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Baris E, Portakal HS, Aslan A, Firtina Karagonlar Z, Tosun M. Liraglutide modulates cyclooxygenase and α7 acetylcholine receptors: in vitro and in silico insights into its anti-inflammatory role in LPS-induced inflammation in RAW 264.7 macrophages. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04225-5. [PMID: 40448826 DOI: 10.1007/s00210-025-04225-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 04/24/2025] [Indexed: 06/02/2025]
Abstract
Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is well-established for its metabolic benefits, including glycemic control and weight loss. Beyond these roles, it exhibits significant anti-inflammatory properties, though the mechanisms remain underexplored. This study investigates the anti-inflammatory effects of liraglutide in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages. Results demonstrate that increasing concentrations of liraglutide suppresses LPS-elevated prostaglandin E2 (PGE2), 6-keto prostaglandin F1α (6-keto-PGF1α, a stable prostacyclin metabolite) and thromboxane A2 (TXA2), similar to that observed with conventional anti-inflammatory agents, ibuprofen and celecoxib. Mechanistic exploration reveals that liraglutide's anti-inflammatory action is dually-modulated by cyclooxygenase (COX) and nicotinic acetylcholine receptor (nAChR) signaling. The application of non-selective, non-competitive nAChR antagonist or selective and potent α7-nAChR antagonist, mecamylamine (MEC) and methyllycaconitine (MLA), respectively, highlights the involvement of cholinergic pathways in liraglutide's activity. Based on in silico molecular docking analyses, liraglutide exhibits favorable binding affinities to COX-1, COX-2, prostacyclin synthase (PGIS), and α7nAChRs, supporting its potential multi-target anti-inflammatory effects. These findings suggest that the therapeutic potential of liraglutide may go beyond metabolic regulation and may be promising for conditions in which metabolic and inflammatory pathways converge, including inflammation and modulation of cholinergic signaling.
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Affiliation(s)
- Elif Baris
- Department of Medical Pharmacology, Faculty of Medicine, Izmir University of Economics, Sakarya Cd. 156, 35330, Izmir, Türkiye.
| | - Huseyin Saygin Portakal
- Department of Genetics and Bioengineering, Faculty of Engineering, Izmir University of Economics, Izmir, Türkiye
| | - Arda Aslan
- Department of Genetics and Bioengineering, Faculty of Engineering, Izmir University of Economics, Izmir, Türkiye
| | - Zeynep Firtina Karagonlar
- Department of Genetics and Bioengineering, Faculty of Engineering, Izmir University of Economics, Izmir, Türkiye
| | - Metiner Tosun
- Department of Medical Pharmacology, Faculty of Medicine, Izmir University of Economics, Sakarya Cd. 156, 35330, Izmir, Türkiye
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Tan Y, Liu S, Tang Q. Effect of GLP-1 receptor agonists on bone mineral density, bone metabolism markers, and fracture risk in type 2 diabetes: a systematic review and meta-analysis. Acta Diabetol 2025; 62:589-606. [PMID: 39985672 DOI: 10.1007/s00592-025-02468-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 02/04/2025] [Indexed: 02/24/2025]
Abstract
AIM To systematically assess randomized controlled trials that evaluated the effect of glucagon-like peptide-1 (GLP-1) receptor agonists on fracture incidence, bone mineral density, and bone metabolism markers in individuals with type 2 diabetes. METHODS From database setup to March 21, 2024, a search was conducted across nine Chinese and English databases. The Cochrane Risk of Bias Tool was applied to assess potential bias. Data analysis was performed using RevMan 5.3 and Stata 14.0. Subgroup analysis and meta regression were employed to explore sources of heterogeneity, and publication bias was evaluated using funnel plots and Egger's test. RESULTS Twenty-five studies were included. The results of the meta-analysis indicated that GLP-1 receptor agonist was not significantly associated with an increased risk of fracture (RR = 0.80; 95% CI 0.47 to 1.36; P = 0.41). Additionally, improvement in lumbar spine BMD (MD = 0.07 g/cm2, 95% CI 0.06 to 0.09, P < 0.00001), hip neck BMD (MD = 0.05 g/cm2, 95% CI 0.03 to 0.08, P = 0.0001) and total hip BMD (MD = 0.06 g/cm2, 95% CI 0.04 to 0.07, P < 0.00001) was superior to the control group. Similarly, GLP-1 receptor agonists significantly improved P1NP (SMD = 0.33, 95% CI 0.07 to 0.59, P = 0.01), OC (MD = 1.46 ug/L, 95% CI 1.10 to 1.83, P < 0.00001), 25-OH-D (SMD = 0.45, 95% CI 0.06 to 0.83, P = 0.02), and b-ALP (MD = 0.91ug/L, 95% CI 0.19 to 1.63, P = 0.01) while reducing β-CTX (SMD = - 0.34, 95% CI - 0.54 to - 0.14, P = 0.001). There was no significant impact on other bone metabolism markers, including N-MID-OT (SMD = 0.43, 95% CI 0.01 to 0.86, P = 0.05), ALP (SMD = - 0.00, 95% CI: - 0.25 to 0.25, P = 0.98), Calcium (MD = 0.00 mmol/L, 95% CI - 0.04 to 0.04, P = 0.94) and Phosphate (MD = 0.02 mmol/L, 95% CI - 0.04 to 0.07, P = 0.57). CONCLUSION This meta-analysis demonstrated no significant effect of GLP-1 receptor agonists on elevated fracture risk. There was a statistically significant improvement in BMD and certain bone turnover markers (β-CTX, P1NP, OC, b-ALP, and 25-OH-D). However, due to some limitations, further high-quality clinical studies with sufficient follow-up time are needed to draw more definitive conclusions.
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Affiliation(s)
- Yimei Tan
- Affiliated Guangdong Hospital of Integrated Traditional Chinese and Western Medicine of Guangzhou University of Chinese Medicine, No.16, Guicheng South Fifth Road, Foshan, 528200, Guangdong, China
- Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine, No.16, Guicheng South Fifth Road, Foshan, 528200, Guangdong, China
| | - Shuanghua Liu
- Jinan University, No.601, Huangpu Avenue West, Guangzhou, 510632, Guangdong, China
| | - Qizhi Tang
- Affiliated Guangdong Hospital of Integrated Traditional Chinese and Western Medicine of Guangzhou University of Chinese Medicine, No.16, Guicheng South Fifth Road, Foshan, 528200, Guangdong, China.
- Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine, No.16, Guicheng South Fifth Road, Foshan, 528200, Guangdong, China.
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Zhang Y, Chen G, Wang W, Yang D, Zhu D, Jing Y. Association of Glucagon-like peptide-1 receptor agonists use with fracture risk in type 2 diabetes: A meta-analysis of randomized controlled trials. Bone 2025; 192:117338. [PMID: 39603373 DOI: 10.1016/j.bone.2024.117338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 10/29/2024] [Accepted: 11/20/2024] [Indexed: 11/29/2024]
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is associated with an increased risk of osteoporosis (OP) and fractures. PURPOSE The aim of this study was to analyze the available evidence on the effect of GLP-1 RAs on fracture risk in patients with type 2 diabetes. METHODS A systematic search based on PubMed, Embase and Web of Science databases was performed to collect relevant literature published until May 2024 on the application of GLP-1 RAs in T2DM patients. Data were extracted from each study for comparative analysis, and meta-analysis was performed using R software to calculate relative risk (RR) and 95 % confidence intervals (CI) for dichotomous variables. Two subgroup analyses were also performed. RESULTS A total of 44 randomized controlled trials (RCTs) involving 47,823 patients were analyzed. There were 292 incident fracture cases (138 in GLP-1 RAs group and 154 in control group). The pooled RR for fractures in patients treated with GLP-1RAs compared with those treated with placebo or other anti-diabetic drugs was 0.77 (95 % CI: 0.61-0.96). Subgroup analyses showed that the beneficial effect was dependent on the period of treatment with GLP-1 RAs, only treated for >78 weeks were effective in reducing the risk of fractures in patients with T2DM (RR 0.77; 95 % CI: 0.61-0.96). Furthermore, subgroup analyses showed that liraglutide treatment was associated with a significant reduction in fracture risk (RR 0.42; 95 % CI: 0.21-0.85). However, other GLP-1 RAs did not present benefits over other anti-diabetic drug treatments. CONCLUSION GLP-1 RAs could reduce the risk of fracture in T2DM patients, and the beneficial effect was interrelated to the period of treatment. Liraglutide could significantly reduce the risk of fracture in T2DM patients compared to placebo and other anti-diabetic drugs. Due to the limited nature of contemporary research, further studies are needed to develop a clear clinical consensus.
