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Murray-Thomas T, Dcruz JM, Harder-Lauridsen NM, Olsen AH, Williams R, Major-Pedersen A. Real-world use of liraglutide for weight management according to label in the United Kingdom: A cohort study using the Clinical Practice Research Datalink primary care databases. Diabetes Obes Metab 2025. [PMID: 40292833 DOI: 10.1111/dom.16393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 03/27/2025] [Accepted: 03/28/2025] [Indexed: 04/30/2025]
Abstract
AIMS To assess real-world use of Saxenda® (liraglutide 3.0 mg) and off-label use of Victoza® (liraglutide 1.2 mg/1.8 mg) for weight management and Saxenda® posology in the United Kingdom. Their similar doses and formulation pose a risk of inadvertent use due to their use for different indications. MATERIALS AND METHODS This retrospective, non-interventional drug utilization cohort study (DUS), based on anonymized patient data from the Clinical Practice Research Datalink databases (CPRD Aurum, GOLD), included adult liraglutide initiators without prior prescription 12 months before the index date. Descriptive statistics were used to characterize Saxenda® and Victoza® user demographics and drug utilization. RESULTS Totally 604 Saxenda® and 4853 Victoza® patients were included. Approximately half of the Saxenda® initiators (Si's) (N = 306) had available body weight, of which 96.4% initiated treatment according to the weight loss indication. Si's were more likely female than Victoza® initiators (Vi's) (86.4% vs. 52.1%), younger (mean age ± SD: 46.5 ± 11.7 years) versus (57.5 ± 12.0 years) and with shorter duration of follow-up observation (18.8 ± 13.9 months) versus (32.9 ± 15.9 months). N < 5 of 16 patients with 24-weeks body mass index (BMI) data did not adhere to the Saxenda® stopping rule. N < 5 of 92 patients with valid dose used Victoza® outside the diabetes indication. CONCLUSIONS This DUS provides descriptive data for initiators of liraglutide in the initial 5-year period following the launch of Saxenda® in the United Kingdom. Real-world use of Saxenda® and Victoza® raised no new safety concerns. Where assessment was possible, Saxenda® and Victoza® were mostly prescribed by physicians according to their approved indications.
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Affiliation(s)
- Tarita Murray-Thomas
- Clinical Practice Research Datalink, Medicines and Healthcare Products Regulatory Agency, London
| | | | | | | | - Rachael Williams
- Clinical Practice Research Datalink, Medicines and Healthcare Products Regulatory Agency, London
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Ali A, Khan D, Dubey V, Tarasov AI, Flatt PR, Irwin N. Comparative Effects of GLP-1 and GLP-2 on Beta-Cell Function, Glucose Homeostasis and Appetite Regulation. Biomolecules 2024; 14:1520. [PMID: 39766228 PMCID: PMC11673903 DOI: 10.3390/biom14121520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 11/21/2024] [Accepted: 11/26/2024] [Indexed: 01/11/2025] Open
Abstract
Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are related intestinal L-cell derived secretory products. GLP-1 has been extensively studied in terms of its influence on metabolism, but less attention has been devoted to GLP-2 in this regard. The current study compares the effects of these proglucagon-derived peptides on pancreatic beta-cell function, as well as on glucose tolerance and appetite. The insulin secretory effects of GLP-1 and GLP-2 (10-12-10-6 M) were investigated in BRIN-BD11 beta-cells as well as isolated mouse islets, with the impact of test peptides (10 nM) on real-time cytosolic cAMP levels further evaluated in mouse islets. The impact of both peptides (10-8-10-6 M) on beta-cell growth and survival was also studied in BRIN BD11 cells. Acute in vivo (peptides administered at 25 nmol/kg) glucose homeostatic and appetite suppressive actions were then examined in healthy mice. GLP-1, but not GLP-2, concentration dependently augmented insulin secretion from BRIN-BD11 cells, with similar observations made in isolated murine islets. In addition, GLP-1 substantially increased [cAMP]cyt in islet cells and was significantly more prominent than GLP-2 in this regard. Both GLP-1 and GLP-2 promoted beta-cell proliferation and protected against cytokine-induced apoptosis. In overnight fasted healthy mice, as well as mice trained to eat for 3 h per day, the administration of GLP-1 or GLP-2 suppressed appetite. When injected conjointly with glucose, both peptides improved glucose disposal, which was associated with enhanced glucose-stimulated insulin secretion by GLP-1, but not GLP-2. To conclude, the impact of GLP-1 and GLP-2 on insulin secretion is divergent, but the effects of beta-cell signaling and overall health are similar. Moreover, the peripheral administration of either hormone in rodents results in comparable positive effects on blood glucose levels and appetite.
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Affiliation(s)
| | | | | | | | | | - Nigel Irwin
- Centre for Diabetes, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine BT52 1SA, Northern Ireland, UK; (A.A.); (D.K.); (V.D.); (A.I.T.); (P.R.F.)
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Moreira RO, Valerio CM, Hohl A, Moulin C, Moura F, Trujilho FR, Gerchman F, Correa LL, Mancini MC, Melo ME, Lamounier RN, van de Sande-Lee S, Trujilho TDG, Miranda PAC, Halpern B. Pharmacologic Treatment of Obesity in adults and its impact on comorbidities: 2024 Update and Position Statement of Specialists from the Brazilian Association for the Study of Obesity and Metabolic Syndrome (Abeso) and the Brazilian Society of Endocrinology and Metabolism (SBEM). ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2024; 68:e240422. [PMID: 39664998 PMCID: PMC11634287 DOI: 10.20945/2359-4292-2024-0422] [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: 10/21/2024] [Accepted: 10/28/2024] [Indexed: 12/13/2024]
Abstract
Pharmacological treatment of obesity is passing through many changes in the last decades; different agents have been approved, and newer options are leaning towards higher efficacy and a more favourable safety profile; however, medications approved for a longer time are still available and useful for many patients. This document is an 2024 Update Position Statement of Specialists from the Brazilian Association for the Study of Obesity and Metabolic Syndrome (Abeso) and the Brazilian Society of Endocrinology and Metabolism (SBEM), with the aim of reviewing all the approved medications for the management of obesity in Brazil (sibutramine, orlistat, liraglutide, semaglutide and bupropion/naltrexone fixed dose), with the addition of tirzepatide, that is approved in other countries and likely approved soon in Brazil. The review is focused on efficacy, safety profile and the impact of drugs (based on existing studies) on different comorbidities.
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Affiliation(s)
- Rodrigo O. Moreira
- Instituto Estadual de Diabetes e Endocrinologia Luis CapriglioneRio de JaneiroRJBrasil Instituto Estadual de Diabetes e Endocrinologia Luis Capriglione, Rio de Janeiro, RJ, Brasil
- Centro Universitário Presidente Antonio CarlosJuiz de ForaMGBrasil Centro Universitário Presidente Antonio Carlos – Campus Juiz de Fora, Juiz de Fora, MG, Brasil
- Centro Universitário de ValençaValençaRJBrasil Centro Universitário de Valença, Valença, RJ, Brasil
| | - Cynthia M. Valerio
- Instituto Estadual de Diabetes e Endocrinologia Luis CapriglioneRio de JaneiroRJBrasil Instituto Estadual de Diabetes e Endocrinologia Luis Capriglione, Rio de Janeiro, RJ, Brasil
| | - Alexandre Hohl
- Departamento de Clínica MédicaUniversidade Federal de Santa CatarinaFlorianópolisSCBrasil Departamento de Clínica Médica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brasil
| | - Cristiane Moulin
- Centro Especializado em Diabetes, Obesidade e HipertensãoSecretaria de Saúde do Distrito FederalBrasíliaDFBrasil Centro Especializado em Diabetes, Obesidade e Hipertensão, Secretaria de Saúde do Distrito Federal, Brasília, DF, Brasil
| | - Fábio Moura
- Universidade de PernambucoRecifePEBrasil Universidade de Pernambuco, Recife, PE, Brasil
- Instituto de Medicina Integrada de PernambucoRecifePEBrasil Instituto de Medicina Integrada de Pernambuco, Recife, PE, Brasil
| | - Fábio R. Trujilho
- Centro de Diabetes e Endocrinologia da BahiaSalvadorBABrasil Serviço de Obesidade e Lipodistrofia, Centro de Diabetes e Endocrinologia da Bahia, Salvador, BA, Brasil
| | - Fernando Gerchman
- Departamento de Clínica MédicaFaculdade de MedicinaUniversidade Federal do Rio Grande do SulPorto AlegreRSBrasil Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
- Hospital de Clínicas de Porto AlegrePorto AlegreRSBrasil Serviço de Endocrinologia e Metabolismo, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil
| | - Livia L. Correa
- Instituto Estadual de Diabetes e Endocrinologia Luis CapriglioneRio de JaneiroRJBrasil Instituto Estadual de Diabetes e Endocrinologia Luis Capriglione, Rio de Janeiro, RJ, Brasil
| | - Marcio C. Mancini
- Hospital das ClínicasFaculdade de MedicinaUniversidade de São PauloSão PauloSPBrasil Grupo de Obesidade, Disciplina de Endocrinologia e Metabolismo, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - Maria Edna Melo
- Hospital das ClínicasFaculdade de MedicinaUniversidade de São PauloSão PauloSPBrasil Grupo de Obesidade, Disciplina de Endocrinologia e Metabolismo, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - Rodrigo N. Lamounier
- Departamento de Clínica MédicaUniversidade Federal de Minas GeraisBelo HorizonteMGBrasil Departamento de Clínica Médica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
- Hospital Mater DeiBelo HorizonteMGBrasil Serviço de Endocrinologia, Hospital Mater Dei, Belo Horizonte, MG, Brasil
| | - Simone van de Sande-Lee
- Departamento de Clínica MédicaUniversidade Federal de Santa CatarinaFlorianópolisSCBrasil Departamento de Clínica Médica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brasil
| | - Thaísa D. G. Trujilho
- Centro de Diabetes e Endocrinologia da BahiaSalvadorBABrasil Serviço de Obesidade e Lipodistrofia, Centro de Diabetes e Endocrinologia da Bahia, Salvador, BA, Brasil
| | - Paulo A. C. Miranda
- Hospital Mater DeiBelo HorizonteMGBrasil Serviço de Endocrinologia, Hospital Mater Dei, Belo Horizonte, MG, Brasil
- Santa Casa da Misericórdia de Belo HorizonteBelo HorizonteMGBrasil Serviço de Endocrinologia e Metabolismo, Santa Casa da Misericórdia de Belo Horizonte, Belo Horizonte, MG, Brasil
| | - Bruno Halpern
- Centro de ObesidadeHospital Nove de JulhoSão PauloSPBrasil Centro de Obesidade, Hospital Nove de Julho, São Paulo, SP, Brasil
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Cai X, Cao J, Wang L, Zou J, Li R, Sun P, Ding X, Zhang B, Liu Z, Pei X, Yang J, Zhan Y, Liu N, Liu T, Liang R, Gao J, Wang S. Liraglutide Protects Pancreatic Islet From Ischemic Injury by Reducing Oxidative Stress and Activating Akt Signaling During Cold Preservation to Improve Islet Transplantation Outcomes. Transplantation 2024; 108:e156-e169. [PMID: 38578708 DOI: 10.1097/tp.0000000000004949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2024]
Abstract
BACKGROUND Islet transplantation is a promising therapy for patients with type 1 diabetes. However, ischemic injury to the donor islets during cold preservation leads to reduced islet quality and compromises transplant outcome. Several studies imply that liraglutide, a glucagon-like peptide-1 receptor agonist, has a positive effect on promoting islet survival, but its impact on islet cold-ischemic injury remains unexplored. Therefore, the aim of this study was to investigate whether liraglutide can improve islet transplantation efficacy by inhibiting cold-ischemic injury and to explore the underlying mechanisms. METHODS Liraglutide was applied in a mouse pancreas preservation model and a human islets cold-preservation model, and islet viability, function, oxidative stress levels were evaluated. Furthermore, islet transplantation was performed in a syngeneic mouse model and a human-to-nude mouse islet xenotransplantation model. RESULTS The supplementation of liraglutide in preservation solution improved islet viability, function, and reduced cell apoptosis. Liraglutide inhibited the oxidative stress of cold-preserved pancreas or islets through upregulating the antioxidant enzyme glutathione levels, inhibiting reactive oxygen species accumulation, and maintaining the mitochondrial membrane integrity, which is associated with the activation of Akt signaling. Furthermore, the addition of liraglutide during cold preservation of donor pancreas or donor islets significantly improved the subsequent transplant outcomes in both syngeneic mouse islet transplantation model and human-to-nude mouse islet xenotransplantation model. CONCLUSIONS Liraglutide protects islets from cold ischemia-related oxidative stress during preservation and hence improved islet transplantation outcomes, and this protective effect of liraglutide in islets is associated with the activation of Akt signaling.
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Affiliation(s)
- Xiangheng Cai
- School of Medicine, Nankai University, Tianjin, China
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Jinglin Cao
- Department of Hepatobiliary Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Le Wang
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Jiaqi Zou
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Rui Li
- Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - Peng Sun
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Xuejie Ding
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Boya Zhang
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Zewen Liu
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Xirui Pei
- First Clinical Department, The First Hospital of China Medical University, China Medical University, Shenyang, China
| | - Jiuxia Yang
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Yixiang Zhan
- School of Medicine, Nankai University, Tianjin, China
| | - Na Liu
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Tengli Liu
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Rui Liang
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Jie Gao
- State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, China
| | - Shusen Wang
- School of Medicine, Nankai University, Tianjin, China
- Research Institute of Transplant Medicine, Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
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Scheen AJ. Underuse of GLP-1 receptor agonists in the management of type 2 diabetes despite a favorable benefit-safety profile. Expert Opin Drug Saf 2024; 23:797-810. [PMID: 38738549 DOI: 10.1080/14740338.2024.2354885] [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: 01/07/2024] [Accepted: 05/09/2024] [Indexed: 05/14/2024]
Abstract
INTRODUCTION Patients with type 2 diabetes (T2DM) are at high risk of atherosclerotic cardiovascular disease (ASCVD) and cardiovascular death. Cardiovascular protection is a key objective in T2DM. AREAS COVERED Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have proven their efficacy in reducing major cardiovascular events in high-risk patients with T2DM in placebo-controlled trials, a finding confirmed in observational studies compared with other glucose-lowering agents. Overall, GLP-1RAs have a good safety profile associated with a favorable benefit/risk ratio for the management of T2DM, even if their cost-effectiveness might be questionable. International guidelines recommend GLP-1RAs as preferred glucose-lowering agents in patients with ASCVD and as a valuable alternative in overweight/obese patients with T2DM. However, real-life studies worldwide revealed that only a minority of patients receive a GLP-1RA, despite a positive trend for increased prescriptions in recent years. Surprisingly, however, fewer patients with established ASCVD are treated with these cardioprotective antihyperglycemic agents versus patients without ASCVD. EXPERT OPINION The reasons for GLP-1RA underuse in clinical practice are multiple. Multifaceted and coordinated interventions targeting all actors of the health-care system must be implemented to stimulate the adoption of GLP-1RAs as part of routine cardiovascular care among patients with T2DM, especially in those with ASCVD.
