracellular cyclic adenosine monophosphate in pancreatic β cells, thereby stimulating insulin secretion glucose‐dependently. In addition to their insulinotropic effects, GIP and GLP‐1 play critical roles in various biological processes in different tissues and organs that express GIPR and GLP‐1R, including the pancreas, fat, bone and the brain. Within the pancreas, GIP and GLP‐1 together promote β cell proliferation and inhibit apoptosis, thereby expanding pancreatic β cell mass, while GIP enhances postprandial glucagon response and GLP‐1 suppresses it. In adipose tissues, GIP but not GLP‐1 facilitates fat deposition. In bone, GIP promotes bone formation while GLP‐1 inhibits bone absorption. In the brain, both GIP and GLP‐1 are thought to be involved in memory formation as well as the control of appetite. In addition to these differences, secretion of GIP and GLP‐1 and their insulinotropic effects on β cells have been shown to differ in patients with type 2 diabetes compared to healthy subjects. We summarize here the similarities and differences of these two incretin hormones in secretion and metabolism, their insulinotropic action on pancreatic β cells, and their non‐insulinotropic effects, and discuss their potential in treatment of type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00022.x, 2010)
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Affiliation(s)
- Yutaka Seino
- The Division of Diabetes, Clinical Nutrition and Endocrinology, Kansai Electric Power Hospital, Osaka
| | - Mitsuo Fukushima
- The Division of Diabetes, Clinical Nutrition and Endocrinology, Kansai Electric Power Hospital, Osaka ; The Department of Nutritional Science, Okayama Prefectural University, Okayama, Japan
| | - Daisuke Yabe
- The Division of Diabetes, Clinical Nutrition and Endocrinology, Kansai Electric Power Hospital, Osaka
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Odawara M, Hamada I, Suzuki M. Efficacy and Safety of Vildagliptin as Add-on to Metformin in Japanese Patients with Type 2 Diabetes Mellitus. Diabetes Ther 2014; 5:169-81. [PMID: 24604395 PMCID: PMC4065285 DOI: 10.1007/s13300-014-0059-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Indexed: 01/27/2023] Open
Abstract
INTRODUCTION The objective of this study was to evaluate the efficacy and safety of vildagliptin, a potent dipeptidyl peptidase-4 inhibitor, as an add-on to metformin in Japanese patients with type 2 diabetes mellitus (T2DM). METHODS This multicenter, 12-week, randomized, double-blind, placebo-controlled, parallel-arm study compared vildagliptin 50 mg bid with placebo in T2DM patients who were inadequately controlled [glycosylated hemoglobin (HbA1c) 7.0-10.0%] on a stable daily dose of metformin monotherapy (250 mg bid or 500 mg bid). RESULTS A total of 139 patients were randomized to receive either vildagliptin (n = 69) or placebo (n = 70). Patient demographics were comparable between the groups at baseline. After 12 weeks of treatment, adjusted mean change in HbA1c was -1.1% in the vildagliptin group (baseline 8.0%) and -0.1% in the placebo group (baseline 8.0%), with a between-treatment difference of -1.0% (P < 0.001). Vildagliptin showed a similar reduction in HbA1c of -1.1% for both the subpopulations of patients receiving metformin 250 mg bid or 500 mg bid (P < 0.001 vs. baseline). Significantly more patients in the vildagliptin group achieved an HbA1c target of ≤6.5% (30.9%) and <7.0% (64.1%) compared with the placebo group (P < 0.001). The between-treatment difference in adjusted mean change in fasting plasma glucose was -1.6 mmol/L (P < 0.001) in favor of vildagliptin. Patients in the vildagliptin and placebo groups reported comparable incidences of adverse events (44.1% vs. 41.4%). No deaths or hypoglycemic events were reported in the study. CONCLUSIONS Vildagliptin 50 mg bid added to metformin improved glycemic control without any tolerability issues and hypoglycemia in Japanese patients with T2DM inadequately controlled on metformin monotherapy.