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Affiliation(s)
- Yuan Zhang
- Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China; Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
| | - Guanhua Chen
- Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China; Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China
| | - Weimin Wang
- Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China; Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Donghui Yang
- Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China; Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Dalong Zhu
- Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China; Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Yali Jing
- Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China; Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China.
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Zhang S, Sidra F, Alvarez CA, Kinaan M, Lingvay I, Mansi IA. Healthcare utilization, mortality, and cardiovascular events following GLP1-RA initiation in chronic kidney disease. Nat Commun 2024; 15:10623. [PMID: 39639039 PMCID: PMC11621321 DOI: 10.1038/s41467-024-54009-3] [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] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 10/28/2024] [Indexed: 12/07/2024] Open
Abstract
Treatment with glucagon-like peptide-1 receptor agonists (GLP1-RA) in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) may attenuate kidney disease progression and cardiovascular events but their real-world impact on healthcare utilization and mortality in this population are not well-defined. Here, we emulate a clinical trial that compares outcomes following initiation of GLP1-RA vs Dipeptidyl peptidase-4 inhibitors (DPP4i), as active comparators, in U.S. veterans aged 35 years of older with moderate to advanced CKD during fiscal years 2006 to 2021. Primary outcome was rate of acute healthcare utilization. Secondary outcomes were all-cause mortality and a composite of acute cardiovascular events. After propensity score matching (16,076 pairs) and 2.2 years mean follow-up duration, use of GLP1-RA in patients with moderate to advanced CKD was associated with lower annual rate of acute healthcare utilization and all-cause mortality. There was no significant difference in acute cardiovascular events.
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Affiliation(s)
- Shuyao Zhang
- Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Fnu Sidra
- Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- The Jones Center for Diabetes & Endocrine Wellness, Macon, GA, USA
| | - Carlos A Alvarez
- Department of Pharmacy Practice and Center for Excellence in Real World Evidence, Texas Tech University Health Science Center, Dallas, TX, USA
| | - Mustafa Kinaan
- Endocrinology, Diabetes, and Metabolism Fellowship, UCF HCA Healthcare GME, Orlando, FL, USA
- Department of Internal Medicine, University of Central Florida, College of Medicine, Orlando, FL, USA
| | - Ildiko Lingvay
- Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ishak A Mansi
- Department of Internal Medicine, University of Central Florida, College of Medicine, Orlando, FL, USA.
- Education Services, Orlando VA Healthcare System, Orlando, FL, USA.
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Drake T, Landsteiner A, Langsetmo L, MacDonald R, Anthony M, Kalinowski C, Ullman K, Billington CJ, Kaka A, Sultan S, Wilt TJ. Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Systematic Review and Network Meta-analysis for the American College of Physicians. Ann Intern Med 2024; 177:618-632. [PMID: 38639549 DOI: 10.7326/m23-1490] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/20/2024] Open
Abstract
BACKGROUND Newer diabetes medications may have beneficial effects on mortality, cardiovascular outcomes, and renal outcomes. PURPOSE To evaluate the effectiveness, comparative effectiveness, and harms of sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP1) agonists, dipeptidyl peptidase-4 (DPP4) inhibitors, and long-acting insulins as monotherapy or combination therapy in adults with type 2 diabetes mellitus (T2DM). DATA SOURCES MEDLINE and EMBASE for randomized controlled trials (RCTs) published from 2010 through January 2023. STUDY SELECTION RCTs lasting at least 52 weeks that included at least 500 adults with T2DM receiving eligible medications and reported any outcomes of interest. DATA EXTRACTION Data were abstracted by 1 reviewer and verified by a second. Independent, dual assessments of risk of bias and certainty of evidence (CoE) were done. DATA SYNTHESIS A total of 130 publications from 84 RCTs were identified. CoE was appraised using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria for direct, indirect, and network meta-analysis (NMA); the highest CoE was reported. Compared with usual care, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality (high CoE) and major adverse cardiovascular events (MACE) (moderate to high CoE), SGLT2 inhibitors reduce progression of chronic kidney disease (CKD) and heart failure hospitalizations and GLP1 agonists reduce stroke (high CoE), and SGLT2 inhibitors reduce serious adverse events and severe hypoglycemia (high CoE). The threshold for minimally important differences, which was predefined with the American College of Physicians Clinical Guidelines Committee, was not met for these outcomes. Compared with usual care, insulin, tirzepatide, and DPP4 inhibitors do not reduce all-cause mortality (low to high CoE). Compared with insulin, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality (low to moderate CoE). Compared with DPP4 inhibitors, GLP1 agonists reduce all-cause mortality (moderate CoE). Compared with DPP4 inhibitors and sulfonylurea (SU), SGLT2 inhibitors reduce MACE (moderate to high CoE). Compared with SU and insulin, SGLT2 inhibitors and GLP1 agonists reduce severe hypoglycemia (low to high CoE). LIMITATIONS Infrequent direct comparisons between drugs of interest; sparse data for NMA on most outcomes; possible incoherence due to differences in baseline patient characteristics and usual care; insufficient data on predefined subgroups, including demographic subgroups, patients with prior cardiovascular disease, and treatment-naive persons. CONCLUSION In adults with T2DM, SGLT2 inhibitors and GLP1 agonists (but not DPP4 inhibitors, insulin, or tirzepatide) reduce all-cause mortality and MACE compared with usual care. SGLT2 inhibitors reduce CKD progression and heart failure hospitalization and GLP1 agonists reduce stroke compared with usual care. Serious adverse events and severe hypoglycemia are less frequent with SGLT2 inhibitors and GLP1 agonists than with insulin or SU. PRIMARY FUNDING SOURCE American College of Physicians. (PROSPERO: CRD42022322129).
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Affiliation(s)
- Tyler Drake
- Department of Medicine, VA Health Care System, and Department of Medicine, University of Minnesota, Minneapolis, Minnesota (T.D., C.J.B., A.K.)
| | - Adrienne Landsteiner
- Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, Minnesota (A.L., R.M., M.A., C.K., K.U.)
| | - Lisa Langsetmo
- Department of Medicine, University of Minnesota; Center for Care Delivery & Outcomes Research, VA Health Care System; and Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota (L.L.)
| | - Roderick MacDonald
- Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, Minnesota (A.L., R.M., M.A., C.K., K.U.)
| | - Maylen Anthony
- Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, Minnesota (A.L., R.M., M.A., C.K., K.U.)
| | - Caleb Kalinowski
- Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, Minnesota (A.L., R.M., M.A., C.K., K.U.)
| | - Kristen Ullman
- Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, Minnesota (A.L., R.M., M.A., C.K., K.U.)
| | - Charles J Billington
- Department of Medicine, VA Health Care System, and Department of Medicine, University of Minnesota, Minneapolis, Minnesota (T.D., C.J.B., A.K.)
| | - Anjum Kaka
- Department of Medicine, VA Health Care System, and Department of Medicine, University of Minnesota, Minneapolis, Minnesota (T.D., C.J.B., A.K.)
| | - Shahnaz Sultan
- Department of Medicine, University of Minnesota, and Center for Care Delivery & Outcomes Research, VA Health Care System, Minneapolis, Minnesota (S.S.)
| | - Timothy J Wilt
- Department of Medicine, VA Health Care System; Department of Medicine, University of Minnesota; Center for Care Delivery & Outcomes Research, VA Health Care System; and Division of Health Policy & Management, School of Public Health, University of Minnesota, Minneapolis, Minnesota (T.J.W.)