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Affiliation(s)
- André J Scheen
- Division of Diabetes, Nutrition and Metabolic Disorders, CHU Liège, Liège, Belgium
- Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), Liège University, Liège, Belgium
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周 蓓, 李 静, 方 晨, 黄 亚, 桑 贵, 陶 少, 何 春. [Comparison of therapeutic effect of metformin hydrochloride/vildagliptin and liraglutide on type 2 diabetes mellitus in obese patients]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2023; 43:436-442. [PMID: 37087589 PMCID: PMC10122729 DOI: 10.12122/j.issn.1673-4254.2023.03.14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Indexed: 04/24/2023]
Abstract
OBJECTIVE To evaluate the therapeutic effects of two therapeutic strategies based on metformin hydrochloride/vildagliptin and liraglutide on type 2 diabetes mellitus (T2DM) in obese patients. METHODS We retrospectively collected the clinical data of 107 obese patients (BMI>25 kg/m2) with T2DM treated in Second Affiliated Hospital of Wannan Medical College (Wuhu, China) during 2019-2021, including 53 patients treated continuously with metformin hydrochloride/vildagliptin and 54 with liraglutide for 3 months. The changes in BMI, waist circumference, fasting blood glucose (FBG), postprandial blood glucose, HbA1C, fasting C-peptide, postprandial C-peptide, fasting insulin and postprandial insulin of the patients after treatment were compared between the two groups. RESULTS In both of the groups, the patients all showed significant reductions of BMI, waist circumference, FBG, postprandial blood glucose and HbA1C (all P < 0.05) with improved fasting and postprandial C-peptide levels after the treatments (P < 0.05). The two treatment regimens showed comparable blood glucoselowering effects, but liraglutide produced better effect in reducing waist circumference (P < 0.01). Neither of two regimens obviously affected insulin level of the patients (P>0.05). CONCLUSION Both metformin hydrochloride/vildagliptin and liraglutide have good therapeutic effects on T2DM in obese patients and can achieve good blood glucose and weight control, but liraglutide has a better effect for weight control.
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Affiliation(s)
- 蓓 周
- 皖南医学院第二附属医院内分泌科，安徽 芜湖 241001Department of Endocrinology, Second Affiliated Hospital of Wannan Medical College, Wuhu 241001, China
| | - 静 李
- 皖南医学院第二附属医院内分泌科，安徽 芜湖 241001Department of Endocrinology, Second Affiliated Hospital of Wannan Medical College, Wuhu 241001, China
| | - 晨圆 方
- 皖南医学院第二附属医院内分泌科，安徽 芜湖 241001Department of Endocrinology, Second Affiliated Hospital of Wannan Medical College, Wuhu 241001, China
| | - 亚楠 黄
- 皖南医学院第二附属医院内分泌科，安徽 芜湖 241001Department of Endocrinology, Second Affiliated Hospital of Wannan Medical College, Wuhu 241001, China
| | - 贵蕊 桑
- 皖南医学院第二附属医院内分泌科，安徽 芜湖 241001Department of Endocrinology, Second Affiliated Hospital of Wannan Medical College, Wuhu 241001, China
| | - 少平 陶
- 皖南医学院第二附属医院内分泌科，安徽 芜湖 241001Department of Endocrinology, Second Affiliated Hospital of Wannan Medical College, Wuhu 241001, China
| | - 春玲 何
- 皖南医学院第一附属医院内分泌科，安徽 芜湖 241004Department of Endocrinology, First Affiliated Hospital of Wannan Medical College, Wuhu 241004, China
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Urinary Proteome Differences in Patients with Type 2 Diabetes Pre and Post Liraglutide Treatment. Curr Issues Mol Biol 2023; 45:1407-1421. [PMID: 36826037 PMCID: PMC9956006 DOI: 10.3390/cimb45020092] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/01/2023] [Accepted: 02/02/2023] [Indexed: 02/10/2023] Open
Abstract
Diabetes mellitus is a chronic multisystem disease with a high global prevalence. The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide is known to lower glucose levels and reduce weight. However, the mechanisms underlying the benefits of liraglutide treatment in patients with type 2 diabetes mellitus (T2DM) remain unclear. Twelve male patients with T2DM (pre and post liraglutide treatment) and HbA1c between 8% and 11% were recruited. In the present study, a two-dimensional difference gel electrophoresis (2D-DIGE) matrix-assisted laser desorption/ionization-time of flight (MALDI TOF) mass spectrometric approach combined with bioinformatics and network pathway analysis was used to explore the urine proteomic profile. The mean age of the patients was 52.4 ± 7.5 years. After treatment with liraglutide, a statistically significant change (p < 0.006) was observed in HbA1c with no significant changes in body weight or markers of dyslipidemia. Two-dimensional difference gel electrophoresis identified significant changes (≥1.5-fold change, ANOVA, p ≤ 0.05) in 32 proteins (4 down- and 28 upregulated) in liraglutide post treatment compared to the pre-treatment state. Albumin, serotransferrin, metallothionein-2 (MT-2), and keratins K1 and K10 were found to be upregulated after liraglutide treatment. The patients showed significant improvement in glycemic control after the 12-week treatment with liraglutide. The renoprotective effect of liraglutide may be linked to the increased urinary abundance of MT-2 and the decreased abundance of zinc alpha 2-glycoprotein (ZAG) and Alpha-1 antitrypsin (α1-AT). More studies are needed to elucidate the molecular mechanisms behind the renoprotective effects of liraglutide.
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Abusnana S, Al Awadi F, Aly H, Bashier A, Kumar Dhanwal D, Halasa T, Jallo M, Medina J, Singhal S. Switching to a fixed-ratio combination of insulin degludec/liraglutide (IDegLira) is associated with improved glycaemic control in a real-world population with type 2 diabetes mellitus in the United Arab Emirates: Results from the multicentre, prospective INTENSIFY study. Diabetes Res Clin Pract 2023; 196:110183. [PMID: 36436550 DOI: 10.1016/j.diabres.2022.110183] [Citation(s) in RCA: 1] [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: 08/22/2022] [Revised: 11/01/2022] [Accepted: 11/18/2022] [Indexed: 11/25/2022]
Abstract
AIM Investigate the effectiveness of IDegLira, a fixed-ratio combination of insulin degludec/liraglutide, in a real-world setting in patients with type 2 diabetes mellitus in the United Arab Emirates. METHODS This non-interventional study enrolled adults switching to IDegLira from basal insulin (BI) or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with/without concomitant oral antidiabetic drugs (OADs). Primary endpoint was change in HbA1c from baseline, assessed using a mixed model for repeated measurements. RESULTS Among 263 patients (BI ± OADs, n = 206; GLP-1 RA ± OADs, n = 57), mean baseline HbA1c was 9.29 % (78 mmol/mol). After 26 weeks, HbA1c was significantly reduced (BI ± OADs, -0.83 % [-9.0 mmol/mol] and GLP-1 RA ± OADs, -1.24 % [-13.5 mmol/mol]; both p < 0.0001). Fasting plasma glucose (FPG) was significantly reduced (-39.48 mg/dL [BI ± OADs] and -82.49 mg/dL [GLP-1 RA ± OADs]; both p < 0.0001). Before treatment initiation, 3/263 patients experienced ≥ 1 severe hypoglycaemic episode and 7/263 patients experienced ≥ 1 non-severe hypoglycaemic episode compared with 1/263 patients who had ≥ 1 severe and 1/263 who had ≥ 1 non-severe episode at end of study. Body weight decreased significantly among patients switching from BI ± OADs (-1.05 kg [p < 0.0001]). Treatment was well tolerated. CONCLUSIONS IDegLira significantly reduced HbA1c and FPG in this real-world setting, along with less frequent episodes of hypoglycaemia. Switching to IDegLira offers effective treatment intensification for type 2 diabetes patients with inadequate glycaemic control.
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Affiliation(s)
| | | | - Hazem Aly
- Novo Nordisk, Pharma Gulf, Dubai World Trade Centre, Dubai, United Arab Emirates
| | | | | | | | - Mahir Jallo
- Gulf Medical University & Thumbay University Hospital, Ajman, United Arab Emirates
| | | | - Sagar Singhal
- Novo Nordisk, Pharma Gulf, Dubai World Trade Centre, Dubai, United Arab Emirates
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Fan D, Wang Y, Liu B, Yin F. Hypoglycemic drug liraglutide alleviates low muscle mass by inhibiting the expression of MuRF1 and MAFbx in diabetic muscle atrophy. J Chin Med Assoc 2023; 86:166-175. [PMID: 36279106 DOI: 10.1097/jcma.0000000000000807] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Low muscle mass, that is, muscular atrophy, is an independent risk factor for type 2 diabetes mellitus (T2DM). Few studies investigated whether hypoglycemic drugs can alleviate low muscle mass and related mechanisms. METHODS This study recruited 51 type 2 diabetes mellitus (T2DM) patients, who were divided into two groups based on skeletal muscle index (SMI) evaluated by Dual-energy X-ray absorptiometry (DXA): the experiment group (n = 25, SMI < 7 kg/m 2 ) and the control group (n = 26, SMI≥7 kg/m 2 ). GLP-1 levels were measured by ELISA. In vitro, 10 KK-A y mice (11- to 12-week-old) were assigned into two groups: liraglutide group (n = 5) and saline group (n = 5). Real-time PCR and Western blot were used to determine the expression levels of muscle specific ubiquitin protease E3, MuRF1, and MAFbx. RESULTS T2DM patients with a higher SMI had significantly higher GLP-1 levels (t = 3.77, p < 0.001). SMI were positively associated with GLP-1 levels (β = 0.435, p = 0.001) and inversely associated with age (β = 0.299, p = 0.015). The incidence of low muscle mass at below the second quartiles was 10.55 times that of above the second quartiles (odds ratio = 10.556, p < 0.001). Liraglutide-treatment mice showed significant decrease in food intake, final body weight, fasting blood glucose, and significant increase in skeletal muscle mass, which coincided with the significant decrease in the expression levels of ubiquitin protease E3 MuRF1 and MAFbx. In vitro studies showed that liraglutide promoted myogenic differentiation and attenuated dexamethasone (DEX)-induced myotube atrophy. Ectopic expression of MuRF1 and MAFbx antagonized the beneficial effects of liraglutide on DEX-induced myotube atrophy. CONCLUSION T2DM patients have muscular atrophy, and liraglutide alleviates muscular atrophy at least in part by inhibiting the expression of MuRF1 and MAFbx.
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Affiliation(s)
- Dongmei Fan
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, China
| | - Yue Wang
- Department of Immunology, School of Medicine, Nankai University, Tianjin, China
| | - Bowei Liu
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, China
- Department of Endocrinology, The First Hospital of Qinhuangdao, Qinhuangdao, China
| | - Fuzai Yin
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, China
- Department of Endocrinology, The First Hospital of Qinhuangdao, Qinhuangdao, China
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10
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Fatty acid chain modification of loxenatide and its kinetics in a continuous flow microchannel reactor. Process Biochem 2023. [DOI: 10.1016/j.procbio.2022.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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11
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Guerci B, Giorgino F, Sapin H, Boye K, Lebrec J, Federici MO, Heitmann E, Dib A, Füchtenbusch M, García‐Pérez L. The Real-World Observational Prospective Study of Health Outcomes with Dulaglutide and Liraglutide in Patients with Type 2 Diabetes (TROPHIES): Patient disposition, clinical characteristics and treatment persistence at 12 months. Diabetes Obes Metab 2022; 24:2373-2382. [PMID: 35876235 PMCID: PMC9804517 DOI: 10.1111/dom.14823] [Citation(s) in RCA: 4] [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: 03/10/2022] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 01/05/2023]
Abstract
AIMS The primary objective of the TROPHIES observational study is to estimate the duration of treatment on dulaglutide or liraglutide without a significant treatment change by 24 months in patients with type 2 diabetes (T2D) initiating their first injectable treatment with these glucagon-like peptide-1 receptor agonists (GLP-1 RAs). This manuscript presents 12-month interim data. MATERIALS AND METHODS TROPHIES is a prospective, non-comparative, observational study of patients with T2D in Europe, naïve to injectable antihyperglycaemic treatments and initiating dulaglutide or liraglutide. Data on clinical characteristics, GLP-1 RA persistence and treatment patterns of glucose-lowering medication were collected at initiation of first injectable therapy and by 12 months. RESULTS By 12 months, 1014 dulaglutide and 991 liraglutide patients were eligible across France, Germany and Italy. Both cohorts presented a high probability [95% confidence interval (CI)] of GLP-1 RA persistence [dulaglutide, 0.88 (0.86 to 0.90); liraglutide, 0.83 (0.80 to 0.85)] and reduction in mean glycated haemoglobin percentage (95% CI) from baseline [dulaglutide, -1.18 (-1.27 to -1.08); liraglutide, -1.15 (-1.26 to -1.05)] with 48.2% of dulaglutide and 41.2% of liraglutide patients reaching their individualized glycated haemoglobin percentage target set by the physician at baseline. Mean weight (95% CI) change from baseline was -3.2 kg (-3.6 to -2.8) for dulaglutide and -3.4 kg (-3.9 to -3.0) for liraglutide. Slight changes in concomitant medications were observed compared with baseline. CONCLUSIONS In the real-world setting, dulaglutide and liraglutide cohorts achieved good persistence with similarly improved glycaemic control that was accompanied by weight loss at 12 months, consistent with previous clinical trial results.