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Affiliation(s)
- Masato Odawara
- The Third Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan,
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Yabe D, Kuroe A, Lee S, Watanabe K, Hyo T, Hishizawa M, Kurose T, Deacon CF, Holst JJ, Hirano T, Inagaki N, Seino Y. Little enhancement of meal-induced glucagon-like peptide 1 secretion in Japanese: Comparison of type 2 diabetes patients and healthy controls. J Diabetes Investig 2014; 1:56-9. [PMID: 24843409 PMCID: PMC4020678 DOI: 10.1111/j.2040-1124.2010.00010.x] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Although glucose-dependent insulinotropic polypeptide (GIP) levels have been characterized previously, GLP-1 levels in Asians remain unclear. Here, we investigate total and intact levels of GLP-1, as well as GIP during oral glucose and meal tolerance tests (OGTT and MTT) in Japanese patients with or without type 2 diabetes (T2DM). Seventeen Japanese healthy controls and 18 age-matched and untreated patients with T2DM of short duration participated in the present study. Fasting levels of total GPL-1 were similar between the two groups (approximately 15 pM), and intact GLP-1 levels were considerably low in both groups (less than 1 pM). In both groups, total GLP-1 reached a peak 30 min after glucose ingestion (30-40 pM), whereas intact GLP-1 levels remained low with no significant peak. In MTT, total and intact GLP-1 showed no obvious peak. The current data indicate that intact GLP-1 levels are considerably low in the Japanese and that meal-induced enhancement of GLP-1 secretion is negligible in the Japanese. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00010.x, 2010).
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Affiliation(s)
- Daisuke Yabe
- Division of Diabetes, Clinical Nutrition and Endocrinology, Kansai Electric Power Hospital, Osaka
| | - Akira Kuroe
- Division of Diabetes, Clinical Nutrition and Endocrinology, Kansai Electric Power Hospital, Osaka
| | - Soushou Lee
- Department of Diabetes, Metabolism and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Koin Watanabe
- Division of Diabetes, Clinical Nutrition and Endocrinology, Kansai Electric Power Hospital, Osaka
| | - Takanori Hyo
- Division of Diabetes, Clinical Nutrition and Endocrinology, Kansai Electric Power Hospital, Osaka
| | - Masahiro Hishizawa
- Division of Diabetes, Clinical Nutrition and Endocrinology, Kansai Electric Power Hospital, Osaka
| | - Takeshi Kurose
- Division of Diabetes, Clinical Nutrition and Endocrinology, Kansai Electric Power Hospital, Osaka
| | - Carolyn F Deacon
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tsutomu Hirano
- Department of Diabetes, Metabolism and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Nobuya Inagaki
- Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yutaka Seino
- Division of Diabetes, Clinical Nutrition and Endocrinology, Kansai Electric Power Hospital, Osaka
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Ravva P, Karlsson MO, French JL. A linearization approach for the model-based analysis of combined aggregate and individual patient data. Stat Med 2014; 33:1460-76. [PMID: 24488864 DOI: 10.1002/sim.6045] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2012] [Revised: 10/22/2013] [Accepted: 10/29/2013] [Indexed: 11/08/2022]
Abstract
The application of model-based meta-analysis in drug development has gained prominence recently, particularly for characterizing dose-response relationships and quantifying treatment effect sizes of competitor drugs. The models are typically nonlinear in nature and involve covariates to explain the heterogeneity in summary-level literature (or aggregate data (AD)). Inferring individual patient-level relationships from these nonlinear meta-analysis models leads to aggregation bias. Individual patient-level data (IPD) are indeed required to characterize patient-level relationships but too often this information is limited. Since combined analyses of AD and IPD allow advantage of the information they share to be taken, the models developed for AD must be derived from IPD models; in the case of linear models, the solution is a closed form, while for nonlinear models, closed form solutions do not exist. Here, we propose a linearization method based on a second order Taylor series approximation for fitting models to AD alone or combined AD and IPD. The application of this method is illustrated by an analysis of a continuous landmark endpoint, i.e., change from baseline in HbA1c at week 12, from 18 clinical trials evaluating the effects of DPP-4 inhibitors on hyperglycemia in diabetic patients. The performance of this method is demonstrated by a simulation study where the effects of varying the degree of nonlinearity and of heterogeneity in covariates (as assessed by the ratio of between-trial to within-trial variability) were studied. A dose-response relationship using an Emax model with linear and nonlinear effects of covariates on the emax parameter was used to simulate data. The simulation results showed that when an IPD model is simply used for modeling AD, the bias in the emax parameter estimate increased noticeably with an increasing degree of nonlinearity in the model, with respect to covariates. When using an appropriately derived AD model, the linearization method adequately corrected for bias. It was also noted that the bias in the model parameter estimates decreased as the ratio of between-trial to within-trial variability in covariate distribution increased. Taken together, the proposed linearization approach allows addressing the issue of aggregation bias in the particular case of nonlinear models of aggregate data.