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Al-Sadawi MA, Aslam FM, Tao M, Alsaiqali M, Almasry IO, Fan R, Rashba EJ, Singh A. Effects of GLP-1 Agonists on mortality and arrhythmias in patients with Type II diabetes. IJC HEART & VASCULATURE 2023; 47:101218. [PMID: 37252197 PMCID: PMC10209701 DOI: 10.1016/j.ijcha.2023.101218] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/29/2023] [Accepted: 05/06/2023] [Indexed: 05/31/2023]
Abstract
Background Glucagon-like Peptide-1 Receptor Agonists (GLP-1 RA) are frequently used for the management of diabetes. The impact of GLP-1 RA on cardiovascular outcomes is unclear. We aim to assess the effect of GLP-1 RA on mortality, atrial and ventricular arrhythmias, and sudden cardiac death in patients with type II diabetes. Methods We searched databases including Ovid MEDLINE, EMBASE, Scopus, Web of Science, Google Scholar and CINAHL, from inception to May 2022, for randomized controlled trials reporting the relationship between GLP-1 RA (including albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide) and mortality, atrial arrhythmias, and the combined incidence of ventricular arrhythmias and sudden cardiac death. The search was not restricted to time or publication status. Results A total of 464 studies resulted from literature search, of which 44 studies, including 78,702 patients (41,800 GLP-1 agonists vs 36,902 control), were included. Follow up ranged from 52 to 208 weeks. GLP-1 RA were associated with lower risk of all-cause mortality (odds ratio 0.891, 95% confidence interval 0.837-0.949; P < 0.01) and reduced cardiovascular mortality (odds ratio 0.88, 95% confidence interval 0.881-0.954; P < 0.01). GLP-1 RA were not associated with increased risk of atrial (odds ratio 0.963, 95% confidence interval 0.869-1.066; P 0.46) or ventricular arrhythmias and sudden cardiac death (odds ratio 0.895, 95% confidence interval 0.706-1.135; P 0.36). Conclusion GLP-1 RA are associated with decreased all-cause and cardiovascular mortality, and no increased risk of atrial and ventricular arrhythmias and sudden cardiac death.
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Affiliation(s)
| | - Faisal M. Aslam
- Cardiovascular Department, Stony Brook Medicine, Stony Brook, NY, USA
| | - Michael Tao
- Cardiovascular Department, Stony Brook Medicine, Stony Brook, NY, USA
| | | | | | - Roger Fan
- Cardiovascular Department, Stony Brook Medicine, Stony Brook, NY, USA
| | - Eric J. Rashba
- Cardiovascular Department, Stony Brook Medicine, Stony Brook, NY, USA
| | - Abhijeet Singh
- Cardiovascular Department, Stony Brook Medicine, Stony Brook, NY, USA
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Nreu B, Dicembrini I, Tinti F, Mannucci E, Monami M. Pancreatitis and pancreatic cancer in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonists: an updated meta-analysis of randomized controlled trials. Minerva Endocrinol (Torino) 2023; 48:206-213. [PMID: 32720500 DOI: 10.23736/s2724-6507.20.03219-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Abstract
INTRODUCTION An association between glucagon-like peptide-1 receptor agonists (GLP1-RA) and risk of pancreatitis and pancreatic cancer has been suggested. Since its first description, several new trials (including three cardiovascular outcome trials) have been published, substantially increasing the available data set. This suggests the need for an update of the previous meta-analysis. EVIDENCE ACQUISITION A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials, with duration ≥52 weeks, enrolling patients with type 2 diabetes, and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. The endpoints were pancreatitis, pancreatic cancer reported as serious adverse events. Mantel-Haenszel Odds Ratio (MH-OR) with 95% confidence interval (95% CI) was calculated for all outcomes defined above, on an intention-to-treat basis. EVIDENCE SYNTHESIS A total of 43 trials fulfilling inclusion criteria (all reporting data on pancreatitis and pancreatic cancer) was identified. GLP-1 RA showed no association with pancreatitis (MH-OR 1.24 [0.94, 1.64]; P=0.13) and pancreatic cancer (MH-OR 1.28 [0.87, 1.89]; P=0.20). CONCLUSIONS No clear evidence of risk for pancreatitis was observed, whereas data on pancreatic cancer are too scarce to draw any conclusion.
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Affiliation(s)
- Besmir Nreu
- Department of Diabetology, Careggi University Hospital, Florence, Italy
| | - Ilaria Dicembrini
- Department of Diabetology, Careggi University Hospital, Florence, Italy
| | - Federico Tinti
- Department of Diabetology, Careggi University Hospital, Florence, Italy
| | - Edoardo Mannucci
- Department of Diabetology, Careggi University Hospital, Florence, Italy
| | - Matteo Monami
- Department of Diabetology, Careggi University Hospital, Florence, Italy -
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Bai S, Lin C, Jiao R, Cai X, Hu S, Lv F, Yang W, Zhu X, Ji L. Is the steady-state concentration, duration of action, or molecular weight of GLP-1RA associated with cardiovascular and renal outcomes in type 2 diabetes? Eur J Intern Med 2023; 109:79-88. [PMID: 36628824 DOI: 10.1016/j.ejim.2023.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 01/02/2023] [Accepted: 01/05/2023] [Indexed: 01/09/2023]
Abstract
IMPORTANCE Disparities were found in the cardiovascular and renal outcomes among different glucagon-like peptide 1 receptor agonist (GLP-1RA) subtypes. However, whether the characteristics of GLP-1RA itself are associated with these disparities remains unclear. OBJECTIVE To assess the association between the steady-state concentration, duration of action, or molecular weight of GLP-1RA and the risks of cardiovascular and renal outcomes in patients with type 2 diabetes (T2D). DATA SOURCES PubMed, MEDLINE, EMBASE, Cochrane and Clinicaltrial.gov from inception to April 2022. STUDY SELECTION Randomized controlled trials (RCTs) investigating GLP-1RAs in patients with T2D were included. DATA EXTRACTION AND SYNTHESIS Literature screening and data extraction were performed independently by 2 researchers. The outcomes were computed as odds ratio (OR) and its 95% confidence interval (CI). Subgroup analyses were conducted according to steady-state concentration, duration of action and molecular weight of GLP-1RAs. MAIN OUTCOMES AND MEASURES Primary outcomes were major adverse cardiovascular events (MACE), composite renal outcome and all-cause mortality. RESULTS In all, 61 RCTs were included. When compared with non-GLP-1RA agents, GLP-1RAs with high steady-state concentration were associated with greater risk reduction in MACE (p for subgroup difference = 0.01) and the composite renal outcome (p for subgroup difference = 0.008) in patients with T2D. Greater risk reductions in MACE between GLP-1RA users versus non-GLP-RA users were observed in long acting stratum when compared with short acting stratum (p for subgroup difference = 0.04) in patients with T2D. The molecular weight of GLP-1RAs was not associated with the risk of cardiovascular and renal outcomes. CONCLUSIONS AND RELEVANCE GLP-1RAs with high steady-state concentrations might be associated with greater risk reductions in cardiovascular and renal outcomes in patients with T2D. Long acting GLP-1RAs might outperform short acting ones in reducing the risk of cardiovascular outcomes. These findings provided new insights for guiding the clinical applications of GLP-1RAs in patients with T2D.
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Affiliation(s)
- Shuzhen Bai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Chu Lin
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Ruoyang Jiao
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
| | - Suiyuan Hu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Fang Lv
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Wenjia Yang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xingyun Zhu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
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Links between Metabolic Syndrome and Hypertension: The Relationship with the Current Antidiabetic Drugs. Metabolites 2023; 13:metabo13010087. [PMID: 36677012 PMCID: PMC9863091 DOI: 10.3390/metabo13010087] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/23/2022] [Accepted: 01/03/2023] [Indexed: 01/06/2023] Open
Abstract
Hypertension poses a significant burden in the general population, being responsible for increasing cardiovascular morbidity and mortality, leading to adverse outcomes. Moreover, the association of hypertension with dyslipidaemia, obesity, and insulin resistance, also known as metabolic syndrome, further increases the overall cardiovascular risk of an individual. The complex pathophysiological overlap between the components of the metabolic syndrome may in part explain how novel antidiabetic drugs express pleiotropic effects. Taking into consideration that a significant proportion of patients do not achieve target blood pressure values or glucose levels, more efforts need to be undertaken to increase awareness among patients and physicians. Novel drugs, such as incretin-based therapies and renal glucose reuptake inhibitors, show promising results in decreasing cardiovascular events in patients with metabolic syndrome. The effects of sodium-glucose co-transporter-2 inhibitors are expressed at different levels, including renoprotection through glucosuria, natriuresis and decreased intraglomerular pressure, metabolic effects such as enhanced insulin sensitivity, cardiac protection through decreased myocardial oxidative stress and, to a lesser extent, decreased blood pressure values. These pleiotropic effects are also observed after treatment with glucagon-like peptide-1 receptor agonists, positively influencing the cardiovascular outcomes of patients with metabolic syndrome. The initial combination of the two classes may be the best choice in patients with type 2 diabetes mellitus and multiple cardiovascular risk factors because of their complementary mechanisms of action. In addition, the novel mineralocorticoid receptor antagonists show significant cardio-renal benefits, as well as anti-inflammatory and anti-fibrotic effects. Overall, the key to better control of hypertension in patients with metabolic syndrome is to consider targeting multiple pathogenic mechanisms, using a combination of the different therapeutic agents, as well as drastic lifestyle changes. This article will briefly summarize the association of hypertension with metabolic syndrome, as well as take into account the influence of antidiabetic drugs on blood pressure control.