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Affiliation(s)
- Bruno Guerci
- Department of Endocrinology, Diabetology and NutritionUniversity Hospital of NancyVandoeuvre‐lès‐NancyFrance
| | - Francesco Giorgino
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic DiseasesUniversity of Bari Aldo MoroBariItaly
| | - Hélène Sapin
- Statistics and Real World AnalyticsLilly France SASNeuilly‐sur‐SeineFrance
| | - Kristina Boye
- Value, Evidence, and OutcomesEli Lilly and CompanyIndianapolisIndianaUSA
| | - Jérémie Lebrec
- Real World Access and AnalyticsHaaPACS GmbHSchriesheimGermany
| | | | - Elke Heitmann
- Medical AffairsLilly Deutschland GmbHBad HomburgGermany
| | - Anne Dib
- Medical AffairsLilly France SASNeuilly‐sur‐SeineFrance
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12
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Park S, Oh S, Kim EK. Glucagon-like peptide-1 analog liraglutide leads to multiple metabolic alterations in diet-induced obese mice. J Biol Chem 2022; 298:102682. [PMID: 36356900 PMCID: PMC9730228 DOI: 10.1016/j.jbc.2022.102682] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 10/27/2022] [Accepted: 10/31/2022] [Indexed: 11/09/2022] Open
Abstract
Liraglutide, a glucagon-like peptide-1 analog, has beneficial metabolic effects in patients with type 2 diabetes and obesity. Although the high efficacy of liraglutide as an anti-diabetic and anti-obesity drug is well known, liraglutide-induced metabolic alterations in diverse tissues remain largely unexplored. Here, we report the changes in metabolic profiles induced by a 2-week subcutaneous injection of liraglutide in diet-induced obese mice fed a high-fat diet for 8 weeks. Our comprehensive metabolomic analyses of the hypothalamus, plasma, liver, and skeletal muscle showed that liraglutide intervention led to various metabolic alterations in comparison with diet-induced obese or nonobese mice. We found that liraglutide remarkably coordinated not only fatty acid metabolism in the hypothalamus and skeletal muscle but also amino acid and carbohydrate metabolism in plasma and liver. Comparative analyses of metabolite dynamics revealed that liraglutide rewired intertissue metabolic correlations. Our study points to a previously unappreciated metabolic alteration by liraglutide in several tissues, which may underlie its therapeutic effects within and across the tissues.
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Affiliation(s)
- Seokjae Park
- Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea,Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
| | - Sungjoon Oh
- Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea,Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
| | - Eun-Kyoung Kim
- Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea,Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea,For correspondence: Eun-Kyoung Kim
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13
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Kunina H, Al‐Mashat A, Chien JY, Garhyan P, Kjellsson MC. Optimization of trial duration to predict long-term HbA1c change with therapy: A pharmacometrics simulation-based evaluation. CPT Pharmacometrics Syst Pharmacol 2022; 11:1443-1457. [PMID: 35899461 PMCID: PMC9662199 DOI: 10.1002/psp4.12854] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 07/10/2022] [Accepted: 07/24/2022] [Indexed: 11/30/2022] Open
Abstract
Glycated hemoglobin (HbA1c) is the main biomarker of diabetes drug development. However, because of its delayed turnover, trial duration is rarely shorter than 12 weeks, and being able to predict long-term HbA1c with precision using data from shorter studies would be beneficial. The feasibility of reducing study duration was therefore investigated in this study, assuming a model-based analysis. The aim was to investigate the predictive performance of 24- and 52-week extrapolations using data from up to 4, 6, 8 or 12 weeks, with six previously published pharmacometric models of HbA1c. Predictive performance was assessed through simulation-based dose-response predictions and model averaging (MA) with two hypothetical drugs. Results were consistent across the methods of assessment, with MA supporting the results derived from the model-based framework. The models using mean plasma glucose (MPG) or nonlinear fasting plasma glucose (FPG) effect, driving the HbA1c formation, showed good predictive performance despite a reduced study duration. The models, using the linear effect of FPG to drive the HbA1c formation, were sensitive to the limited amount of data in the shorter studies. The MA with bootstrap demonstrated strongly that a 4-week study duration is insufficient for precise predictions of all models. Our findings suggest that if data are analyzed with a pharmacometric model with MPG or FPG with a nonlinear effect to drive HbA1c formation, a study duration of 8 weeks is sufficient with maintained accuracy and precision of dose-response predictions.
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Affiliation(s)
- Hanna Kunina
- Pharmacometrics Research Group, Department of PharmacyUppsala UniversityUppsalaSweden
| | - Alex Al‐Mashat
- Pharmacometrics Research Group, Department of PharmacyUppsala UniversityUppsalaSweden
| | - Jenny Y. Chien
- Global Pharmacokinetics/Pharmacodynamics and Pharmacometrics, Lilly Research LaboratoriesLilly Corporate CenterIndianapolisIndianaUSA
| | - Parag Garhyan
- Global Pharmacokinetics/Pharmacodynamics and Pharmacometrics, Lilly Research LaboratoriesLilly Corporate CenterIndianapolisIndianaUSA
| | - Maria C. Kjellsson
- Pharmacometrics Research Group, Department of PharmacyUppsala UniversityUppsalaSweden
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14
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Coke LA, Deedwania PC, Hinnen D, Magwire M, Miller NH. GLP-1 receptor agonists and cardiovascular outcomes in patients with type 2 diabetes: Clinical evidence and best practice. J Am Assoc Nurse Pract 2022; 34:418-440. [PMID: 35120085 DOI: 10.1097/jxx.0000000000000661] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 09/02/2021] [Indexed: 12/13/2022]
Abstract
ABSTRACT Cardiovascular disease (CVD) is a major cause of death and disability among people with type 2 diabetes (T2D), presenting a significant impact on longevity, patient quality of life, and health care costs. In the United States, attainment of recommended glycemic targets is low and T2D-related cardiovascular complications remain a significant burden. Many glucose-lowering treatment options are available, but glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors are recommended in recent guidelines as the preferred add-on therapy to metformin to improve glycemic control. This is particularly the case for patients with T2D and established atherosclerotic CVD, at high risk of atherosclerotic CVD, and/or with chronic kidney disease. Recommendations were based on GLP-1RA and SGLT-2 inhibitor cardiovascular outcomes trials (CVOTs), which consistently showed that these agents pose no additional cardiovascular risk compared with placebo. Three GLP-1RAs (liraglutide, dulaglutide, and subcutaneous semaglutide) demonstrated significantly lower major adverse cardiovascular events versus placebo and are now approved for this indication. However, to realize improvement in outcomes in the clinical setting, organized, systematic, and coordinated approaches to patient management are also needed. For example, nurse-led diabetes self-management education and support programs have been shown to be effective. This article explores T2D management with emphasis on cardiovascular risk and CVOTs performed to date and reviews the clinical experience with GLP-1RAs for managing hyperglycemia and their impact on cardiovascular risk. In addition, practical guidance is given for key health care providers involved in the care of patients with T2D with cardiovascular risk outside of diabetes clinics/endocrinology centers.
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Affiliation(s)
- Lola A Coke
- Kirkhof College of Nursing, Grand Valley State University, Allendale, Michigan
| | | | - Debbie Hinnen
- University of Colorado Health, Diabetes Clinic, Colorado Springs, Colorado
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15
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Prediction scale of response to liraglutide therapy as the method for increase of treatment efficacy in type 2 diabetes. Future Sci OA 2022; 8:FSO779. [PMID: 35251693 PMCID: PMC8890266 DOI: 10.2144/fsoa-2021-0070] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 01/04/2022] [Indexed: 11/24/2022] Open
Abstract
Background: The effects of liraglutide on body weight and hemoglobin A1C (HbA1c) level vary greatly. The cost of this drug negatively affects treatment adherence. Aim: To reveal the baseline patient characteristics, associated with a better response to liraglutide. Materials and methods: A total of 41 patients with BMI of 39.63 ± 7.59 kg/m2 who received liraglutide injection up to 1.8 or 3.0 mg/day for 6 months were enrolled. Demographic and anthropometric data, parameters of glycemic control, food intake, hormones and responses to the eating behavior questionnaire were collected. Results: Weight reduction was dose-dependent (p = 0.007). Liraglutide was not effective in patients with BMI >45 kg/m2. The baseline HbA1c level was a significant factor for HbA1c reduction. Lower leptin and higher glucagon-like-peptide 1 concentrations might predict better weight loss response to liraglutide. Conclusion: Drug-specific efficacy predictors were assumed; thus, further studies are needed to prove their significance. The objective of this study was to identify the baseline patient characteristics as a predictors associated with a better response to liraglutide. It is related to different effect of liraglutide on body weight and hemoglobin A1c (HbA1c) in different patients. We found that weight reduction was dose-dependent (p = 0.007) and liraglutide was not effective in patients with BMI >45 kg/m2. The baseline HbA1c level significantly correlated with HbA1c reduction. Lower leptin and higher glucagon-like peptide-1 concentrations might predict better weight loss response to liraglutide.
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Ferrari F, Scheffel RS, Martins VM, Santos RD, Stein R. Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes Mellitus and Cardiovascular Disease: The Past, Present, and Future. Am J Cardiovasc Drugs 2021; 22:363-383. [PMID: 34958423 DOI: 10.1007/s40256-021-00515-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/23/2021] [Indexed: 12/13/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is associated with high cardiovascular morbidity and mortality, and cardiovascular diseases are the leading causes of death and disability in people with T2DM. Unfortunately, therapies strictly aimed at glycemic control have poorly contributed to a significant reduction in the risk of cardiovascular events. On the other hand, randomized controlled trials have shown that five glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and one exendin-based GLP-1 RA reduced atherosclerotic cardiovascular events in patients with diabetes at high cardiovascular risk. Furthermore, a meta-analysis including these six agents showed a reduction in major adverse cardiovascular events as well as all-cause mortality compared with placebo, regardless of structural homology. Evidence has also shown that some drugs in this class have beneficial effects on renal outcomes, such as preventing the onset of macroalbuminuria. In addition to lowering blood pressure, these drugs also favorably impacted on body weight in large randomized controlled trials as in real-world studies, a result considered a priority in T2DM management; these and other factors may justify the benefits of GLP-1 RAs upon the cardiovascular system, regardless of glycemic control. Finally, studies showed safety with a low risk of hypoglycemia and no increase in pancreatitis events. Given these benefits, GLP-1 RAs were preferentially endorsed in the guidelines of the European and American societies for patients with these conditions. This narrative review provides a current and comprehensive overview of GLP-1 RAs as cardiovascular and renal protective agents, far beyond their use as glucose-lowering drugs, supporting their effectiveness in treating patients with T2DM at high cardiovascular risk.
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Affiliation(s)
- Filipe Ferrari
- Postgraduate Program in Cardiology and Cardiovascular Sciences, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, School of Medicine, Rua Ramiro Barcelos 2350, Serviço de Fisiatria/Térreo, Porto Alegre, RS, 90470-260, Brazil
- Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
| | - Rafael S Scheffel
- Pharmacology Department, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
- Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, School of Medicine, Porto Alegre, RS, Brazil
| | - Vítor M Martins
- Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
| | - Raul D Santos
- Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
- Lipid Clinic Heart Institute (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
| | - Ricardo Stein
- Postgraduate Program in Cardiology and Cardiovascular Sciences, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, School of Medicine, Rua Ramiro Barcelos 2350, Serviço de Fisiatria/Térreo, Porto Alegre, RS, 90470-260, Brazil.
- School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
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Blonde L, Fainberg U, Kaltoft MS, Mosenzon O, Ramesh C, Rea R. Efficacy of liraglutide added to sodium-glucose cotransporter-2 inhibitors in type 2 diabetes, stratified by baseline characteristics: Post-hoc analysis of LIRA-ADD2SGLT2i. Diabetes Obes Metab 2021; 23:2234-2241. [PMID: 34132018 PMCID: PMC8518913 DOI: 10.1111/dom.14464] [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: 02/11/2021] [Revised: 05/28/2021] [Accepted: 06/09/2021] [Indexed: 11/29/2022]
Abstract
AIMS The LIRA-ADD2SGLT2i trial demonstrated that liraglutide + sodium-glucose cotransporter-2 inhibitors (SGLT2is) ± metformin significantly improved glycaemic control (not body weight) versus placebo in adults with type 2 diabetes (T2D). This post-hoc analysis assessed whether baseline characteristics influenced these findings. MATERIALS AND METHODS LIRA-ADD2SGLT2i (NCT02964247) was a placebo-controlled, double-blind, multinational trial, wherein participants received liraglutide (≤1.8 mg/day) or placebo (randomized 2:1). Changes from baseline to week 26 in haemoglobin A1c (HbA1c), body weight and waist circumference stratified by HbA1c, body mass index (BMI), diabetes duration, duration of pre-trial SGLT2i use and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) were analysed. These five baseline characteristics were divided into tertiles, and the treatment effect was evaluated using the trial product estimand. RESULTS Data from all 303 participants were analysed. There was a significant interaction between baseline HbA1c tertiles (7.0%-<7.6%; 7.6%-8.1%; ≥8.2%-9.5%) and glycaemic control at week 26 (p[interaction] = .011), with the lowest HbA1c estimated treatment difference (95% confidence interval) observed in patients with lowest baseline HbA1c [-0.20% (-0.59, 0.19); -0.68% (-1.03, -0.33); -0.98% (-1.33, -0.64), respectively]. There were no significant interactions in glycaemic control across baseline BMI, diabetes duration, insulin resistance determined by HOMA-IR or SGLT2i use duration (p[interaction] > .05, all). Across the five characteristics assessed, no significant interactions were found for body weight or waist circumference changes from baseline (p[interaction] > .05, all). CONCLUSION For individuals with T2D and inadequate glycaemic control despite therapy with SGLT2is ± metformin, liraglutide 1.8 mg would provide an effective treatment intensification option, irrespective of HbA1c, BMI, diabetes duration, insulin resistance determined by HOMA-IR and SGLT2i use duration.