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Affiliation(s)
- Patanjali Ravva
- Pharmacometrics, Primary Care Business Unit, Pfizer Inc, Eastern Point Road, Groton, CT 06340, U.S.A
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Nakamura Y, Tsuji M, Hasegawa H, Kimura K, Fujita K, Inoue M, Shimizu T, Gotoh H, Goto Y, Inagaki M, Oguchi K. Anti-inflammatory effects of linagliptin in hemodialysis patients with diabetes. Hemodial Int 2014; 18:433-42. [PMID: 24405885 DOI: 10.1111/hdi.12127] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Inflammation and glycemic control are important prognosis-related factors for hemodialysis (HD) patients; moreover, inflammation affects insulin secretion. Here, we evaluated the anti-inflammatory effects of monotherapy with linagliptin-a dipeptidase-4 inhibitor-in HD patients with type 2 diabetes. We examined 21 diabetic HD patients who were not receiving oral diabetes drugs or insulin therapy and with poor glycemic control (glycated albumin [GA] level, >20%). Linagliptin (5 mg) was administered to the patients daily. The levels of prostaglandin E2 (PGE2), interleukin-6 (IL-6), high-sensitivity C-reactive protein, GA, blood glucose, and active glucagon-like peptide-1 were determined before and 6 months after treatment. Body weight and serum levels of albumin, hemoglobin, total cholesterol, and low-density lipoprotein cholesterol were also recorded before and after treatment. The levels of PGE2 and GA were significantly decreased 1 month after starting linagliptin therapy, whereas the IL-6 levels were significantly decreased 6 months after starting linagliptin therapy. After 6 months of treatment, the PGE2 levels decreased from 188 ± 50 ng/mL to 26 ± 5 ng/mL; IL-6 levels, from 1.5 ± 0.4 pg/mL to 0.6 ± 0.1 pg/mL; and GA levels, from 21.3% ± 0.6% to 18.0% ± 0.6%. Glucagon-like peptide-1 levels increased 2.5-fold during the treatment. Over the 6-month treatment period, body weight and levels of high-sensitivity C-reactive protein, blood glucose, albumin, hemoglobin, and cholesterol did not change; none of the patients exhibited hypoglycemia. The anti-inflammatory effects of linagliptin monotherapy indicate that it may serve as a useful glucose control strategy for HD patients with diabetes.