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Lasalvia P, Gil-Rojas Y, García Á. Cost-effectiveness of dapagliflozin compared to DPP-4 inhibitors as combination therapy with metformin in the treatment of type 2 diabetes mellitus without established cardiovascular disease in Colombia. Expert Rev Pharmacoecon Outcomes Res 2022; 22:955-964. [PMID: 35259045 DOI: 10.1080/14737167.2022.2044310] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION SGLT2 inhibitors or DPP-4 inhibitors are among the preferred options in patients with type 2 diabetes mellitus (T2DM) without established cardiovascular disease. OBJECTIVE To evaluate the incremental cost-effectiveness of dapagliflozin versus DPP-4 inhibitors as a complement to metformin in the treatment ofT2D, from the perspective of the Colombian health system. METHODS The Cardiff model was used to estimate the incremental cost-effectiveness ratio (ICER) of dapagliflozin plus metformin compared to DPP-4 inhibitors plus metformin in adults with T2DM who did not respond adequately to metformin monotherapy. We estimated the incidence of micro- and macrovascular complications from risk equations incorporating the effect of treatment. The time horizon for analysis was 5 years and a discount rate of 5% was applied, for both costs and outcomes. The costs were expressed in 2020 USD (1 USD = $3,693.36 COP). RESULTS Dapagliflozin in association with metformin resulted in a higher number of quality-adjusted life years (QALYs) compared to the intervention. The ICER was US$1,964.80 per QALY gained. CONCLUSION From the point of view of Colombian healthcare system, the combination of dapagliflozin with metformin is a cost-effective option compared to DPP-4 + metformin inhibitors in the treatment of T2D without established cardiovascular disease.
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Affiliation(s)
| | | | - Ángel García
- Cardiology Unit, San Ignacio University Hospital. Pontificia Universidad Javeriana, Bogotá, Colombia
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Pacheco-Soto BT, Elguezabal-Rodelo RG, Porchia LM, Torres-Rasgado E, Pérez-Fuentes R, Gonzalez-Mejia ME. Denosumab improves glucose parameters in patients with impaired glucose tolerance: a systematic review and meta-analysis. J Drug Assess 2021; 10:97-105. [PMID: 34676131 PMCID: PMC8525927 DOI: 10.1080/21556660.2021.1989194] [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] [Indexed: 11/03/2022] Open
Abstract
Objective Receptor activator of NF-κβ ligand (RANKL) is crucial for the development of hepatic insulin resistance and poor glucose uptake; therefore, inhibiting RANKL with Denosumab could improve fasting plasma glucose (FPG) and insulin (FPI). Methods A systematic review was conducted to evaluate the effects of Denosumab on glycemic parameters. PubMed, SCOPUS, EBSCO, and LILACS databases were searched for studies that investigated the effect of Denosumab on FPG, glycated hemoglobin (HbA1c), FPI, and Homeostatic Model Assessment for Insulin Resistance (HOMA1-IR). The pooled standard difference in means (SDM) and 95% confidence intervals (95%CI) were calculated. The results were stratified into (1) Normal Glucose Tolerance (NGT) and (2) Impaired Glucose Tolerance (IGT). Results Six publications (1203 participants) were included. There was a significant association between Denosumab and FPG (SDM = -0.388, 95%CI: -0.705 to -0.070, p = .017) and with HOMA1-IR (SDM = -0.223, 95%CI: -0.388 to -0.058, p = .008), but not for HbA1c and FPI. When stratified by glucose tolerance, the association between Denosumab and FPG, HbA1c, and HOMA1-IR was present for the IGT group. Lastly, Denosumab had a time-dependent effect on HbA1c (slope = -0.037, 95%CI: -0.059 to -0.015, p < .005). Conclusions Denosumab significantly improved glycemic parameters. This outcome was more prominent for subjects with compromised glucose tolerance, positing that Denosumab can be used as a treatment to improve glucose metabolism for persons with pre-diabetes and diabetes.
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Affiliation(s)
| | | | - Leonardo M Porchia
- Laboratorio de Fisiopatología en Enfermedades Crónicas, Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Delegación Puebla, Puebla, Mexico
| | | | - Ricardo Pérez-Fuentes
- Facultad de Medicina, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico.,Laboratorio de Fisiopatología en Enfermedades Crónicas, Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Delegación Puebla, Puebla, Mexico
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Alsugair HA, Alshugair IF, Alharbi TJ, Bin Rsheed AM, Tourkmani AM, Al-Madani W. Weekly Semaglutide vs. Liraglutide Efficacy Profile: A Network Meta-Analysis. Healthcare (Basel) 2021; 9:healthcare9091125. [PMID: 34574899 PMCID: PMC8466858 DOI: 10.3390/healthcare9091125] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/20/2021] [Accepted: 08/22/2021] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Glucagon-like peptide 1 receptor agonist (GLP-1 RA) is a class of hypoglycemic medications. Semaglutide once-weekly (QW) and liraglutide once-daily (OD) significantly improved glycemic control compared to placebo. To date, no long-term phase III trials directly comparing semaglutide and liraglutide are available. This network meta-analysis (NMA) aims to compare the long-term efficacy of semaglutide and liraglutide. METHODS PubMed, Embase, and Cochrane Library were searched from inception until June 2019 to identify relevant articles. Nine long-term randomized controlled trials comparing once-weekly semaglutide or liraglutide with placebo or other active comparisons were identified. The outcomes of interest were changes in HbA1c and weight after 52 weeks. A Bayesian framework and NMA were used for data synthesis. This is a sub-study of the protocol registered in PROSPERO (number CRD42018091598). RESULTS The data showed significant superiority in HbA1c reduction of semaglutide 1 mg QW over liraglutide 1.2 and 1.8 mg with a treatment difference of 0.47% and 0.3%, respectively. Semaglutide 0.5 mg QW was found to be significantly superior to liraglutide 1.2 mg in HbA1c reduction with a treatment difference of 0.17%. Regarding weight reduction analysis, semaglutide 0.5 and 1 mg QW were significantly associated with a greater reduction than liraglutide 0.6 mg with a treatment difference of 2.42 and 3.06 kg, respectively. However, no significant reduction was found in comparison to liraglutide 1.2 and 1.8 mg. CONCLUSIONS Semaglutide improved the control of blood glucose and body weight. The capacity of long-term glycemic control and body weight control of semaglutide appears to be more effective than other GLP-1 RAs, including liraglutide. However, considering the number of included studies and potential limitations, more large-scale, head-to-head, well-designed randomized-controlled trials (RCTs) are needed to confirm these findings.
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Affiliation(s)
- Hassan A. Alsugair
- Family Medicine Department, Prince Sultan Military Medical City, Riyadh 12624, Saudi Arabia; (A.M.B.R.); (A.M.T.)
- Correspondence: or (H.A.A.); or (T.J.A.); Tel.: +966-114777714-40438 (T.J.A.)
| | - Ibrahim F. Alshugair
- Orthopedic Surgery Department, King Saud Medical City, Riyadh 12746, Saudi Arabia;
| | - Turki J. Alharbi
- Family Medicine Department, Prince Sultan Military Medical City, Riyadh 12624, Saudi Arabia; (A.M.B.R.); (A.M.T.)