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Affiliation(s)
- Lawrence Blonde
- Ochsner Diabetes Clinical Research Unit, Frank Riddick Diabetes Institute, Department of EndocrinologyOchsner Medical CenterNew OrleansLouisianaUSA
| | | | | | - Ofri Mosenzon
- Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Faculty of MedicineHebrew University of JerusalemJerusalemIsrael
| | | | - Rosangela Rea
- Hospital de ClínicasUniversidade Federal do Paraná (SEMPR)CuritibaBrazil
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Brown E, Heerspink HJL, Cuthbertson DJ, Wilding JPH. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Lancet 2021; 398:262-276. [PMID: 34216571 DOI: 10.1016/s0140-6736(21)00536-5] [Citation(s) in RCA: 295] [Impact Index Per Article: 73.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 02/12/2021] [Accepted: 02/24/2021] [Indexed: 12/21/2022]
Abstract
SGLT2 inhibitors and GLP-1 receptor agonists are used in patients with type 2 diabetes as glucose lowering therapies, with additional benefits of weight loss and blood pressure reduction. Data from cardiovascular outcome trials have highlighted that these drugs confer protection against major cardiovascular disease in those with established atherosclerotic cardiovascular disease, reduce the risk of admission to hospital for heart failure, and reduce cardiovascular and all-cause mortality. Ongoing research using hard renal endpoints such as end stage kidney disease rather than surrogate markers might clarify the renoprotective benefits of both agents. When used for glucose lowering, SGLT2 inhibitors are most effective if the estimated glomerular filtration rate is more than 60 ml per min per 1·73m2 at initiation and should be avoided where there is a risk of diabetic ketoacidosis. GLP-1 receptor agonists are contraindicated in those with a history of medullary thyroid cancer and used with caution in patients with a history of pancreatitis of a known cause. These drugs are now second-line, or even arguably first-line, glucose lowering therapies in patients with cardiorenal disease, irrespective of glycaemic control. If an SGLT2 inhibitor or GLP-1 receptor agonist is considered suitable in patients with type 2 diabetes, treatment should be prioritised according to existing evidence: GLP-1 receptor agonists should be considered in patients at a high risk of, or with established, cardiovascular disease and SGLT2 inhibitors considered for patients with heart failure (with reduced ejection fraction) or chronic kidney disease (with or without established cardiovascular disease). There is now compelling data on the benefits of these drugs for a range of other clinical indications even without type 2 diabetes, including for GLP-1 receptor agonists in patients with obesity and overweight with weight-related comorbidities.
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Affiliation(s)
- Emily Brown
- Department of Metabolic and Cardiovascular Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK; Liverpool University Hospitals NHS Foundation Trust, Longmoor Lane, Liverpool, UK
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands
| | - Daniel J Cuthbertson
- Department of Metabolic and Cardiovascular Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK; Liverpool University Hospitals NHS Foundation Trust, Longmoor Lane, Liverpool, UK.
| | - John P H Wilding
- Department of Metabolic and Cardiovascular Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK; Liverpool University Hospitals NHS Foundation Trust, Longmoor Lane, Liverpool, UK
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Epigenetics in NAFLD/NASH: Targets and therapy. Pharmacol Res 2021; 167:105484. [PMID: 33771699 DOI: 10.1016/j.phrs.2021.105484] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 12/15/2022]
Abstract
Recently non-alcoholic fatty liver disease (NAFLD) has grabbed considerable scientific attention, owing to its rapid increase in prevalence worldwide and growing burden on end-stage liver diseases. Metabolic syndrome including obesity, diabetes, and hypertension poses a grave risk to NAFLD etiology and progression. With no drugs available, the mainstay of NAFLD management remains lifestyle changes with exercise and dietary modifications. Nonselective drugs such as metformin, thiazolidinediones (TZDs), ursodeoxycholic acid (UDCA), silymarin, etc., are also being used to target the interrelated pathways for treating NAFLD. Considering the enormous disease burden and the unmet need for drugs, fresh insights into pathogenesis and drug discovery are required. The emergence of the field of epigenetics offers a convincing explanation for the basis of lifestyle, environmental, and other risk factors to influence NAFLD pathogenesis. Therefore, understanding these epigenetic modifications to target the primary cause of the disease might prove a rational strategy to prevent the disease and develop novel therapeutic interventions. Apart from describing the role of epigenetics in the pathogenesis of NAFLD as in other reviews, this review additionally provides an elaborate discussion on exploiting the high plasticity of epigenetic modifications in response to environmental cues, for developing novel therapeutics for NAFLD. Besides, this extensive review provides evidence for epigenetic mechanisms utilized by several potential drugs for NAFLD.
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Casey R, Adelfio A, Connolly M, Wall A, Holyer I, Khaldi N. Discovery through Machine Learning and Preclinical Validation of Novel Anti-Diabetic Peptides. Biomedicines 2021; 9:276. [PMID: 33803471 PMCID: PMC8000967 DOI: 10.3390/biomedicines9030276] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/05/2021] [Accepted: 03/07/2021] [Indexed: 12/19/2022] Open
Abstract
While there have been significant advances in drug discovery for diabetes mellitus over the past couple of decades, there is an opportunity and need for improved therapies. While type 2 diabetic patients better manage their illness, many of the therapeutics in this area are peptide hormones with lengthy sequences and a molecular structure that makes them challenging and expensive to produce. Using machine learning, we present novel anti-diabetic peptides which are less than 16 amino acids in length, distinct from human signalling peptides. We validate the capacity of these peptides to stimulate glucose uptake and Glucose transporter type 4 (GLUT4) translocation in vitro. In obese insulin-resistant mice, predicted peptides significantly lower plasma glucose, reduce glycated haemoglobin and even improve hepatic steatosis when compared to treatments currently in use in a clinical setting. These unoptimised, linear peptides represent promising candidates for blood glucose regulation which require further evaluation. Further, this indicates that perhaps we have overlooked the class of natural short linear peptides, which usually come with an excellent safety profile, as therapeutic modalities.
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Affiliation(s)
| | | | | | - Audrey Wall
- Nuritas Ltd., Joshua Dawson House, D02 RY95 Dublin, Ireland; (R.C.); (A.A.); (M.C.); (I.H.); (N.K.)
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Blonde L, Rosenstock J, Frias J, Birkenfeld AL, Niemoeller E, Souhami E, Ji C, Del Prato S, Aroda VR. Durable Effects of iGlarLixi Up to 52 Weeks in Type 2 Diabetes: The LixiLan-G Extension Study. Diabetes Care 2021; 44:774-780. [PMID: 33468520 PMCID: PMC7896258 DOI: 10.2337/dc20-2023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 12/11/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE In the LixiLan-G trial, switching to iGlarLixi, a once-daily titratable fixed-ratio combination of insulin glargine 100 units/mL and the glucagon-like peptide 1 receptor agonist (GLP-1 RA) lixisenatide, improved glucose control in type 2 diabetes uncontrolled with GLP-1 RAs over 26 weeks versus continuing prior GLP-1 RA. A prespecified, 26-week, single-arm extension of LixiLan-G aimed to determine the durability of iGlarLixi efficacy and safety over 52 weeks. RESEARCH DESIGN AND METHODS Participants with type 2 diabetes uncontrolled by GLP-1 RAs (glycated hemoglobin [HbA1c] 7-9% [53-75 mmol/mol]) were initially randomized to switch to iGlarLixi or continue prior GLP-1 RA. Those randomized to iGlarLixi who completed the 26-week primary end point period could continue iGlarLixi open-label treatment over a 26-week extension to assess durability of efficacy and safety. RESULTS Glycemic control achieved with iGlarLixi at week 26 (mean HbA1c 6.7% [50 mmol/mol]) was maintained at week 52 (mean HbA1c 6.7% [50 mmol/mol]; mean ± SD change from baseline at week 52: -1.0 ± 0.9% [11 ± 10 mmol/mol]). Proportions of participants reaching HbA1c <7% (53 mmol/mol) with iGlarLixi were similar at week 26 (62%) and 52 (64%), as were those reaching this target without documented symptomatic (<3.0 mmol/L) hypoglycemia (57% and 58%). Safety of iGlarLixi was similar at weeks 26 and 52, with low rates of documented symptomatic hypoglycemia and gastrointestinal events. CONCLUSIONS The efficacy and safety of iGlarLixi at the end of the 26-week randomized treatment period was maintained over the 26-week extension period in the LixiLan-G trial.
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Affiliation(s)
- Lawrence Blonde
- Frank Riddick Diabetes Institute, Department of Endocrinology, Ochsner Medical Center, New Orleans, LA
| | | | - Juan Frias
- National Research Institute, Los Angeles, CA
| | - Andreas L Birkenfeld
- Medical Clinic IV, Department of Endocrinology, Diabetology, Angiology and Nephrology, University Hospital Tübingen, Tübingen, Germany.,German Center for Diabetes Research and Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
| | | | | | | | | | - Vanita R Aroda
- MedStar Health Research Institute, Hyattsville, MD.,Brigham and Women's Hospital, Boston, MA
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Rainkie DC, Abedini ZS, Abdelkader NN. Reporting and methodological quality of systematic reviews and meta-analysis with protocols in Diabetes Mellitus Type II: A systematic review. PLoS One 2020; 15:e0243091. [PMID: 33326429 PMCID: PMC7743973 DOI: 10.1371/journal.pone.0243091] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 11/15/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Systematic reviews with or without meta-analyses (SR/MAs) are strongly encouraged to work from a protocol to facilitate high quality, transparent methodology. The completeness of reporting of a protocol (PRISMA-P) and manuscript (PRISMA) is essential to the quality appraisal (AMSTAR-2) and appropriate use of SR/MAs in making treatment decisions. OBJECTIVES The objectives of this study were to describe the completeness of reporting and quality of SR/MAs, assess the correlations between PRISMA-P, PRISMA, and AMSTAR-2, and to identify reporting characteristics between similar items of PRISMA-P and PRISMA. METHODS We performed a systematic review of Type 2 Diabetes Mellitus SR/MAs of hypoglycemic agents with publicly available protocols. Cochrane reviews, guidelines, and specific types of MA were excluded. Two reviewers independently, (i) searched PubMed and Embase between 1/1/2015 to 20/3/2019; (ii) identified protocols of included studies by searching the manuscript bibliography, supplementary material, PROSPERO, and Google; (iii) completed PRISMA-P, PRISMA, and AMSTAR-2 tools. Data analysis included descriptive statistics, Pearson correlation, and multivariable linear regression. RESULTS Of 357 relevant SR/MAs, 51 had available protocols and were included. The average score for PRISMA-P was 15.8±3.3 (66%; maximum 24) and 25.2±1.1 (93%; maximum 27) for PRISMA. The quality of SR/MAs assessed using the AMSTAR-2 tool identified an overall poor quality (63% critically low, 18% low, 8% moderate, 12% high). The correlation between the PRISMA-P and PRISMA was not significant (r = 0.264; p = 0.06). Correlation was significant between PRISMA-P and AMSTAR-2 (r = 0.333; p = 0.02) and PRISMA and AMSTAR-2 (r = 0.555; p<0.01). Discrepancies in reporting were common between similar PRISMA-P and PRISMA items. CONCLUSION Adherence to protocol reporting guidance was poor while manuscript reporting was comprehensive. Protocol completeness is not associated with a completely reported manuscript. Independently, PRISMA-P and PRISMA scores were weakly associated with higher quality assessments but insufficient as a surrogate for quality. Critical areas for quality improvement include protocol description, investigating causes of heterogeneity, and the impact of risk of bias on the evidence synthesis.
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Wilke T, Mueller S, Fuchs A, Kaltoft MS, Kipper S, Cel M. Diabetes-Related Effectiveness and Cost of Liraglutide or Insulin in German Patients with Type 2 Diabetes: A 5-Year Retrospective Claims Analysis. Diabetes Ther 2020; 11:2357-2370. [PMID: 32876862 PMCID: PMC7509007 DOI: 10.1007/s13300-020-00903-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Indexed: 11/22/2022] Open
Abstract
INTRODUCTION Liraglutide is a glucagon-like peptide-1 analogue used to treat type 2 diabetes mellitus (T2DM). To date, limited long-term data (> 2 years) exist comparing real-world diabetes-related effectiveness and costs for liraglutide versus insulin treatment. METHODS This retrospective claims data analysis covered the period from 1 January 2010 to 31 December 2017 and included continuously insured patients with T2DM who initiated insulin or liraglutide and had 3.5 or 5 years' follow-up data, identified using the German AOK PLUS dataset. Propensity score matching (PSM) was used to adjust for patient characteristics. RESULTS After PSM, there were 825 and 436 patients in the liraglutide and insulin groups at 3.5 and 5 years' follow-up, respectively. Baseline characteristics were similar between compared cohorts. The respective change from baseline to follow-up in mean glycated haemoglobin for liraglutide and insulin patients was - 0.88% and - 0.81% (p > 0.100) after 3.5 years and - 1.15%/ - 1.02% (p > 0.100) after 5 years. Mean respective changes in body mass index (kg/m2) were - 1.21/+ 1.14 (p < 0.001) after 3.5 years and - 1.29/+ 1.13 after 5 years (p < 0.001). Liraglutide- versus insulin-treated patients were less likely to have an early T2DM-related hospitalisation (3.5-year hazard ratio [HR]: 0.414 [95% confidence interval (CI) 0.263-0.651]; 5-year HR: 0.448 [95% CI 0.286-0.701]). At 5 years' follow-up, there was no statistically significant difference in total direct costs between treatment groups (cost ratio: 1.069 [95% CI 0.98-1.13]; p > 0.100). CONCLUSION The clinical effectiveness of liraglutide is maintained long term (up to 5 years). Liraglutide treatment is not associated with higher total direct healthcare costs.
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Affiliation(s)
- Thomas Wilke
- Institut für Pharmakoökonomie und Arzneimittellogistik (IPAM) an der Hochschule Wismar, Alter Holzhafen 19, 23966, Wismar, Germany.
| | | | | | - Margit S Kaltoft
- Global Development, Novo Nordisk A/S, Vandtårnsvej 108-114, 2860, Søborg, Denmark
| | - Stefan Kipper
- Novo Nordisk Pharma GmbH, Brucknerstraße 1, E55127, Mainz, Germany
| | - Malgorzata Cel
- Novo Nordisk Region Europe, 3 City Place, Beehive Ring Road, West Sussex, Gatwick, RH6 0PA, UK
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Brunton SA, Wysham CH. GLP-1 receptor agonists in the treatment of type 2 diabetes: role and clinical experience to date. Postgrad Med 2020; 132:3-14. [DOI: 10.1080/00325481.2020.1798099] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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John M, Gopinath D, Oommen T. Co-Formulations as the First Injectable in Type 2 Diabetes: A Review of Efficacy, Safety, and Implications in Clinical Practice. DUBAI DIABETES AND ENDOCRINOLOGY JOURNAL 2020. [DOI: 10.1159/000509045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
<b><i>Background:</i></b> Progression of type 2 diabetes will necessitate the use of injectable therapies in a significant number of people. Co-formulations of degludec with liraglutide (IDegLira) and glargine with lixisenatide (IGlarLixi) are currently recommended for intensification in people with type 2 diabetes on basal insulin or glucagon-like peptide receptor agonist (GLP-1RA) alone or in people with type 2 diabetes who are naïve to insulin with very high glycated haemoglobin. Co-formulation of aspart with degludec (IDegAsp) is recommended as a substitute for premixed insulin. The aim of this article is to review the evidence in the use of co-formulations as the first injectable in type 2 diabetes and its clinical implications. <b><i>Summary:</i></b> In people with type 2 diabetes who are naïve to insulin or GLP-1RA, IDegLira and IGlarLixi achieved stable and durable glycaemic control over a wide range of baseline glycated haemoglobin (HbA1c) levels. People on IDegLira and IGlarLixi had lesser risk of hypoglycaemia and weight gain in studies compared to basal insulin and lesser gastrointestinal adverse effects in comparison to GLP-1RA. IDegAsp achieved similar glycaemic control to basal and premixed insulin with lesser risk of nocturnal hypoglycaemia. <b><i>Key Messages:</i></b> IDegLira, IGlarLixi, and IDegAsp can be used as the first injectable in people with type 2 diabetes with very high glycated haemoglobin on oral antidiabetic drugs. These co-formulations combine efficacy and durability with lesser injection burden. The components of these agents have proven cardiovascular and renal safety. Their limitations in flexibility of dosing, renal and cardiovascular considerations, and adverse effects are discussed.