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Affiliation(s)
- Yuya Nakamura
- Saiyu Soka Hospital, Soka, Japan; Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan
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Li CJ, Liu XJ, Bai L, Yu Q, Zhang QM, Yu P, Yu DM. Efficacy and safety of vildagliptin, Saxagliptin or Sitagliptin as add-on therapy in Chinese patients with type 2 diabetes inadequately controlled with dual combination of traditional oral hypoglycemic agents. Diabetol Metab Syndr 2014; 6:69. [PMID: 24917890 PMCID: PMC4050987 DOI: 10.1186/1758-5996-6-69] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2014] [Accepted: 05/26/2014] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The oral DPP-4 inhibitors are new incretin-based therapies for treatment of type 2 diabetes. To assess the efficacy and safety of three DPP-4 inhibitors (Saxagliptin, Sitagliptin and Vildagliptin) as add-on therapy to dual combination of traditional oral hypoglycemic agents in Chinese type 2 diabetes patients. METHODS In this 24-week, randomized, open-label, parallel clinical trial, we enrolled inadequately controlled (glycosylated haemoglobin A1c [HbA1c] ≥7.5% to ≤10%) patients with type 2 diabetes, who were treated by dual combination of metformin and another traditional oral hypoglycemic agent (glimepiride, acarbose or pioglitazone). 207 patients had been randomized to add-on 5 mg saxagliptin group or 100 mg sitagliptin once daily group, or 50 mg vildagliptin twice daily group for 24 weeks. HbA1c, fasting and postprandial blood glucose (FBG and P2hBG), body weight, body mass index (BMI), episodes of hypoglycemia and adverse events were evaluated. RESULT After 24 weeks, HbA1c, FBG, and P2hBG of each group were significantly decreased. (saxagliptin vs vildagliptin vs sitagliptin: HbA1c: -1.2% vs -1.3% vs -1.1%; FBG: -1.8 mmol/l vs -2.4 mmol/l vs -1.5 mmol/l; P2hBG: -3.4 mmol/l vs -3.7 mmol/l vs -3.2 mmol/l). The changes of HbA1c and P2hBG among the three groups had no significance. However, vildagliptin-added group showed the greatest reduction (p < 0.001), while, sitagliptin-added group showed the lowest reduction (p < 0.001) in terms of FPG changes. Proportions of patients achieving HbA1c < 7% at the end were similar in three groups (saxagliptin 59%, vildagliptin 65%, sitagliptin 59%). Mild hypoglycemia was commonly reported among the three groups (saxagliptin 6%, vildagliptin 2%, sitagliptin 3%). No significant between-group difference was shown in other AEs. CONCLUSION The three gliptins showed almost similar glycemic control and incidence of adverse events. However, for FBG control, saxagliptin demonstrated superiority to sitagliptin, while, inferiority to vildagliptin.
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Affiliation(s)
- Chun-Jun Li
- Department of Endocrinology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Xiao-Juan Liu
- Department of Endocrinology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Lian Bai
- Department of Endocrinology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Qian Yu
- Department of Endocrinology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Qiu-Mei Zhang
- Department of Endocrinology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Pei Yu
- Department of Endocrinology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - De-Min Yu
- Department of Endocrinology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
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Shima K, Komatsu M, Noma Y, Miya K. Glycated albumin (GA) is more advantageous than hemoglobin A1c for evaluating the efficacy of sitagliptin in achieving glycemic control in patients with type 2 diabetes. Intern Med 2014; 53:829-35. [PMID: 24739602 DOI: 10.2169/internalmedicine.53.1364] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
OBJECTIVE The aim of this study was to compare the utility of hemoglobin A1c (HbA1c) and glycated albumin (GA) for evaluating the efficacy of the dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin, in patients with type 2 diabetes. METHODS Sitagliptin (50 mg) was administered orally once daily in 67 outpatients with type 2 diabetes. Drug effectiveness was deemed present if the HbA1c or GA level decreased by 5% at week 4 and week 12 relative to the baseline value. RESULTS The mean HbA1c level decreased from 8.1 ± 1.0% at baseline to 7.8 ± 0.9% at week 4 and 7.2 ± 0.8% at week 12. The mean GA level decreased from 25.0 ± 4.5% at baseline to 22.2 ± 3.8% at week 4 and 20.8 ± 3.5% at week 12. At week 4 and week 12, the drug was effective in 37.8% and 71.6% of the patients, respectively, when assessed based on changes in HbA1c, and in 83.6% and 97.0% of the patients, respectively, when assessed based on changes in GA. CONCLUSION GA is superior to HbA1c for evaluating the efficacy of sitagliptin treatment in patients with type 2 diabetes.