- Correspondence: or (H.A.A.); or (T.J.A.); Tel.: +966-114777714-40438 (T.J.A.)
| | - Abdulaziz M. Bin Rsheed
- Family Medicine Department, Prince Sultan Military Medical City, Riyadh 12624, Saudi Arabia; (A.M.B.R.); (A.M.T.)
| | - Ayla M. Tourkmani
- Family Medicine Department, Prince Sultan Military Medical City, Riyadh 12624, Saudi Arabia; (A.M.B.R.); (A.M.T.)
| | - Wedad Al-Madani
- General Authority of Statistics, Riyadh 11481, Saudi Arabia;
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Campos C, Unger J. Primary care management of type 2 diabetes: a comparison of the efficacy and safety of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Postgrad Med 2021; 133:843-853. [PMID: 34416133 DOI: 10.1080/00325481.2021.1971461] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors (DPP4is) exert their effects via the incretin system, which augments glucose-dependent insulin secretion in response to nutrient intake (the 'incretin effect'). Both classes are well-established pharmacologic options for the management of glycemic control in individuals with type 2 diabetes (T2D) after failure of first-line metformin; however, they have inherent differences in their mechanisms of action that are reflected in their clinical safety and efficacy profiles. GLP-1RAs have high glycemic efficacy and are associated with weight loss and, in some cases, cardioprotective effects, with a side-effect profile of predominantly transient gastrointestinal adverse events. Most GLP-1RAs are administered as subcutaneous injection, although an oral formulation of one GLP-1RA, semaglutide, has recently become available. DPP4is provide moderate glycemic control, are weight-neutral, and do not offer any cardiovascular benefits, but are generally well tolerated. DPP4is are all administered orally. This narrative review aims to provide guidance for a primary care audience on the similarities and differences between GLP-1RA and DPP4i therapies, with a focus on their mechanism of action, clinical safety, efficacy, and real-world effectiveness. The role of incretin-based therapies in the T2D treatment paradigm, including key considerations for guiding treatment decisions, will also be discussed.
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Affiliation(s)
- Carlos Campos
- Department of Family Medicine, University of Texas Health Science Center, San Antonio, USA
| | - Jeff Unger
- Unger Primary Care Concierge Medical Group, Rancho Cucamonga, USA
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Gill L, Mackey S. Obstetrician-Gynecologists' Strategies for Patient Initiation and Maintenance of Antiobesity Treatment with Glucagon-Like Peptide-1 Receptor Agonists. J Womens Health (Larchmt) 2021; 30:1016-1027. [PMID: 33626287 PMCID: PMC8290308 DOI: 10.1089/jwh.2020.8683] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Obesity is a chronic disease affecting women at higher rates than men. In an obstetrics and gynecology setting, frequently encountered obesity-related complications are polycystic ovary syndrome, fertility and pregnancy complications, and increased risk of breast and gynecological cancers. Obstetrician-gynecologists (OBGYNs) are uniquely positioned to diagnose and treat obesity, given their role in women's primary health care and the increasing prevalence of obesity-related fertility and pregnancy complications. The metabolic processes of bodyweight regulation are complex, which makes weight-loss maintenance challenging, despite dietary modifications and exercise. Antiobesity medications (AOMs) can facilitate weight loss by targeting appetite regulation. There are four AOMs currently approved for long-term use in the United States, of which liraglutide 3.0 mg is among the most efficacious. Liraglutide 3.0 mg, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), is superior to placebo in achieving weight loss and improving cardiometabolic profile, in both clinical trial and real-world settings. In addition, women with fertility complications receiving liraglutide 1.8–3.0 mg can benefit from improved ovarian function and fertility. Liraglutide 3.0 mg is generally well tolerated, but associated with transient gastrointestinal side effects, which can be mitigated. In this review, we present the risks of obesity and benefits of weight loss for women, and summarize clinical development of GLP-1 RAs for weight management. Finally, we provide practical advice and recommendations for OBGYNs to open the discussion about bodyweight with their patients, initiate lifestyle modification and GLP-1 RA treatment, and help them persist with these interventions to achieve optimal weight loss with associated health benefits.
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Affiliation(s)
- Lisa Gill
- Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, Minnesota, USA
| | - Suzanne Mackey
- Salvéo Weight Management, Voorhees Township, New Jersey, USA
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Taylor SI, Yazdi ZS, Beitelshees AL. Pharmacological treatment of hyperglycemia in type 2 diabetes. J Clin Invest 2021; 131:142243. [PMID: 33463546 PMCID: PMC7810496 DOI: 10.1172/jci142243] [Citation(s) in RCA: 140] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus is a major public health problem, affecting about 10% of the population. Pharmacotherapy aims to protect against microvascular complications, including blindness, end-stage kidney disease, and amputations. Landmark clinical trials have demonstrated that intensive glycemic control slows progression of microvascular complications (retinopathy, nephropathy, and neuropathy). Long-term follow-up has demonstrated that intensive glycemic control also decreases risk of macrovascular disease, albeit rigorous evidence of macrovascular benefit did not emerge for over a decade. The US FDA's recent requirement for dedicated cardiovascular outcome trials ushered in a golden age for understanding the clinical profiles of new type 2 diabetes drugs. Some clinical trials with sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP1) receptor agonists reported data demonstrating cardiovascular benefit (decreased risk of major adverse cardiovascular events and hospitalization for heart failure) and slower progression of diabetic kidney disease. This Review discusses current guidelines for use of the 12 classes of drugs approved to promote glycemic control in patients with type 2 diabetes. The Review also anticipates future developments with potential to improve the standard of care: availability of generic dipeptidylpeptidase-4 (DPP4) inhibitors and SGLT2 inhibitors; precision medicine to identify the best drugs for individual patients; and new therapies to protect against chronic complications of diabetes.
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Rayner CK, Wu T, Aroda VR, Whittington C, Kanters S, Guyot P, Shaunik A, Horowitz M. Gastrointestinal adverse events with insulin glargine/lixisenatide fixed-ratio combination versus glucagon-like peptide-1 receptor agonists in people with type 2 diabetes mellitus: A network meta-analysis. Diabetes Obes Metab 2021; 23:136-146. [PMID: 32991041 PMCID: PMC7756611 DOI: 10.1111/dom.14202] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 09/08/2020] [Accepted: 09/23/2020] [Indexed: 02/05/2023]
Abstract
AIMS Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are the recommended first injectable therapy in type 2 diabetes. However, long-term persistence is suboptimal and partly attributable to gastrointestinal tolerability, particularly during initiation/escalation. Gradual titration of fixed-ratio combination GLP-1 RA/insulin therapies may improve GLP-1 RA gastrointestinal tolerability. We compared gastrointestinal adverse event (AE) rates for iGlarLixi versus GLP-1 RAs during the first 12 weeks of therapy, including a sensitivity analysis with IDegLira. MATERIALS AND METHODS The PICO framework was used to identify studies from MEDLINE, EMBASE and CENTRAL searches using a proprietary, web-based, standardized tool with single data extraction. Gastrointestinal AEs were modelled using a Bayesian network meta-analysis (NMA), using fixed and random effects for each recommended dose (treatment-specific NMA) and class (drug-class NMA). RESULTS Treatment-specific NMA included 17 trials (n = 9030; 3665 event-weeks). Nausea rates were significantly lower with iGlarLixi versus exenatide 10 μg twice daily (rate ratio: 0.32; 95% credible interval: 0.15, 0.66), once-daily lixisenatide 20 μg (0.35; 0.24, 0.50) and liraglutide 1.8 mg once daily (0.48; 0.23, 0.98). Rates were numerically, but not statistically, lower versus once-weekly semaglutide 1 mg (0.60; 0.30, 1.23) and dulaglutide 1.5 mg (0.60; 0.29, 1.26), and numerically, but not statistically, higher versus once-weekly exenatide (1.91; 0.91, 4.03). Sensitivity analysis results were similar. In a naïve, pooled analysis, vomiting was lower with iGlarLixi versus other GLP-1 RAs. CONCLUSIONS During the first 12 weeks of treatment, iGlarLixi was generally associated with less nausea and vomiting than single-agent GLP-1 RAs. Enhanced gastrointestinal tolerability with fixed-ratio combinations may favour treatment persistence.