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Rykalina NV, Askerova EV, Bulushova NV, Kozlov DG. Intranasal Human Recombinant Modified Glucagon-Like Peptide-1: High Antihyperglycemic Activity and Duration of Action in Mice. Bull Exp Biol Med 2020; 169:53-56. [PMID: 32495167 DOI: 10.1007/s10517-020-04822-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Indexed: 10/24/2022]
Abstract
The study compared effectiveness of intranasal administration of glypin (human recombinant modified glucagon-like peptide-1) and reference drug Victoza in BALB/c mice. The minimum effective dose of intranasal glypin was 0.5 mg/kg, and a 2-fold elevation of this dose increased the parameters of glypin activity up to the maximal levels. During the first 2 h after intranasal administration, the effectiveness of glypin greatly surpassed that of Victoza. Duration of action and the time course of antihyperglycemic activity of intranasal glypin (1 mg/kg) matched to the best parameters attained during its subcutaneous application. A high effectiveness of intranasal glypin opens the vistas to its further examination and employment.
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Affiliation(s)
- N V Rykalina
- State Research Institute of Genetics and Selection of Industrial Microorganisms of the National Research Center" Kurchatov Institute" (National Research Center Kurchatov Institute - GosNIIgenetika), Moscow, Russia
| | - E V Askerova
- State Research Institute of Genetics and Selection of Industrial Microorganisms of the National Research Center" Kurchatov Institute" (National Research Center Kurchatov Institute - GosNIIgenetika), Moscow, Russia
| | - N V Bulushova
- State Research Institute of Genetics and Selection of Industrial Microorganisms of the National Research Center" Kurchatov Institute" (National Research Center Kurchatov Institute - GosNIIgenetika), Moscow, Russia
| | - D G Kozlov
- State Research Institute of Genetics and Selection of Industrial Microorganisms of the National Research Center" Kurchatov Institute" (National Research Center Kurchatov Institute - GosNIIgenetika), Moscow, Russia.
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Yu M, Yuan GY, Zhang B, Wu HY, Lv XF. Efficacy and Safety of Dulaglutide by Baseline HbA1c in Chinese Patients with Type 2 Diabetes: A Post Hoc Analysis. Diabetes Ther 2020; 11:1147-1159. [PMID: 32277401 PMCID: PMC7192976 DOI: 10.1007/s13300-020-00804-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Indexed: 01/31/2023] Open
Abstract
INTRODUCTION To evaluate the efficacy and safety of dulaglutide 0.75 and 1.5 mg in patients with type 2 diabetes mellitus (T2DM) by baseline glycated hemoglobin (HbA1c) < 8.5% or ≥ 8.5% after 26 weeks of treatment. METHODS Assessment of the Weekly AdministRation of dulaglutide in Diabetes (AWARD) China 1 (CHN1) study (NCT01644500, n = 556) included patients on dulaglutide vs. glimepiride who were treatment naïve or on monotherapy but discontinued therapy. AWARD-CHN2 (NCT01648582, n = 591) patients were on dulaglutide vs. insulin glargine and continued on metformin and/or sulfonylurea. Mean daily dose of glimepiride and insulin glargine was 2.51 mg and 21.0 IU, respectively. Post hoc analyses were conducted based on mixed-model repeated measures using a modified intent-to-treat analysis set with only the Chinese population. Change from baseline in HbA1c and body weight was analyzed by individual study. RESULTS In the two studies, 70.1% of patients in AWARD-CHN1 and 59.7% in AWARD-CHN2 had baseline HbA1c < 8.5% (mean HbA1c 7.4% and 7.6%, respectively) and 29.9% in AWARD-CHN1 and 40.3% in AWARD-CHN2 had baseline HbA1c ≥ 8.5% (mean HbA1c 9.2% and 9.4%, respectively). In AWARD-CHN1, the HbA1c reductions at 26 weeks with baseline HbA1c < 8.5% and ≥ 8.5%, respectively, were dulaglutide 1.5 mg: - 1.1% and - 2.2%; dulaglutide 0.75 mg: - 0.9% and - 2.0%; glimepiride: - 0.7% and - 1.4%. In AWARD-CHN2, the HbA1c reductions at 26 weeks with baseline HbA1c < 8.5% and ≥ 8.5%, respectively, were dulaglutide 1.5 mg: - 1.2% and - 2.3%; dulaglutide 0.75 mg: - 1.0% and - 1.7%; and insulin glargine: - 0.6% and - 1.7%. Irrespective of baseline HbA1c, body weight decreased with both dulaglutide doses and increased with either glimepiride or insulin glargine at 26 weeks. Dulaglutide demonstrated low incidence of hypoglycemia in both doses in the two trials. Hypoglycemia incidence was generally lower in patients with baseline HbA1c ≥ 8.5%. CONCLUSIONS Dulaglutide demonstrated significantly greater HbA1c reduction with weight loss and lower risk of hypoglycemia compared with active comparators in Chinese patients with T2DM irrespective of baseline HbA1c, with much greater HbA1c reductions in patients with a higher baseline HbA1c. TRIAL REGISTRATION ClinicalTrials.gov identifier, NCT01644500 and NCT01648582.
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Affiliation(s)
- Miao Yu
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730 China
| | - Guo Yue Yuan
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Jiangsu, China
| | - Bin Zhang
- Medical Department, Lilly Suzhou Pharmaceutical Co. Ltd, Shanghai, China
| | - Hai Ya Wu
- Medical Department, Lilly Suzhou Pharmaceutical Co. Ltd, Shanghai, China
| | - Xiao Feng Lv
- Department of Endocrinology, The Seventh Medical Center of PLA General Hospital, Beijing, China
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Xiao X, Wang C, Lai X, Zhang B, Gu L, Hou J, Zhou Z. Achieving the composite end-point of glycated hemoglobin <7.0% without weight gain or hypoglycemia with once-weekly dulaglutide in Chinese patients with type 2 diabetes: A post-hoc analysis. J Diabetes Investig 2020; 11:647-652. [PMID: 31758850 PMCID: PMC7232276 DOI: 10.1111/jdi.13187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 11/13/2019] [Accepted: 11/20/2019] [Indexed: 01/19/2023] Open
Abstract
AIMS/INTRODUCTION To assess the effect of dulaglutide (DU) 1.5/0.75 mg in comparison with glimepiride (GLIM) or insulin glargine (GLAR) on the composite end-point in Chinese type 2 diabetes patients. MATERIALS AND METHODS Post-hoc analyses of two randomized phase III trials (NCT01644500 and NCT01648582) were carried out using Fisher's exact test. The primary composite end-point was the number of patients reaching glycated hemoglobin (HbA1c) <7.0%, without weight gain and hypoglycemia. Secondary composite end-points included the number of patients reaching HbA1c <7.0% without weight gain and HbA1c <7.0% without hypoglycemia. RESULTS Data of 1,147 Chinese type 2 diabetes patients were analyzed (NCT01644500 = 556; NCT01648582 = 591). In each analyzed trial, 40-48% of patients received DU (1.5 mg), 30-39% of patients received DU (0.75 mg) and 15-20% of patients on active comparators (GLIM/GLAR) reached the primary composite end-point at week 26 (P < 0.001 for DU vs GLIM/GLAR). At 52 weeks, 26% of patients that received DU (1.5 mg), 23% of patients that received DU (0.75 mg) and 7% of patients that received GLAR attained the primary composite end-point (P < 0.001 for DU vs GLAR). A similar trend of results was found for secondary composite end-points. CONCLUSIONS Dulaglutide is found to be an effective therapeutic alternative for Chinese type 2 diabetes patients. Compared with GLIM/GLAR, significantly greater proportions of patients on DU attained the HbA1c target of <7.0% without weight gain or hypoglycemia.
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Affiliation(s)
- Xinhua Xiao
- Department of EndocrinologyKey Laboratory of EndocrinologyNational Health CommissionChinese Academy of Medical SciencePeking Union Medical College HospitalBeijingChina
| | | | - Xiaoyang Lai
- The Second Affiliated Hospital of Nanchang UniversityNanchangChina
| | - Bin Zhang
- Lilly Suzhou Pharmaceutical Co. Ltd.ShanghaiChina
| | - Liqun Gu
- Lilly Suzhou Pharmaceutical Co. Ltd.ShanghaiChina
| | - Jianing Hou
- Clinical Research PhysicianDiabetes Therapeutic AreaEli Lilly and CompanyLilly Suzhou Pharmaceutical Co. LtdShanghaiChina
| | - Zhiguang Zhou
- Institute of Metabolism and EndocrinologyKey Laboratory of Diabetes ImmunologyMinistry of EducationNational Clinical Research Center for Metabolic DiseasesThe Second Xiangya HospitalCentral South UniversityChangshaChina
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Xing Y, Chen J, Zhao L, Ma H. Analysis of the effect of liraglutide on glycemic variability in patients with type 2 diabetes. Endocr J 2020; 67:455-468. [PMID: 31996492 DOI: 10.1507/endocrj.ej19-0530] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The efficacy of liraglutide in the treatment of glycemic variability in type 2 diabetic patients remains to be fully elucidated. Some studies evaluated the efficacy and safety of liraglutide in glycemic variability, and this meta-analysis was performed to evaluate the accuracy of the results of existing studies on the efficacy of liraglutide. We conducted a comprehensive search for all relevant studies published in PubMed, EMBASE, Cochrane Library, and China Academic Journal Full-Text Database from the beginning of 2011 to October 31, 2019. The mean ± SD and 95% confidence interval were used for evaluation, and subgroup and sensitivity analysis were carried out. Publication bias was estimated by funnel plots and Egger's tests. A total of 16 studies were included in the meta-analysis involving 492 participants. MAGE (mean amplitude of glycemic excursion), LAGE (largest amplitude of glycemic excursions), SD (standard deviation of blood glucose), and MODD (mean of daily differences) were collected to reflect the variability of blood glucose. The glycemic variability indexes of patients before and after treatment with liraglutide were compared. Patients with treatment had lower glycemic variability compared with patients receiving treatment of liraglutide. Compared with the patients before the treatment, the patients after the treatment had a smaller glycemic variability (MAGE: I2 = 92%, p < 0.01, Z = 11.91, p < 0.01, MD = -2.78, 95%CI: -3.24 - -2.32; LAGE: I2 = 76%, p = 0.08, Z = 9.94, p < 0.01, MD = -2.20, 95%CI: -2.59 - -1.81; MODD: I2 = 74%, p = 0.002, Z = 14.03, p < 0.01, MD = -0.90, 95%CI: -1.02 - -0.77; SD: I2 = 93%, p < 0.01, Z = 3.62, p < 0.01, SMD = -1.77, 95%CI: -2.73 - -0.81). Sensitivity analysis showed that our results were reliable and no evidence of significant publication bias was detected. The results of this study suggest that patients with type 2 diabetes treated with liraglutide are associated with lower glycemic variability.
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Affiliation(s)
- Yuling Xing
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang 050017, China
- Graduate School of Hebei Medical University, Shijiazhuang 050017, China
| | - Jinhu Chen
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang 050017, China
| | - Liying Zhao
- Graduate School of Hebei Medical University, Shijiazhuang 050017, China
| | - Huijuan Ma
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang 050017, China
- Hebei Key Laboratory of Metabolic Diseases, Hebei General Hospital Shijiazhuang, Hebei 050051, China
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050017, China
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Capehorn M, Catarig AM, Furberg J, Janez A, Price H, Tadayon S, Vergès B, Marre M. Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily liraglutide 1.2 mg as add-on to 1–3 oral antidiabetic drugs in subjects with type 2 diabetes (SUSTAIN 10). DIABETES & METABOLISM 2020; 46:100-109. [DOI: 10.1016/j.diabet.2019.101117] [Citation(s) in RCA: 127] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 08/28/2019] [Accepted: 09/01/2019] [Indexed: 02/07/2023]
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Paccosi S, Cresci B, Pala L, Rotella CM, Parenti A. Obesity Therapy: How and Why? Curr Med Chem 2020; 27:174-186. [DOI: 10.2174/0929867326666190124121725] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 05/11/2018] [Accepted: 12/24/2018] [Indexed: 12/25/2022]
Abstract
Background:
Obesity represents the second preventable mortality cause worldwide,
and is very often associated with type 2 Diabetes Mellitus (T2DM). The first line treatment
is lifestyle modification to weight-loss, but for those who fail to achieve the goal or have
difficulty in maintaining achieved results, pharmacological treatment is needed. Few drugs are
available today, because of their side effects.
Objective:
We aim to review actual pharmacological management of obese patients, highlighting
differences between Food and Drug Administration - and European Medicine
Agency-approved molecules, and pointing out self-medications readily obtainable and widely
distributed.
Methods:
Papers on obesity, weight loss, pharmacotherapy, self- medication and diet-aid
products were selected using Medline. Research articles, systematic reviews, clinical trials
and meta-analyses were screened.
Results:
Anti-obesity drugs with central mechanisms, such as phentermine and lorcaserin, are
available in USA, but not in Europe. Phentermine/topiramate and naltrexone/bupropion combinations
are now available, even though the former is still under investigation from EMA.
Orlistat, with peripheral mechanisms, represents the only drug approved for weight reduction
in adolescents. Liraglutide has been approved at higher dose for obesity. Anti-obesity drugs,
readily obtainable from the internet, include crude-drug products and supplements for which
there is often a lack of compliance to national regulatory standards.
Conclusion:
Mechanisms of weight loss drugs include the reduction of energy intake or the
increase in energy expenditure and sense of satiety as well as the decrease of hunger or the
reduction in calories absorption. Few drugs are approved, and differences exist between USA
and Europe. Moreover, herbal medicines and supplements often sold on the internet and
widely used by obese patients, present a risk of adverse effects.