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Affiliation(s)
- Kenji Shima
- Department of Diabetes and Medicine, Kawashima Hospital, Japan
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Kozlovski P, Foley J, Shao Q, Lukashevich V, Kothny W. Vildagliptin-insulin combination improves glycemic control in Asians with type 2 diabetes. World J Diabetes 2013; 4:151-156. [PMID: 23961326 PMCID: PMC3746088 DOI: 10.4239/wjd.v4.i4.151] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Revised: 05/11/2013] [Accepted: 06/19/2013] [Indexed: 02/05/2023] Open
Abstract
AIM: To assess the efficacy and safety of vildagliptin 50 mg bid as add-on therapy to insulin in Asian patients with type 2 diabetes mellitus (T2DM).
METHODS: This was a post hoc analysis of a subgroup of Asian patients from a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in T2DM patients inadequately controlled by stable insulin therapy, with or without metformin. A total of 173 patients were randomized 1:1 to receive treatment with vildagliptin 50 mg bid (n = 87) or placebo (n = 86) for 24 wk. Changes in HbA1c and fasting plasma glucose (FPG), from baseline to study endpoint, were analyzed using an analysis of covariance model. Change from baseline to endpoint in body weight was summarized by treatment. Safety and tolerability of vildagliptin was also evaluated.
RESULTS: After 24 wk, the difference in adjusted mean change in HbA1c between vildagliptin and placebo was 0.82% (8.96 mmol/mol; P < 0.001) in Asian subgroup, 0.85% (9.29 mmol/mol; P < 0.001) in patients also receiving metformin, and 0.73% (7.98 mmol/mol; P < 0.001) in patients without metformin, all in favor of vildagliptin. There was no significant difference in the change in FPG between treatments. Weight was stable in both treatment groups (+ 0.3 kg and -0.2 kg, for vildagliptin and placebo, respectively). Overall, vildagliptin was safe and well tolerated with similarly low incidences of hypoglycemia (8.0% vs 8.1%) and no severe hypoglycemic events were experienced in either group.
CONCLUSION: In Asian patients inadequately controlled with insulin (with or without concomitant metformin), insulin-vildagliptin combination treatment significantly reduced HbA1c compared with placebo, without an increase in risk of hypoglycemia or weight gain.
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Nakamura Y, Inagaki M, Shimizu T, Fujita K, Inoue M, Gotoh H, Oguchi K, Goto Y. Long-term effects of alogliptin benzoate in hemodialysis patients with diabetes: a 2-year study. Nephron Clin Pract 2013; 123:46-51. [PMID: 23774306 DOI: 10.1159/000351678] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Accepted: 04/22/2013] [Indexed: 12/24/2022] Open
Abstract
AIM To evaluate the long-term efficacy of monotherapy with the dipeptidase-4 inhibitor alogliptin benzoate in hemodialysis (HD) patients with type 2 diabetes. METHODS Sixteen diabetic HD patients with inadequate glycemic control (hemoglobin A1c (HbA1c) level >6.5% and glycated albumin (GA) level >20%) on diet and exercise participated in the study. No patients were taking other oral antidiabetic drugs or receiving insulin therapy. Alogliptin 6.25 mg was administered to patients once daily. HbA1c, GA levels were obtained before and after 2 years of treatment. Body weight and active glucagon-like peptide-1, blood glucose, insulin, C-peptide immunoreactivity, glucagon, albumin, hemoglobin, and total cholesterol levels were also examined before and after treatment. RESULTS Both HbA1c and GA levels decreased after starting alogliptin administration. As compared to the pretreatment levels, HbA1c and GA levels significantly decreased at 3 and 18 months, respectively, after starting alogliptin administration. HbA1c and GA levels decreased from 7.1 ± 0.2 to 5.8 ± 1.6% and from 22.5 ± 0.7 to 19.6 ± 0.6%, respectively, 24 months after beginning treatment. Glucagon-like peptide-1 levels (8.9 ± 5.7 pmol/l before treatment) doubled after treatment. Body weight and blood glucose, insulin, C-peptide immunoreactivity, glucagon, albumin, hemoglobin, and total cholesterol levels did not change with treatment. Only one significant adverse effect, a drug-related rash, was seen in 1 patient. CONCLUSION Long-term (2-year) effects of alogliptin benzoate monotherapy suggest its efficacy as a new treatment strategy in diabetic HD patients.