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Affiliation(s)
- Christopher K. Rayner
- Centre of Research Excellence in Translating Nutritional Science to Good HealthUniversity of AdelaideAdelaideSouth AustraliaAustralia
| | - Tongzhi Wu
- Centre of Research Excellence in Translating Nutritional Science to Good HealthUniversity of AdelaideAdelaideSouth AustraliaAustralia
| | - Vanita R. Aroda
- Brigham and Women's HospitalHarvard Medical SchoolBostonMassachusettsUSA
| | | | | | | | | | - Michael Horowitz
- Centre of Research Excellence in Translating Nutritional Science to Good HealthUniversity of AdelaideAdelaideSouth AustraliaAustralia
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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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Comparisons between dipeptidyl peptidase-4 inhibitors and other classes of hypoglycemic drugs using two distinct biomarkers of pancreatic beta-cell function: A meta-analysis. PLoS One 2020; 15:e0236603. [PMID: 32706828 PMCID: PMC7380634 DOI: 10.1371/journal.pone.0236603] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 07/08/2020] [Indexed: 01/09/2023] Open
Abstract
Background and objective Dipeptidyl peptidase-4 (DPP-4) inhibitors have been suggested to have pancreatic beta-cell preserving effect according to studies using homeostatic model of assessment for beta-cell function (HOMA-β). However, whether HOMA-β is a suitable biomarker for comparisons between hypoglycemic drugs with different mechanisms of action remains unclear. Therefore, we conducted a meta-analysis to compare the effects of DPP-4 inhibitors and other classes of hypoglycemic drugs on HOMA-β and proinsulin-to-insulin ratio (PIR). Methods We searched MEDLINE, CENTRAL, and Ichushi-web for the period of 1966 to May 2020. We collected randomized, controlled clinical trials in patients with type 2 diabetes mellitus comparing DPP-4 inhibitors and other classes of hypoglycemic agents [α-glucosidase inhibitors (α-GIs), glucagon-like peptide-1 (GLP-1) analogues, metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, sulfonylureas, or thiazolidinediones]. Weighted mean differences and 95% confidence intervals of changes in HOMA-β or PIR during study periods were calculated for pairwise comparisons. Results Thirty-seven and 21 relevant trials were retrieved for comparisons of HOMA-β and PIR, respectively. HOMA-β and PIR consistently showed superiority of DPP-4 inhibitors compared with α-GIs. Both biomarkers consistently supported inferiority of DPP-4 inhibitors compared with GLP-1 analogues. However, PIR showed inferiority of DPP-4 inhibitors compared with metformin, and superiority compared with SGLT2 inhibitors, whereas HOMA-β showed no significant differences between DPP-4 inhibitors and the two other agents. Conclusion DPP-4 inhibitors appear to be superior to α-GIs but inferior to GLP-1 analogues in preservation of beta-cell function assessed by either HOMA-β or PIR. DPP-4 inhibitors seem to be superior to SGLT2 inhibitors but inferior to metformin on islet function assessed only by PIR. Because HOMA-β and PIR may indicate different aspects of beta-cell function, results of beta-cell function preserving effects of hypoglycemic agents should be interpreted with caution.
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Morales J, Shubrook JH, Skolnik N. Practical guidance for use of oral semaglutide in primary care: a narrative review. Postgrad Med 2020; 132:687-696. [PMID: 32643514 DOI: 10.1080/00325481.2020.1788340] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
As the cornerstone of type 2 diabetes (T2D) management within the community, primary care providers are now faced with the challenge of not only managing diabetes itself, but also preventing hypoglycemia and weight gain associated with intensive disease management, and reducing cardiovascular risk. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are well established as efficacious treatments for T2D, and the safety/tolerability profile of this drug class is well defined. However, despite their beneficial effects, GLP-1RAs are under-utilized, highlighting the need for novel approaches to increase their use in primary care. Oral semaglutide is the first oral GLP-1RA approved for the treatment of T2D, offering glucose lowering and body weight loss, a low risk of hypoglycemia, and no increase in cardiovascular risk. Oral semaglutide represents an additional treatment option for patients not achieving their glycemic goal despite treatment with metformin, either alone or with other hypoglycemic agents. Oral semaglutide has the potential to increase usage of GLP-1RAs in the primary care setting by addressing clinician and patient concerns about injections, and may facilitate earlier initiation of GLP-1RA therapy in T2D. Due to the formulation of oral semaglutide, clinicians need to be aware of specific considerations in order to ensure optimal use. Such considerations include dosing conditions and use of concomitant medications. This article provides practical guidance on the use of oral semaglutide in the primary care setting, based on evidence from clinical studies, including the phase 3a PIONEER program, and the authors' clinical experience.
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Affiliation(s)
- Javier Morales
- Department of Medicine, Donald and Barbara Zucker School of Medicine, Hofstra/Northwell University , New York, NY, USA
| | - Jay H Shubrook
- Primary Care Department, College of Osteopathic Medicine, Touro University California , Vallejo, CA, USA
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Nreu B, Dicembrini I, Tinti F, Sesti G, Mannucci E, Monami M. Major cardiovascular events, heart failure, and atrial fibrillation in patients treated with glucagon-like peptide-1 receptor agonists: An updated meta-analysis of randomized controlled trials. Nutr Metab Cardiovasc Dis 2020; 30:1106-1114. [PMID: 32448716 DOI: 10.1016/j.numecd.2020.03.013] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 03/13/2020] [Accepted: 03/14/2020] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND AIMS Glucagon-like Peptide 1 Receptor Agonists (GLP1-RA) has been associated with a reduction of major cardiovascular events (MACE) and mortality on the basis of the results of cardiovascular outcome trials (CVOT). Several meta-analyses on this issue have been recently published; however, they were all restricted to CVOT, with the exclusion of all studies designed for other endpoints; moreover, other cardiovascular endpoints, such as atrial fibrillation and heart failure have not been fully explored. METHODS AND RESULTS A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials with a duration ≥52 weeks, enrolling patients with type 2 diabetes, and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. We included 43 trials, enrolling 63,134 patients. A significant reduction of MACE (MH-OR 0.87 [0.83, 0.92]), all-cause mortality (MH-OR 0.89 [0.83, 0.96]), and a nonstatistical trend toward reduction of heart failure (MH-OR 0.93 [0.85, 1.01]) was observed - GLP1-RA did not increase the risk of atrial fibrillation (MH-OR 0.94 [0.84, 1.04]). CONCLUSION The present meta-analysis confirms the favorable effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events, cardiovascular and all-cause mortality, stroke, and possibly myocardial infarction. Conversely, the effects on heart failure remain uncertain. Available data on atrial fibrillation seems to exclude any major safety issues in this respect. REGISTRATION NUMBER (PROSPERO) CRD42018115577.
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Affiliation(s)
- Besmir Nreu
- Diabetology, Careggi Hospital and University of Florence, Italy
| | | | - Federico Tinti
- Diabetology, Careggi Hospital and University of Florence, Italy
| | - Giorgio Sesti
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology of the Sapienza University of Rome, Rome, Italy
| | | | - Matteo Monami
- Diabetology, Careggi Hospital and University of Florence, Italy.