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Affiliation(s)
- Sara Paccosi
- Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy
| | - Barbara Cresci
- Diabetology, Careggi University Hospital, Florence, Italy
| | - Laura Pala
- Diabetology, Careggi University Hospital, Florence, Italy
| | | | - Astrid Parenti
- Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy
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Rebello CJ, Greenway FL. Obesity medications in development. Expert Opin Investig Drugs 2020; 29:63-71. [PMID: 31847611 PMCID: PMC6990416 DOI: 10.1080/13543784.2020.1705277] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 12/12/2019] [Indexed: 12/21/2022]
Abstract
Introduction: Obesity is compounded by a neurobiology that is resistant to weight loss. Therefore, the development of pharmacotherapies to address the pathology underlying the dysregulation of energy homeostasis is critical.Areas covered: This review examines selected clinical trial evidence for the pharmacologic treatment of obesity and provides an expert opinion on anti-obesity drug development. The article includes the outcomes of anti-obesity medications that have been evaluated in clinical trials but have not yet received approval from the U.S. Food and Drug Administration. The mechanisms of action of glucagon-like peptide-1 agonists and co-agonists, diabetes medications being investigated for weight loss, and medications acting on the central nervous system as well as peripherally are reviewed. A search was conducted on PubMed using the terms 'Obesity AND Medications' restricted to clinical trials reported in English. Using similar terms, a search was also conducted on ClinicalTrials.gov.Expert opinion: The goal of anti-obesity therapy is finding compounds that are effective and have minimal side effects. Combining medications targeting more than one of the redundant mechanisms driving obesity increases efficacy. However, targeting peripheral mechanisms to overcome the trickle-down effects of centrally acting drugs may be the key to success in treating obesity.
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Affiliation(s)
- Candida J. Rebello
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA
| | - Frank L. Greenway
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, USA
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Mirabelli M, Chiefari E, Caroleo P, Arcidiacono B, Corigliano DM, Giuliano S, Brunetti FS, Tanyolaç S, Foti DP, Puccio L, Brunetti A. Long-Term Effectiveness of Liraglutide for Weight Management and Glycemic Control in Type 2 Diabetes. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 17:ijerph17010207. [PMID: 31892206 PMCID: PMC6981922 DOI: 10.3390/ijerph17010207] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 12/17/2019] [Accepted: 12/24/2019] [Indexed: 12/15/2022]
Abstract
Background: Liraglutide is the first glucagon-like peptide-1 receptor agonist (GLP-1 RA) based on the human GLP-1 sequence, with potential weight loss benefits, approved for the treatment of type 2 diabetes (T2D) mellitus. Herein, we aimed to assess the 5-year effectiveness of Liraglutide in the management of weight and glycometabolic control in a Southern Italian cohort of overweight/obese T2D patients, who were naïve to GLP-1 RAs. Patients and Methods: Forty overweight or obese patients treated with Liraglutide at doses up to 1.8 mg/day, in combination with one or more oral antidiabetic agents, were retrospectively assessed at baseline, during, and after 60 months of continuous therapy. Results: After 5 years of Liraglutide treatment, body weight decreased from 92.1 ± 20.5 kg to 87.3 ± 20.0 Kg (p < 0.001), with a mean reduction of 5.0 ± 7.0 Kg and a body mass index (BMI) decrement of −2.0 ± 3.1 Kg/m2. On Spearman’s univariate analysis, change in body weight was correlated with female gender and baseline BMI. Hemoglobin A1c (HbA1c) decreased from 7.9 ± 0.9% at baseline to 7.0 ± 0.7% at the end of the study period (p < 0.001), followed by a significant reduction in fasting plasma glucose. No significant differences emerged in other biochemical parameters, despite a trend toward improvement in lipid profile. Notwithstanding encouraging effects on several markers of cardiovascular disease (CVD), increments in the 5- and 10-year risk for the first atherosclerotic cardiovascular event were documented, as four incident cases of myocardial infarction. Conclusions: Prolonging treatment with Liraglutide can lead to durable benefits in relation to weight and glycemic control, with a greater impact on women. These results extend and corroborate previous observations, suggesting that gender per se may modulate the response to Liraglutide. Despite favorable effects on some established CVD risks factors, the long-term role of Liraglutide in primary prevention of CVD in patients with T2D remains controversial.
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Affiliation(s)
- Maria Mirabelli
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.M.); (E.C.); (B.A.); (D.M.C.); (S.G.); (F.S.B.); (D.P.F.)
| | - Eusebio Chiefari
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.M.); (E.C.); (B.A.); (D.M.C.); (S.G.); (F.S.B.); (D.P.F.)
| | - Patrizia Caroleo
- Complex Operative Structure Endocrinology-Diabetology, Hospital Pugliese-Ciaccio, 88100 Catanzaro, Italy; (P.C.); (L.P.)
| | - Biagio Arcidiacono
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.M.); (E.C.); (B.A.); (D.M.C.); (S.G.); (F.S.B.); (D.P.F.)
| | - Domenica Maria Corigliano
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.M.); (E.C.); (B.A.); (D.M.C.); (S.G.); (F.S.B.); (D.P.F.)
| | - Stefania Giuliano
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.M.); (E.C.); (B.A.); (D.M.C.); (S.G.); (F.S.B.); (D.P.F.)
| | - Francesco Saverio Brunetti
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.M.); (E.C.); (B.A.); (D.M.C.); (S.G.); (F.S.B.); (D.P.F.)
| | - Sinan Tanyolaç
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Biruni University, 34010 Istanbul, Turkey;
| | - Daniela Patrizia Foti
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.M.); (E.C.); (B.A.); (D.M.C.); (S.G.); (F.S.B.); (D.P.F.)
| | - Luigi Puccio
- Complex Operative Structure Endocrinology-Diabetology, Hospital Pugliese-Ciaccio, 88100 Catanzaro, Italy; (P.C.); (L.P.)
| | - Antonio Brunetti
- Department of Health Sciences, University “Magna Græcia” of Catanzaro, 88100 Catanzaro, Italy; (M.M.); (E.C.); (B.A.); (D.M.C.); (S.G.); (F.S.B.); (D.P.F.)
- Correspondence: ; Tel.: +39-0961-3694368; Fax: +39-0961-3694147
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Sannikova EP, Bulushova NV, Cheperegin SE, Zalunin IA, Klebanov FA, Gracheva TS, Yurin VL, Rykalina NV, Askerova EV, Yarotskii SV, Tatarnikova OG, Bobkova NV, Kozlov DG. Specific Activity of Recombinant Modified Human Glucagon-Like Peptide 1. APPL BIOCHEM MICRO+ 2019. [DOI: 10.1134/s0003683819070068] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Kalra S, Das AK, Sahay RK, Baruah MP, Tiwaskar M, Das S, Chatterjee S, Saboo B, Bantwal G, Bhattacharya S, Priya G, Chawla M, Brar K, Raza SA, Aamir AH, Shrestha D, Somasundaram N, Katulanda P, Afsana F, Selim S, Naseri MW, Latheef A, Sumanatilleke M. Consensus Recommendations on GLP-1 RA Use in the Management of Type 2 Diabetes Mellitus: South Asian Task Force. Diabetes Ther 2019; 10:1645-1717. [PMID: 31359367 PMCID: PMC6778554 DOI: 10.1007/s13300-019-0669-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Indexed: 12/17/2022] Open
Abstract
The advent of incretin mimetics such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) has enriched the armamentarium for diabetes management owing to their glycaemic as well as extra-glycaemic benefits. The approval status and availability of this class of drugs vary widely across the globe. Being a relatively newer class of drug with numerous benefits, several national and international guidelines are working towards addressing clinical questions pertaining to the optimal use of GLP-1 RAs for the management of diabetes. Although the newer class of drugs are associated with significant benefits such as patient-centric approach, these drugs demand the providers to be vigilant and knowledgeable about the medication. The South Asian population is at higher risk of type 2 diabetes mellitus (T2DM) because of their genetic predisposition and lifestyle changes. Hence, prevention and management of T2DM and its associated complications in this population are of paramount importance. The current report aims to present an overview of current knowledge on GLP-1 RAs based on pragmatic review of the available clinical evidence. In addition, this report is a consensus of expert endocrinologists representing South Asian countries including India, Pakistan, Bangladesh, Nepal, Sri Lanka, Afghanistan and the Maldives on essential recommendations related to the use of GLP-1 RAs in a real-world scenario.
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Affiliation(s)
| | - Ashok Kumar Das
- Pondicherry Institute of Medical Sciences, Pondicherry, India
| | | | | | | | - Sambit Das
- Hi Tech Medical College and Hospital, Bhubaneshwar, India
| | | | | | | | | | | | | | | | - Syed Abbas Raza
- Shaukat Khanum Memorial Cancer Hospital and Research Centre and National Defence Hospital, Lahore, Pakistan
| | | | | | | | | | | | - Shahjada Selim
- Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh
| | | | - Ali Latheef
- Department of Medicine, Indra Gandhi Hospital, Male, Maldives
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Glucagon-Like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes: Prescription According to Reimbursement Constraints and Guideline Recommendations in Catalonia. J Clin Med 2019; 8:jcm8091389. [PMID: 31491916 PMCID: PMC6780172 DOI: 10.3390/jcm8091389] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 08/30/2019] [Accepted: 09/03/2019] [Indexed: 12/12/2022] Open
Abstract
To assess the clinical characteristics, the prescription pattern of GLP-1 receptor agonists (GLP-1RA) users, and HbA1c and weight change, we retrospectively assessed patients with type 2 diabetes by initiating GLP-1RA as an add-on to the standard of care in Catalonia. The mean change from the baseline in glycated hemoglobin (HbA1c) and weight at 6 and 12 months of therapy was calculated, and we assessed the predictors of the HbA1c reduction of ≥1% and/or the weight reduction of ≥3% as recommended by the Catalan Health Service. In 2854 patients who initiated a GLP-1RA during 2014 and 2015, the overall mean HbA1c values were reduced from the baseline by −0.84% (SD = 1.66) (−9.2 mmol/mol) and lost on average 2.73 kg (SD = 6.2). About 44% percent of patients decreased their HbA1c by ≥1%; 44% decreased their weight by ≥3%; and only 22% met both of them together. The odds of achieving a reduction of ≥1% in initial HbA1c were two-fold higher for patients with higher baseline levels, and the likelihood of a reduction of ≥3% in the initial weight was associated with a higher BMI at the baseline, but they were independent of each other. The composite outcome (target 1% HbA1c reduction and 3% weight loss) to evaluate both the GLP-1RA clinical benefit and treatment withdrawal should be judged from a patient-centered approach.
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Anholm C, Kumarathurai P, Pedersen LR, Samkani A, Walzem RL, Nielsen OW, Kristiansen OP, Fenger M, Madsbad S, Sajadieh A, Haugaard SB. Liraglutide in combination with metformin may improve the atherogenic lipid profile and decrease C-reactive protein level in statin treated obese patients with coronary artery disease and newly diagnosed type 2 diabetes: A randomized trial. Atherosclerosis 2019; 288:60-66. [PMID: 31326727 DOI: 10.1016/j.atherosclerosis.2019.07.007] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 06/28/2019] [Accepted: 07/05/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Atherosclerosis in obesity and type 2 diabetes (T2DM) is associated with low-grade inflammation (LGI) and dyslipidemia, where especially small, dense lipoprotein particles are atherogenic. The glucagon-like peptide-1 receptor agonist, liraglutide, reduces cardiovascular events by poorly understood mechanisms. We investigated the effect of liraglutide combined with metformin on LGI and lipoprotein density profiles in patients with stable coronary artery disease (CAD) and newly diagnosed T2DM. METHODS We conducted a randomized, double-blind, placebo-controlled, cross-over trial over a 12 + 12-week period, with ≥2-week wash-out. INTERVENTION liraglutide/metformin vs. placebo/metformin. Lipoproteins were separated by continuous density gradient ultracentrifugation, and LDL divided into five subfractions between 226 and 270 Å, considering particle size ≤255 Å as the atherogenic pattern. Plasma C-reactive protein and tumor necrosis factor-α were assessed by the enzyme-linked immunosorbent-assay. RESULTS 28 out of 41 randomized patients completed all visits. Intention-to-treat analysis was performed but one patient had statin dosage and was excluded from the analysis. 95% of the patients were on statin therapy. Overall, liraglutide did not affect lipid subfractions or markers of LGI compared to placebo. The combination of liraglutide and metformin reduced the total LDL subfractions, primarily by reducing the most atherogenic subfraction LDL5, and reduced CRP but not TNF-α. Explorative analyses suggested that the subfraction LDL5 during the wash-out period rebounded significantly at least in a per-protocol analysis of the sub-group of patients starting the liraglutide therapy. CONCLUSIONS In patients with CAD and newly diagnosed T2DM on stable statin therapy, liraglutide combined with metformin may improve the atherogenic LDL lipid profile and CRP.
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Affiliation(s)
- Christian Anholm
- Department of Internal Medicine, Copenhagen University Hospital, Glostrup, Denmark; Department of Internal Medicine, Copenhagen University Hospital, Amager, Denmark.
| | - Preman Kumarathurai
- Department of Cardiology, Copenhagen University Hospital, Bispebjerg, Denmark
| | | | - Amirsalar Samkani
- Department of Endocrinology, Copenhagen University Hospital, Bispebjerg, Denmark
| | - Rosemary L Walzem
- Department of Poultry Science and Faculty of Nutrition, Texas A&M University, Texas, USA
| | | | | | - Mogens Fenger
- Department of Clinical Biochemistry, Copenhagen University Hospital, Hvidovre, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Copenhagen University Hospital, Hvidovre, Denmark
| | - Ahmad Sajadieh
- Department of Cardiology, Copenhagen University Hospital, Bispebjerg, Denmark
| | - Steen Bendix Haugaard
- Department of Internal Medicine, Copenhagen University Hospital, Amager, Denmark; Department of Endocrinology, Copenhagen University Hospital, Bispebjerg, Denmark
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Hooda A, Mehta A, Hannallah F. Metformin-associated lactic acidosis precipitated by liraglutide use: adverse effects of aggressive antihyperglycaemic therapy. Drug Ther Bull 2019; 57:109-111. [PMID: 31253605 DOI: 10.1136/dtb.2019.227102rep] [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: 06/09/2023]
Abstract
In conjunction with BMJ Case Reports, DTB will feature occasional drug-related cases that are likely to be of interest to readers. These will include cases that involve recently marketed drugs for which there is limited knowledge of adverse effects and cases that highlight unusual reactions to drugs that have been marketed for several years.