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Affiliation(s)
- Yuya Nakamura
- Saiyu Soka Hospital, Showa University, Soka City, Saitama-ken, Japan.
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Oh TJ, Jung HS, Bae JH, Kim YG, Park KS, Cho YM, Park KS, Kim SY. Clinical characteristics of the responders to dipeptidyl peptidase-4 inhibitors in Korean subjects with type 2 diabetes. J Korean Med Sci 2013; 28:881-7. [PMID: 23772153 PMCID: PMC3678005 DOI: 10.3346/jkms.2013.28.6.881] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Accepted: 04/01/2013] [Indexed: 11/20/2022] Open
Abstract
We investigated characteristics associated with the efficacy of dipeptidyl peptidase-4 inhibitors (DPP4i) in Korean patients with type 2 diabetes. We reviewed medical records of 477 patients who had taken sitagliptin or vildagliptin longer than 40 weeks. Response to DPP4i was evaluated with HbA1c change after therapy (ΔHbA1c). The Student's t-test between good responders (GR: ΔHbA1c > 1.0%) and poor responders (PR: ΔHbA1c < 0.5%), a correlation analysis among clinical parameters, and a linear multivariate regression analysis were performed. The mean age was 60 yr, duration of diabetes 11 yr and HbA1c was 8.1%. Baseline fasting plasma glucose (FPG), HbA1c, C-peptide, and creatinine were significantly higher in the GR compared to the PR. Duration of diabetes, FPG, HbA1c, C-peptide and creatinine were significantly correlated with ΔHbA1c. In the multivariate analysis, age (r(2) = 0.006), duration of diabetes (r(2) = 0.019), HbA1c (r(2) = 0.296), and creatinine levels (r(2) = 0.024) were independent predictors for the response to DPP4i. Body mass index and insulin resistance were not associated with the response to DPP4i. In conclusion, better response to DPP4i would be expected in Korean patients with type 2 diabetes who have higher baseline HbA1c and creatinine levels with shorter duration of diabetes.
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Affiliation(s)
- Tae Jung Oh
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Hye Seung Jung
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Hyun Bae
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Yeong Gi Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Kyeong Seon Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Young Min Cho
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Kyong Soo Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Seong Yeon Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
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George RE, Joseph S. A review of newer treatment approaches for type-2 diabetes: Focusing safety and efficacy of incretin based therapy. Saudi Pharm J 2013; 22:403-10. [PMID: 25473328 DOI: 10.1016/j.jsps.2013.05.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Accepted: 05/17/2013] [Indexed: 02/06/2023] Open
Abstract
Diabetes resulting from both genetic and lifestyle factors causes high insulin deficiency or its resistance. As hyperglycemia and decreased insulin secretion and/or its sensitivity appear to be the primary defects associated with diabetes, available treatments focus on reducing those defects. A novel approach of treatment is to target the incretin mimetic hormones, which are secreted by intestinal cells in response to food intake, provoking glucose-dependent insulin secretion from the pancreas. Efficacy and safety studies of dipetidyl peptidase inhibitors (DPP-IV), sitagliptin, vildagliptin and linagliptin provide similar improvements in HbA1c levels when compared with metformin, sulfonylureas or glitazones without contributing to weight gain and hypoglycemia. Caution is required when choosing the gliptin in people with renal or hepatic impairment and with a risk of pancreatitis. The glucagon like peptide (GLP-1) analogues Exenatide and Liraglutide also have positive impact on glycemic control especially when used as a combination therapy. Another upcoming approach is using sodium-glucose co transporter two inhibitors in kidney, by exploring pathophysiology of renal glucose re absorption in the proximal tubule.
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Affiliation(s)
- Regin Elsa George
- Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita Viswa Vidyapeetham University, Amrita Institute of Medical Sciences, Ponekkara, Kochi, Kerala, India
| | - Siby Joseph
- Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita Viswa Vidyapeetham University, Amrita Institute of Medical Sciences, Ponekkara, Kochi, Kerala, India
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