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21
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Chudleigh RA, Bain SC. Efficacy of newer agents in the glycaemic management of patients with type 2 diabetes. Curr Med Res Opin 2020; 36:209-211. [PMID: 31596638 DOI: 10.1080/03007995.2019.1678344] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Affiliation(s)
- Richard A Chudleigh
- Institute of Life Science, Singleton Hospital, Swansea Bay University Health Board, Swansea, UK
| | - Steve C Bain
- Diabetes Research Unit Cymru, Swansea University Medical School, Swansea, UK
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22
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Dang-Tan T, Kamble PS, Meah Y, Gamble C, Ganguly R, Horter L. Real-world Effectiveness of Liraglutide vs. Sitagliptin Among Older Patients with Type 2 Diabetes Enrolled in a Medicare Advantage Prescription Drug Plan: A Retrospective Observational Study. Diabetes Ther 2020; 11:213-228. [PMID: 31820328 PMCID: PMC6965544 DOI: 10.1007/s13300-019-00739-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Indexed: 12/26/2022] Open
Abstract
INTRODUCTION Liraglutide and sitagliptin were compared on glycemic control and all-cause healthcare costs over a 1-year period among older adults with type 2 diabetes (65-89 years) enrolled in a national Medicare Advantage Prescription Drug health plan. METHODS This was a retrospective study in which the index date was the first prescription fill for liraglutide or sitagliptin between 25 January 2010 and 31 December 2014. Post-index treatment persistence and glycosylated hemoglobin (HbA1c) at baseline and 1 year (± 90 days) post-index date were required. Patients were excluded if their record included use of insulin during the baseline period. Inverse probability of treatment weighting using stabilized weights was employed with final covariate adjusted regression modeling to estimate the primary outcome (mean change in HbA1c) and secondary outcomes (achieving glycemic goal and costs), each at 1-year post-index date. RESULTS Overall, 3056 patients met the selection criteria, of whom 218 filled prescriptions for liraglutide and 2838 for sitagliptin. Adjusted mean change in HbA1c at 1 year post-index was - 0.42 with liraglutide versus - 0.12 with sitagliptin (P = 0.0012). Adjusted odds of achieving the treatment goals of HbA1c < 7% and achieving an HbA1c reduction of ≥ 1% were higher for those on liraglutide than for those on sitagliptin (1.68, 95% confidence interval [CI] 1.25-2.24 and 1.76, 95% CI 1.31-2.36), respectively. Total healthcare costs in those achieving an HbA1c of < 7% were not significantly different between treatment groups but were higher within the liraglutide group for those achieving an HbA1c < 8%. CONCLUSIONS When compared to sitagliptin, liraglutide was associated with greater achievement of an HbA1c < 7% over a 1-year period in an older population. This finding was not associated with a statistically significant increase in all-cause total healthcare costs, although costs were slightly higher in the liraglutide group than in the sitagliptin group.
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Affiliation(s)
| | | | | | | | | | - Libby Horter
- Humana Healthcare Research, Inc., Louisville, KY, USA
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23
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Gilbert MP, Pratley RE. GLP-1 Analogs and DPP-4 Inhibitors in Type 2 Diabetes Therapy: Review of Head-to-Head Clinical Trials. Front Endocrinol (Lausanne) 2020; 11:178. [PMID: 32308645 PMCID: PMC7145895 DOI: 10.3389/fendo.2020.00178] [Citation(s) in RCA: 206] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 03/12/2020] [Indexed: 12/15/2022] Open
Abstract
The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells in response to the presence of nutrients in the small intestines. These homones facilitate glucose regulation by stimulating insulin secretion in a glucose dependent manner while suppressing glucagon secretion. In patients with type 2 diabetes (T2DM), an impaired insulin response to GLP-1 and GIP contributes to hyperglycemia. Dipeptidyl peptidase-4 (DPP-4) inhibitors block the breakdown of GLP-1 and GIP to increase levels of the active hormones. In clinical trials, DPP-4 inhibitors have a modest impact on glycemic control. They are generally well-tolerated, weight neutral and do not increase the risk of hypoglycemia. GLP-1 receptor agonists (GLP-1 RA) are peptide derivatives of either exendin-4 or human GLP-1 designed to resist the activity of DPP-4 and therefore, have a prolonged half-life. In clinical trials, they have demonstrated superior efficacy to many oral antihyperglycemic drugs, improved weight loss and a low risk of hypoglycemia. However, GI adverse events, particularly nausea, vomiting, and diarrhea are seen. Both DPP-4 inhibitors and GLP-1 RAs have demonstrated safety in robust cardiovascular outcome trials, while several GLP-1 RAs have been shown to significantly reduce the risk of major adverse cardiovascular events in persons with T2DM with pre-existing cardiovascular disease (CVD). Several clinical trials have directly compared the efficacy and safety of DPP-4 inhibitors and GLP-1 RAs. These studies have generally demonstrated that the GLP-1 RA provided superior glycemic control and weight loss relative to the DPP-4 inhibitor. Both treatments were associated with a low and comparable incidence of hypoglycemia, but treatment with GLP-1 RAs were invariably associated with a higher incidence of GI adverse events. A few studies have evaluated switching patients from DPP-4 inhibitors to a GLP-1RA and, as expected, improved glycemic control and weight loss are seen following the switch. According to current clinical guidelines, GLP-1RA and DPP-4 inhibitors are both indicated for the glycemic management of patients with T2DM across the spectrum of disease. GLP-1RA may be preferred over DPP- 4 inhibitors for many patients because of the greater reductions in hemoglobin A1c and weight loss observed in the clinical trials. Among patients with preexisting CVD, GLP-1 receptor agonists with a proven cardiovascular benefit are indicated as add-on to metformin therapy.
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Affiliation(s)
- Matthew P. Gilbert
- Division of Endocrinology and Diabetes, Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT, United States
- *Correspondence: Matthew P. Gilbert
| | - Richard E. Pratley
- AdventHealth Diabetes Institute, Translational Research Institute for Metabolism and Diabetes, Orlando, FL, United States
- Richard E. Pratley
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24
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Cope RJ, Fischetti BS, Kavanagh RK, Lepa TM, Sorbera MA. Safety and Efficacy of Weight-Loss Pharmacotherapy in Persons Living with HIV: A Review of the Literature and Potential Drug-Drug Interactions with Antiretroviral Therapy. Pharmacotherapy 2019; 39:1204-1215. [PMID: 31602703 DOI: 10.1002/phar.2342] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The prevalence of obesity among persons living with human immunodeficiency virus (HIV) has increased significantly and may be linked to the use of antiretroviral therapy. Although weight-loss medications approved by the U.S. Food and Drug Administration are recommended as an adjunct to diet and exercise to treat obesity in the general population, little is known about the safety and efficacy of these drugs specifically in persons living with HIV. We review the available evidence regarding the effective use of weight-loss pharmacotherapy in persons living with HIV and its potential to interact with antiretroviral therapy. Persons living with HIV are frequently not reported or included in clinical trials for weight-loss medications; however, treatment efficacy is likely similar to the general population. Several important reported or theoretical drug-drug interactions exist between antiobesity pharmacotherapy and antiretroviral therapy. Orlistat is a weight-loss drug available in the United States without a prescription and was linked to HIV viral rebound in several case reports. Clinicians should be aware of the potential for loss of HIV viremia control when certain weight-loss pharmacotherapies are used in combination with antiretrovirals.
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25
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Shah FA, Mahmud H, Gallego-Martin T, Jurczak MJ, O’Donnell CP, McVerry BJ. Therapeutic Effects of Endogenous Incretin Hormones and Exogenous Incretin-Based Medications in Sepsis. J Clin Endocrinol Metab 2019; 104:5274-5284. [PMID: 31216011 PMCID: PMC6763279 DOI: 10.1210/jc.2019-00296] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 06/13/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Sepsis, a complex disorder characterized by a dysregulated immune response to an inciting infection, affects over one million Americans annually. Dysglycemia during sepsis hospitalization confers increased risk of organ dysfunction and death, and novel targets for the treatment of sepsis and maintenance of glucose homeostasis are needed. Incretin hormones are secreted by enteroendocrine cells in response to enteral nutrients and potentiate insulin release from pancreatic β cells in a glucose-dependent manner, thereby reducing the risk of insulin-induced hypoglycemia. Incretin hormones also reduce systemic inflammation in preclinical studies, but studies of incretins in the setting of sepsis are limited. METHODS In this bench-to-bedside mini-review, we detail the evidence to support incretin hormones as a therapeutic target in patients with sepsis. We performed a PubMed search using the medical subject headings "incretins," "glucagon-like peptide-1," "gastric inhibitory peptide," "inflammation," and "sepsis." RESULTS Incretin-based therapies decrease immune cell activation, inhibit proinflammatory cytokine release, and reduce organ dysfunction and mortality in preclinical models of sepsis. Several small clinical trials in critically ill patients have suggested potential benefit in glycemic control using exogenous incretin infusions, but these studies had limited power and were performed in mixed populations. Further clinical studies examining incretins specifically in septic populations are needed. CONCLUSIONS Targeting the incretin hormone axis in sepsis may provide a means of not only promoting euglycemia in sepsis but also attenuating the proinflammatory response and improving clinical outcomes.