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Affiliation(s)
- Ananya Hooda
- Hematology and Oncology, Emory University School ofMedicine, Atlanta, Georgia, USA
| | - Anurag Mehta
- Cardiology, Emory UniversitySchool of Medicine, Atlanta, Georgia, USA
| | - Franck Hannallah
- Department of InternalMedicine, Pulmonary andCritical Care, University of TexasSouthwestern, Dallas, Texas, USA
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Melzer-Cohen C, Chodick G, Husemoen LLN, Rhee N, Shalev V, Karasik A. A Retrospective Database Study of Liraglutide Persistence Associated with Glycemic and Body Weight Control in Patients with Type 2 Diabetes. Diabetes Ther 2019; 10:683-696. [PMID: 30815829 PMCID: PMC6437242 DOI: 10.1007/s13300-019-0583-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Indexed: 12/25/2022] Open
Abstract
INTRODUCTION In both randomized controlled trials and real-world studies, liraglutide has demonstrated glycemic and body weight benefits in patients with type 2 diabetes. However, persistence with diabetes medication can be challenging. This study compared glycated hemoglobin (HbA1c) and other outcomes in patients with type 2 diabetes who continued treatment with liraglutide for over 12 months with those who discontinued treatment earlier, in a real-life setting. METHODS This is a retrospective study of adult patients with type 2 diabetes from Maccabi Healthcare Services in Israel, who initiated treatment with liraglutide from 2010 to 2015. Mean HbA1c and body weight change from initiation to after 24 months was compared between patients who received liraglutide for at least 12 months ("continuers") and those who discontinued within the first year ("discontinuers"). Adjustment for HbA1c, body weight, and other potentially confounding factors was performed using 1:1 propensity score matching. RESULTS The 3580 patients comprised 2695 continuers and 885 discontinuers; 882 patients per group were matched. A significant (p < 0.001) reduction in HbA1c (- 0.80% vs - 0.32%) was seen in continuers compared with discontinuers, despite higher insulin usage (70.2% vs 59.0%; p < 0.001), and a higher proportion of patients using ≥ 3 oral glucose-lowering drugs (20.6% vs 6.2%; p < 0.001) at 24 months among discontinuers. Mean body weight reduction was greater in continuers than discontinuers (3.57 vs 1.25 kg; p < 0.001). CONCLUSION In a real-world setting, persistent use of liraglutide was associated with good glycemic and body weight control. FUNDING Novo Nordisk Health Care AG.
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Affiliation(s)
- Cheli Melzer-Cohen
- Maccabi Institute for Research and Innovation, Maccabi Healthcare Services, Tel Aviv, Israel
| | - Gabriel Chodick
- Maccabi Institute for Research and Innovation, Maccabi Healthcare Services, Tel Aviv, Israel
- School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | | | - Nicolai Rhee
- Novo Nordisk Health Care AG Zurich, Zurich, Switzerland
| | - Varda Shalev
- Maccabi Institute for Research and Innovation, Maccabi Healthcare Services, Tel Aviv, Israel
- School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Avraham Karasik
- School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
- Institute of Endocrinology, Chaim Sheba Medical Center, Tel Hashomer, Israel.
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Wang SC, Wang XD, Teng XN, Xiu ZL. Chemical modification of recombinant hirudin with palmitic acid in mixed aqueous-organic solutions. Process Biochem 2019. [DOI: 10.1016/j.procbio.2018.11.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Anholm C, Kumarathurai P, Jürs A, Pedersen LR, Nielsen OW, Kristiansen OP, Fenger M, Holst JJ, Madsbad S, Sajadieh A, Haugaard SB. Liraglutide improves the beta-cell function without increasing insulin secretion during a mixed meal in patients, who exhibit well-controlled type 2 diabetes and coronary artery disease. Diabetol Metab Syndr 2019; 11:42. [PMID: 31164926 PMCID: PMC6543623 DOI: 10.1186/s13098-019-0438-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 05/17/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Hyperinsulinemia aggravates insulin resistance and cardio-vascular disease. How the insulinotropic glucagon-like peptide-1 receptor agonist liraglutide in a physiologic post-prandial setting may act on pancreatic alpha and beta-cell function in patients with coronary artery disease (CAD) and type 2 diabetes (T2DM) is less clear. METHODS Insulin resistant patients with established CAD and newly diagnosed well-controlled T2DM were recruited to a placebo-controlled, cross-over trial with two treatment periods of 12 weeks and a 2 weeks wash-out period before and in-between. Treatment was liraglutide or placebo titrated from 0.6 mg q.d. to 1.8 mg q.d. within 4 weeks and metformin titrated from 500 mg b.i.d to 1000 mg b.i.d. within 4 weeks. Before and after intervention in both 12 weeks periods insulin, C-peptide, glucose, and glucagon were measured during a meal test. Beta-cell function derived from the oral glucose tolerance setting was calculated as changes in insulin secretion per unit changes in glucose concentration (Btotal) and whole-body insulin resistance using ISIcomposite. RESULTS Liraglutide increased the disposition index [Btotal × ISIcomposite, by 40% (n = 24, p < 0.001)] compared to placebo. Post-prandial insulin and glucose was reduced by metformin in combination with liraglutide and differed, but not significantly different from placebo, moreover, glucagon concentration was unaffected. Additionally, insulin clearance tended to increase during liraglutide therapy (n = 26, p = 0.06). CONCLUSIONS The insulinotropic drug liraglutide may without increasing the insulin concentration reduce postprandial glucose but not glucagon excursions and improve beta-cell function in newly diagnosed and well-controlled T2DM.Trial registration Clinicaltrials.gov ID: NCT01595789.
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Affiliation(s)
- Christian Anholm
- Department of Internal Medicine, Copenhagen University Hospital Glostrup, Nordre Ringvej 57, 2600 Glostrup, Denmark
- Department of Cardiology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark
| | - Preman Kumarathurai
- Department of Cardiology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark
| | - Anders Jürs
- Department of Cardiology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark
| | - Lene Rørholm Pedersen
- Department of Cardiology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark
| | - Olav Wendelboe Nielsen
- Department of Cardiology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark
| | - Ole Peter Kristiansen
- Department of Cardiology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark
| | - Mogens Fenger
- Department of Clinical Biochemistry, Copenhagen University Hospital Hvidovre, Copenhagen, Denmark
| | - Jens Juul Holst
- NovoNordisk Foundation Center for Metabolic Research and Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Copenhagen, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Copenhagen University Hospital Hvidovre, Copenhagen, Denmark
| | - Ahmad Sajadieh
- Department of Cardiology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark
| | - Steen Bendix Haugaard
- Department of Internal Medicine, Copenhagen University Hospital Glostrup, Nordre Ringvej 57, 2600 Glostrup, Denmark
- Department of Endocrinology I, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark
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Alonso-Troncoso I, Carollo-Limeres C, Rios-Prego M, Guler I, Cadarso-Suárez C, F-Mariño A. Liraglutide in a real-world setting: Joint modeling of metabolic response, prediction of efficacy, and cardiovascular risk. ACTA ACUST UNITED AC 2018; 66:376-384. [PMID: 30528642 DOI: 10.1016/j.endinu.2018.09.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 09/06/2018] [Accepted: 09/07/2018] [Indexed: 01/14/2023]
Abstract
INTRODUCTION AND OBJECTIVES The worldwide prevalence of type 2 diabetes mellitus increases in parallel to that of obesity. Liraglutide (LRG), a glucagon-like peptide-1 receptor agonist, can reduce body weight. This study assessed the metabolic efficacy of LRG in real-world clinical practice. METHODS An observational, retrospective cohort study including patients treated with LRG for at least one year (187 patients). Anthropometric and metabolic variables, a composite endpoint, factors predicting response to LRG, and cardiovascular risk over time were assessed. A linear mixed-effects model with a bivariate structure was constructed to investigate the time-dependent relationship between weight and HbA1c values. RESULTS HbA1c levels and weight significantly decreased in the first 12 weeks, and the decrease persisted at 12 and 24 months in all subgroups studied. Mean weight and HbA1c decreases after 24 months were 8.5kg and 1.7% respectively. HbA1c values <7% were achieved by 42% of patients at 12 months and by 40% at 24 months. Treatment with LRG allowed for reduction in insulin dose. No serious adverse events were noted. Cardiovascular risk decreased from high to moderate-low. CONCLUSIONS Under standard clinical practice conditions, LRG achieved a better metabolic response than seen in clinical trials. Efficacy at 12 weeks of treatment is a good predictor of response. LRG allows for delaying or reducing insulin dose by improving both weight and glucose control. Cardiovascular risk improved.
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Affiliation(s)
| | - Carmen Carollo-Limeres
- Unidad de Bioestadística, Facultad de Medicina, Universidad Santiago de Compostela, Santiago de Compostela, Spain
| | - Mónica Rios-Prego
- Servicio Medicina Interna, Complejo Hospitalario Universitario de Pontevedra, Spain
| | - Ipek Guler
- Unidad de Bioestadística, Facultad de Medicina, Universidad Santiago de Compostela, Santiago de Compostela, Spain
| | - Carmen Cadarso-Suárez
- Unidad de Bioestadística, Facultad de Medicina, Universidad Santiago de Compostela, Santiago de Compostela, Spain
| | - Alexis F-Mariño
- Servicio Endocrinología, Complejo Hospitalario Universitario de Vigo, Spain
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Frison V, Simioni N, Marangoni A, Balzano S, Vinci C, Zenari L, De Moliner L, Tadiotto F, D'Ambrosio M, Confortin L, Marin N, Lombardi S, Costa S, Prosperini G, Lapolla A. Clinical Impact of 5 Years of Liraglutide Treatment on Cardiovascular Risk Factors in Patients with Type 2 Diabetes Mellitus in a Real-Life Setting in Italy: An Observational Study. Diabetes Ther 2018; 9:2201-2208. [PMID: 30238228 PMCID: PMC6250628 DOI: 10.1007/s13300-018-0503-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Indexed: 01/15/2023] Open
Abstract
INTRODUCTION Based on existing data regarding the durability of liraglutide in type 2 diabetes, this study aimed to assess its long-term effectiveness at 5 years and its overall impact on cardiovascular (CV) risk. METHODS This was a multicenter retrospective observational study. Liraglutide was used under routine clinical practice conditions. Changes from baseline to 60 months in HbA1c, fasting plasma glucose (FPG), body weight, blood pressure, and lipid profile were assessed. United Kingdom Prospective Diabetes Study (UKPDS) scores were calculated at baseline and after 60 months to assess changes in the estimated 5- and 10-year risk for fatal and nonfatal coronary heart disease (CHD) and fatal and nonfatal stroke. RESULTS Overall, 103 patients (age 59.0 ± 7.9 years, diabetes duration 10.4 ± 6.8 years) were involved in the study. After 60 months, HbA1c levels were reduced by - 1.0 ± 1.2%, FPG levels by - 24.5 ± 43.4 mg/dl, body weight by - 5.3 ± 6.4 kg, systolic blood pressure by - 6.5 ± 18.5 mmHg, diastolic blood pressure by - 3.6 ± 11.8 mmHg, and total cholesterol by - 16.9 ± 37.4 mg/dl. The proportion of patients achieving HbA1c levels of < 7% increased from 12.7% to 39.8% (p = 0.02). Based on the UKPDS scores, statistically significant reductions in the 5- and 10-year risk of nonfatal CHD and fatal CHD were found, with no change in the 5- and 10-year risk of fatal and nonfatal stroke. CONCLUSION In patients prolonging treatment with liraglutide for 5 years, the benefits in relation to metabolic control and CV risk factors are maintained. The UKPDS risk scores suggest that liraglutide is associated with a reduced CHD risk, but not with a reduced stroke risk.
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Affiliation(s)
- Vera Frison
- UO Diabetologia, Ospedale di Cittadella, Cittadella, PD, Italy
| | | | - Alberto Marangoni
- US Diabetologia, Ospedale San Bassiano, Bassano del Grappa, VI, Italy
| | - Sara Balzano
- US Diabetologia, Ospedale San Bassiano, Bassano del Grappa, VI, Italy
| | - Carmela Vinci
- UOD, Ospedale San Donà di Piave, San Donà di Piave, VE, Italy
| | - Luciano Zenari
- UO Diabetologia Ospedale Sacro Cuore Don Calabria, Negrar, VR, Italy
| | - Lorena De Moliner
- Centro Diabetologico, Ospedale S. Maria del Carmine, Rovereto, TN, Italy
| | - Federica Tadiotto
- UOSD Ospedali Riuniti Padova sud Madre Teresa di Calcutta, Monselice, PD, Italy
| | - Michele D'Ambrosio
- UOSD Ospedali Riuniti Padova sud Madre Teresa di Calcutta, Monselice, PD, Italy
| | - Loris Confortin
- UOSD, Presidio Ospedaliero di Castelfranco Veneto, Castelfranco Veneto, TV, Italy
| | - Narciso Marin
- UOSD, Presidio Ospedaliero di Castelfranco Veneto, Castelfranco Veneto, TV, Italy
| | - Simonetta Lombardi
- UOSD Diabetologia ed Endocrinologia Distretto Ovest ULSS 8 Berica, Conselve, Italy
| | - Silvana Costa
- UOSD Diabetologia ed Endocrinologia Distretto Ovest ULSS 8 Berica, Conselve, Italy
| | - Giuseppe Prosperini
- CORESEARCH-Center for Outcomes Research and Clinical Epidemiology, Pescara, Italy.
| | - Annunziata Lapolla
- UOC Diabetologia e Dietologia, Presidio Sanitario dei Colli, Padua, Italy
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Hooda A, Mehta A, Hannallah F. Metformin-associated lactic acidosis precipitated by liraglutide use: adverse effects of aggressive antihyperglycaemic therapy. BMJ Case Rep 2018; 11:11/1/e227102. [PMID: 30567126 DOI: 10.1136/bcr-2018-227102] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Older patients with type 2 diabetes are prone to developing adverse events with aggressive antihyperglycaemic therapy. Metformin-associated lactic acidosis (MALA) is one such rare, life-threatening adverse drug effect. We report the case of a 70-year-old man with a glycated haemoglobin of 7.9% who was on a stable, maximally tolerated dose of metformin for managing his type 2 diabetes. He was initiated on liraglutide injections with hopes to achieve better glycaemic control, but developed unrelenting nausea and vomiting during the third week of treatment. He presented to the hospital with these symptoms and was noted to have severe MALA. He sustained an in-hospital cardiac arrest requiring emergent resuscitation along with vasopressor and mechanical ventilator support. He underwent continuous venovenous haemodiafiltration to remove metformin and correct the acidosis, following which he stabilised and supportive therapy was weaned off. He was discharged from the hospital on insulin therapy with incomplete renal recovery.
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Affiliation(s)
- Ananya Hooda
- Hematology and Oncology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Anurag Mehta
- Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Franck Hannallah
- Department of Internal Medicine, Pulmonary and Critical Care, University of Texas Southwestern, Dallas, Texas, USA
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Gomez-Peralta F, Lecube A, Fernández-Mariño A, Alonso Troncoso I, Morales C, Morales-Pérez FM, Guler I, Cadarso-Suárez C. Interindividual differences in the clinical effectiveness of liraglutide in Type 2 diabetes: a real-world retrospective study conducted in Spain. Diabet Med 2018; 35:1605-1612. [PMID: 29943854 DOI: 10.1111/dme.13769] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/20/2018] [Indexed: 12/24/2022]
Abstract
AIMS To study the response of clinical variables (HbA1c , body weight, lipid profile and blood pressure) over 24 months of liraglutide treatment in a real-world clinical setting, and to describe the evolution of HbA1c and body weight reduction in response to liraglutide treatment by employing generalized additive mixed models (GAMMs). METHODS We included people aged ≥ 18 years with Type 2 diabetes mellitus that initiated liraglutide treatment between November 2011 and May 2015. Demographic and clinical data were retrieved retrospectively over 24 months from electronic medical records with a median duration of observation of 7.0 (IQR 3.0-12.0) months. RESULTS Individuals that initiated liraglutide therapy were obese (BMI 39.1 kg/m2 ), with inadequate HbA1c (68 mmol/mol [8.4%]), blood pressure and lipid levels. Upon liraglutide treatment, HbA1c , body weight, mean systolic and diastolic blood pressure, and lipid levels decreased gradually. GAMMs demonstrated that longer treatment with liraglutide was a predictor of improved HbA1c response, whereas higher baseline HbA1c , longer Type 2 diabetes duration and treatment with insulin were predictors of worse HbA1c response. Higher baseline weight, longer treatment with liraglutide and the interaction between metformin and time were predictors of improved weight response. CONCLUSIONS In this real-world study, we showed the effectiveness of liraglutide in improving body weight, HbA1c , mean systolic and diastolic blood pressure, and lipid levels. GAMMs indicated that baseline HbA1c and weight, time of treatment with liraglutide, diabetes duration and the use of metformin or insulin are predictors of clinical response to liraglutide.
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Affiliation(s)
- F Gomez-Peralta
- Endocrinology and Nutrition Unit, Segovia General Hospital, Segovia
| | - A Lecube
- Endocrinology and Nutrition Unit, University Hospital Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida and CIBERDEM (CIBER de Diabetes y Enfermedades Metabólicas Asociadas, ISCIII), University of Lleida, Lleida
| | | | | | - C Morales
- Endocrinology and Nutrition Unit, Virgen Macarena Hospital, Seville
| | - F M Morales-Pérez
- Endocrinology Unit, Hospital Universitario Infanta Cristina, Badajoz
| | - I Guler
- Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, A Coruña, Spain
| | - C Cadarso-Suárez
- Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, A Coruña, Spain
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DeVries JH, Desouza C, Bellary S, Unger J, Hansen OKH, Zacho J, Woo V. Achieving glycaemic control without weight gain, hypoglycaemia, or gastrointestinal adverse events in type 2 diabetes in the SUSTAIN clinical trial programme. Diabetes Obes Metab 2018; 20:2426-2434. [PMID: 29862621 PMCID: PMC6175309 DOI: 10.1111/dom.13396] [Citation(s) in RCA: 9] [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: 02/02/2018] [Revised: 05/11/2018] [Accepted: 05/25/2018] [Indexed: 11/30/2022]
Abstract
AIM To evaluate the potential for semaglutide to help people with type 2 diabetes (T2D) achieve glycated haemoglobin (HbA1c) targets while avoiding unwanted outcomes, such as weight gain, hypoglycaemia and gastrointestinal (GI) side effects. MATERIALS AND METHODS Data from the phase IIIa SUSTAIN 1 to 5 clinical trials were analysed. Participants had inadequately controlled T2D and were drug-naïve (SUSTAIN 1) or on a range of background treatments (SUSTAIN 2 to 5). The main protocol-specified composite endpoint was the proportion of participants achieving HbA1c <53 mmol/mol (7.0%) at end of treatment (30 or 56 weeks) without weight gain and with no severe or blood glucose (BG)-confirmed symptomatic hypoglycaemia. A post hoc composite endpoint was the proportion of participants achieving the primary composite endpoint without moderate or severe GI adverse events (AEs). RESULTS Across the SUSTAIN trials 1 to 5, 3918 participants with T2D were randomized to once-weekly subcutaneous semaglutide 0.5 mg, 1.0 mg, or comparators (placebo, sitagliptin 100 mg, exenatide extended release 2.0 mg or insulin glargine). The proportion of participants achieving HbA1c <53 mmol/mol (7.0%) with no weight gain and no severe/BG-confirmed symptomatic hypoglycaemia was 47% to 66% (semaglutide 0.5 mg) and 57% to 74% (semaglutide 1.0 mg) vs 7% to 19% (placebo) and 16% to 29% (active comparators; all P < .0001). More participants achieved the primary composite endpoint with no moderate or severe GI AEs with semaglutide vs comparators (all P < .0001). CONCLUSION Semaglutide helped more people with T2D achieve HbA1c targets than did comparators in the SUSTAIN 1 to 5 trials, while avoiding unwanted outcomes such as weight gain, hypoglycaemia and GI side effects.
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Affiliation(s)
- J. Hans DeVries
- Department of EndocrinologyAcademic Medical CentreAmsterdamThe Netherlands
- Profil Institute for Metabolic ResearchNeussGermany
| | - Cyrus Desouza
- Division of Diabetes Endocrinology & MetabolismUniversity of Nebraska Medical CenterOmahaNebraska
| | | | - Jeffrey Unger
- Director, Metabolic StudiesCatalina Research InstituteChino, California
| | | | | | - Vincent Woo
- Section of Endocrinology and Metabolism, Health Sciences CentreUniversity of ManitobaWinnipegCanada
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47
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Liraglutide and cardiovascular outcomes in a real world type 2 diabetes cohort. Pharmacol Res 2018; 137:270-279. [PMID: 30213563 DOI: 10.1016/j.phrs.2018.09.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 07/26/2018] [Accepted: 09/04/2018] [Indexed: 11/22/2022]
Abstract
In the last years, due to new regulatory guidelines requiring a stringent documentation of cardiovascular (CV) safety of novel drugs for type 2 diabetes, cardiovascular outcomes safety trials (CVOTs) are requested. CVOTs increase the knowledge about the safety profile of the new drugs, but they have intrinsic limits that make difficult their transferability to clinical practice. For this reason, real world evidence is considered an important complement to experimental data. Among the glucagon-like peptide-1 receptor agonists, liraglutide in the LEADER CVOT demonstrated superiority in reducing the risk of major CV events (MACEs) vs. placebo. We conducted an observational, retrospective, longitudinal study based on 307 patients with T2DM treated with liraglutide under routine clinical practice conditions. Real world impact of liraglutide on metabolic control, CV risk factors, hypoglycemia and CV events was assessed. Improvements during 36 months were found in HbA1c (-1.0%; p < 0.0001), fasting blood glucose (-17.6 mg/dL; p < 0.0001), body weight (-3.2 kg; p < 0.0001), waist circumference (-1.45 cm; p = 0.004), systolic blood pressure (-10.41 mmHg; p < 0.0001), diastolic blood pressure (-3.69 mmHg; p < 0.0001), total cholesterol (-7.96 mg/dL; p =0.008) and triglycerides (-20.60 mg/dl; p = 0.01). No severe hypoglycemia occurred. Incidence of MACEs in this cohort was lower than in the LEADER study (2.59 vs. 3.4 events per 100 person-years), confirming CV safety of liraglutide even in the real world. On the other hand, a higher incidence of CV event in patients with established CV disease was documented (8.1 events per 100 person-years), in spite of the use of liraglutide. In conclusion, 36-month durability and CV safety of liraglutide were documented in a real world cohort of T2DM patients, with sustained benefits on a large array of CV risk factors.
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Scheen AJ. Cardiovascular outcome studies in type 2 diabetes: Comparison between SGLT2 inhibitors and GLP-1 receptor agonists. Diabetes Res Clin Pract 2018; 143:88-100. [PMID: 29944969 DOI: 10.1016/j.diabres.2018.06.008] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 05/14/2018] [Accepted: 06/13/2018] [Indexed: 12/22/2022]
Abstract
Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are two pharmacological classes that have proven their efficacy to reduce major cardiovascular events (MACEs) in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease in large prospective cardiovascular outcome trials (CVOTs): EMPA-REG OUTCOME (empagliflozin), CANVAS (canagliflozin), LEADER (liraglutide) and SUSTAIN 6 (semaglutide). Some heterogeneity appears to exist between the various agents within the two pharmacological classes. Whether these positive results could be extrapolated to patients without cardiovascular disease is still unknown. The underlying mechanisms remain a matter of debate but appear to differ between SGLT2is and GLP-1RAs. One crucial question is which patient's characteristics should be taken into account to guide the choice between a SGLT2i or a GLP-1RA according to a personalized approach. Heart failure should encourage the use of a SGLT2i whereas moderate to severe chronic kidney disease should favour the prescription of a GLP-1RA. Despite the results of recent CVOTs, numerous patients who are good candidates for benefiting of these agents do not receive them in clinical practice. Currently, there is a paradigm shift in T2DM management, moving from a primary objective of glucose control to a cardiovascular and renal protection.
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Affiliation(s)
- André J Scheen
- Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, University of Liège, Liège, Belgium; Clinical Pharmacology Unit, CHU Liège, Center for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.
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49
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Overbeek JA, Heintjes EM, Huisman EL, Tikkanen CK, van Diermen AW, Penning‐van Beest FJ, Herings RM. Clinical effectiveness of liraglutide vs basal insulin in a real-world setting: Evidence of improved glycaemic and weight control in obese people with type 2 diabetes. Diabetes Obes Metab 2018; 20:2093-2102. [PMID: 29726082 PMCID: PMC6099315 DOI: 10.1111/dom.13335] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 04/17/2018] [Accepted: 04/20/2018] [Indexed: 12/19/2022]
Abstract
AIMS To compare real-world antidiabetic treatment outcomes over 12 months in obese people with type 2 diabetes mellitus (T2DM) who previously received oral antidiabetic therapy and then initiated a first injectable therapy with liraglutide or basal insulin. PATIENTS AND METHODS This was a retrospective, propensity score-matched, longitudinal cohort study using real-world data (January 2010 to December 2015) from the Dutch PHARMO Database Network. Adult obese (body mass index [BMI] ≥35 kg/m2 ) patients with T2DM with ≥2 dispensing dates for liraglutide or basal insulin supported oral therapy (BOT) were selected. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline during 12 months of follow-up. The secondary endpoints were the changes in weight, BMI and cardiovascular risk factors from baseline. Clinical data were analysed using descriptive statistics and compared using mixed models for repeated measures. RESULTS Obese patients with T2DM (N = 1157) in each treatment group were matched (liraglutide cohort, n = 544; BOT cohort, n = 613). From 3 months onwards, glycaemic control improved in both cohorts but improved significantly more with liraglutide than with BOT (12 months: -12.2 mmol/mol vs -8.8 mmol/mol; P = .0053). In addition, weight and BMI were significantly lower for treatments with liraglutide vs BOT (12 months: -6.0 kg vs -1.6 kg and - 2.1 kg/m2 vs -0.5 kg/m2 , respectively; P < .0001 for both). No significant differences were seen in changes in cardiovascular risk factors. CONCLUSIONS The results of this real-world study in matched obese patients with T2DM showed that liraglutide was more effective than BOT for HbA1c control and weight/BMI reductions. Patients were more likely to maintain glycaemic control over time after initiating liraglutide than after initiating BOT.
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Affiliation(s)
- Jetty A. Overbeek
- PHARMO Institute for Drug Outcomes ResearchUtrechtthe Netherlands
- Department of General Practice and Elderly Care Medicine, Amsterdam Public Health Research InstituteVU University Medical CentreAmsterdamthe Netherlands
| | | | | | | | | | | | - Ron M.C. Herings
- PHARMO Institute for Drug Outcomes ResearchUtrechtthe Netherlands
- Department of Epidemiology and BiostatisticsVU University Medical CenterAmsterdamthe Netherlands
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50
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Watson KT, Wroolie TE, Tong G, Foland-Ross LC, Frangou S, Singh M, McIntyre RS, Roat-Shumway S, Myoraku A, Reiss AL, Rasgon NL. Neural correlates of liraglutide effects in persons at risk for Alzheimer's disease. Behav Brain Res 2018; 356:271-278. [PMID: 30099030 DOI: 10.1016/j.bbr.2018.08.006] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 07/30/2018] [Accepted: 08/08/2018] [Indexed: 12/12/2022]
Abstract
Insulin resistance (IR) is a metabolic state preceding development of type 2 diabetes (DM2), cardiovascular disease, and neurodegenerative disorders, including Alzheimer's Disease (AD). Liraglutide, a glucagon-like peptide-1 (GLP) agonist, is an insulin-sensitizing agent with neuroprotective properties, as shown in animal studies. The purpose of this double-blinded, placebo-controlled study was to examine the neural effects of administration of liraglutide in cognitively normal late middle-aged individuals with subjective cognitive complaints (half of subjects had family history of AD). Seed-based resting state connectivity using functional magnetic resonance imaging (fMRI) was conducted before and after 12 weeks of liraglutide treatment or placebo. Neuropsychological testing was conducted before and after treatment to determine whether there were any potential behavioral correlates to neural changes. RESULTS At baseline (time point 1), higher fasting plasma glucose (FPG) was associated with decreased connectivity between bilateral hippocampal and anterior medial frontal structures. At time point 2, we observed significant improvement in intrinsic connectivity within the default mode network (DMN) in the active group relative to placebo. There were no detectable cognitive differences between study groups after this duration of treatment. To our knowledge, this is the first placebo-controlled study to report neural effects of liraglutide in a middle-aged population with subjective cognitive complaints. Larger and longer duration studies are warranted to determine whether liraglutide has neuroprotective benefits in individuals at risk for AD.
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Affiliation(s)
- Kathleen T Watson
- Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Tonita E Wroolie
- Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Gabby Tong
- Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Lara C Foland-Ross
- Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Sophia Frangou
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Manpreet Singh
- Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Roger S McIntyre
- Department of Psychiatry, University of Toronto, Toronto, ON, Canada
| | - Siena Roat-Shumway
- Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Alison Myoraku
- Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Allan L Reiss
- Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA
| | - Natalie L Rasgon
- Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.
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