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Affiliation(s)
- Faraaz Ali Shah
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
- Veteran Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
- Correspondence and Reprint Requests: Faraaz Ali Shah, MD, MPH, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, 3459 Fifth Avenue NW, 628 MUH, Pittsburgh, Pennsylvania 15213. E-mail:
| | - Hussain Mahmud
- Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Teresa Gallego-Martin
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Michael J Jurczak
- Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Christopher P O’Donnell
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Bryan J McVerry
- Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
- Center for Medicine and the Microbiome, University of Pittsburgh, Pittsburgh, Pennsylvania
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26
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Cao C, Yang S, Zhou Z. GLP-1 receptor agonists and risk of cancer in type 2 diabetes: an updated meta-analysis of randomized controlled trials. Endocrine 2019; 66:157-165. [PMID: 31420784 DOI: 10.1007/s12020-019-02055-z] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 08/06/2019] [Indexed: 02/08/2023]
Abstract
PURPOSE Some preliminary studies reported a link between GLP-1 receptor agonists (GLP-1RAs) and thyroid/pancreatic neoplasms, while its human relevance remained undetermined. The present meta-analysis was performed to collect information on cancers associated with GLP-1RAs in patients with type 2 diabetes mellitus (T2DM). METHODS Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and ClinicalTrials.gov were extensively searched to identify randomized controlled trials that reported cancer events in T2DM patients treated with GLP-1RAs for at least 52 weeks, up to March 18, 2019. Odds ratio (OR) with 95% Confidence Interval (CI) was calculated for overall cancer (primary outcome), thyroid and pancreatic cancer. RESULTS A total of 37 eligible trials were identified. The OR for overall cancer associated with GLP-1RAs was 1.03 (95% CI 0.95-1.12; p = 0.41) compared with comparators. Subgroup analyses showed that treatment with albiglutide was associated with a lower risk of overall cancer (OR 0.76 [95% CI 0.60-0.97]; p = 0.03), and no elevated risk of overall cancer was identified for other GLP-1RAs. No significant differences in the risks of thyroid nor pancreatic cancer were disclosed between GLP-1RAs and comparators. CONCLUSIONS This meta-analysis did not suggest any increased risk of cancers associated with GLP-1RAs use in T2DM. The reduction in the risk of overall cancer associated with albiglutide needs to be examined further.
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Affiliation(s)
- Chuqing Cao
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Shuting Yang
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Zhiguang Zhou
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, China.
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China.
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27
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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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Nauck MA, Muus Ghorbani ML, Kreiner E, Saevereid HA, Buse JB. Effects of Liraglutide Compared With Placebo on Events of Acute Gallbladder or Biliary Disease in Patients With Type 2 Diabetes at High Risk for Cardiovascular Events in the LEADER Randomized Trial. Diabetes Care 2019; 42:1912-1920. [PMID: 31399438 PMCID: PMC7364668 DOI: 10.2337/dc19-0415] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 06/29/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To explore gallbladder- and biliary tract-related events reported for the liraglutide and placebo groups in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial. RESEARCH DESIGN AND METHODS LEADER was an international, randomized, double-blind, controlled cardiovascular (CV) outcomes trial. Participants with type 2 diabetes at high risk for CV events (n = 9,340) were randomized 1:1 to receive either liraglutide (≤1.8 mg daily; n = 4,668) or placebo (n = 4,672), with both groups also receiving standard care (treatment period: 3.5-5 years). Acute gallstone disease was a medical event of special interest. This post hoc analysis categorized captured events of acute gallbladder or biliary disease into four groups: uncomplicated gallbladder stones, complicated gallbladder stones, cholecystitis, and biliary obstruction. Time to first event by treatment group was analyzed using Cox regression. RESULTS There was an increased risk of acute gallbladder or biliary disease with liraglutide versus placebo (n = 141 of 4,668 vs. n = 88 of 4,672 patients, respectively; hazard ratio [HR] 1.60; 95% CI 1.23, 2.09; P < 0.001). Similar trends were observed for each of the four categories of gallbladder- or biliary tract-related events. Cholecystectomy was performed more frequently in liraglutide-treated patients (HR 1.56; 95% CI 1.10, 2.20; P = 0.013) but for similar proportions of the patients who experienced gallbladder- or biliary tract-related events (57% with liraglutide vs. 59% with placebo). CONCLUSIONS Although LEADER was not specifically designed to assess acute gallbladder or biliary disease, the trial showed an increased risk of gallbladder- or biliary tract-related events with liraglutide versus placebo, which appeared to be consistent across four categories of these events. Further studies should investigate the relevant mechanisms.
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Affiliation(s)
- Michael A Nauck
- Diabetes Center Bochum-Hattingen, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
| | | | | | | | - John B Buse
- University of North Carolina School of Medicine, Chapel Hill, NC
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29
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Deerochanawong C, Kosachunhanun N, Gadekar AV, Chotikanokrat P, Permsuwan U. Cost-benefit comparison of liraglutide and sitagliptin in the treatment of type 2 diabetes in Thailand. CLINICOECONOMICS AND OUTCOMES RESEARCH 2019; 11:423-430. [PMID: 31372015 PMCID: PMC6635895 DOI: 10.2147/ceor.s201951] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 05/16/2019] [Indexed: 01/03/2023] Open
Abstract
Aim Liraglutide, a once-daily subcutaneous glucagon-like peptide-1 (GLP-1) agonist, is approved for treatment of hyperglycemia in patients with type 2 diabetes mellitus (T2DM). For patients with established cardiovascular diseases, liraglutide has also been shown to reduce major cardiovascular events. However, its cost is relatively higher than other oral antidiabetic drugs. This study aims to compare the costs and benefits of liraglutide vs sitagliptin, in treating T2DM in Thailand. Methods This study consists of two parts. In part 1, the cost of keeping T2DM under control per patient (HbA1c<7.0% with no reported hypoglycemia and no body weight gain) with liraglutide (1.2 and 1.8 mg daily) was compared with using sitagliptin (100 mg daily). Costs were based on Thai local data. Clinical outcomes were based on head-to-head randomized controlled trials. Part 2 estimated the cost-per-controlled patient, based on major cardiovascular outcomes (cardiovascular death, nonfatal myocardial infarction, non-fatal stroke). Economic benefit was calculated as the reduction in cardiovascular outcomes. Results In Thailand, liraglutide (1.8 mg daily) costs 7.37-times more than sitagliptin 100 mg. The cost per patient achieving a composite clinical endpoint (HbA1c<7.0%, with no weight gain and no hypoglycemic events) in patients with T2DM receiving liraglutide 1.8 mg is 2.80-times higher than patients receiving sitagliptin 100 mg. When cardiovascular benefits (reduced composite endpoint of major cardiovascular events, ie, cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) were taken into account, it was found that liraglutide had lower cost than sitagliptin, resulting in estimated savings of 20,085 THB (620 USD) per patient per year. Conclusion The clinical benefits of liraglutide (HbA1c<7.0%, no hypoglycemia, no weight gain, reduced cardiovascular outcomes) partly offset its high price. Therefore, liraglutide should be considered as an appropriate treatment alternative to sitagliptin, particularly for T2DM patients with high cardiovascular risks.
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Affiliation(s)
- Chaicharn Deerochanawong
- Rajavithi Hospital, College of Medicine, Rangsit University, Ministry of Public Health, Bangkok 10400, Thailand
| | - Natapong Kosachunhanun
- Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | | | | | - Unchalee Permsuwan
- Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
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Rasalam R, Barlow J, Kennedy M, Phillips P, Wright A. GLP-1 Receptor Agonists for Type 2 Diabetes and Their Role in Primary Care: An Australian Perspective. Diabetes Ther 2019; 10:1205-1217. [PMID: 31183762 PMCID: PMC6612351 DOI: 10.1007/s13300-019-0642-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Indexed: 02/08/2023] Open
Abstract
The ever-increasing number of drugs available to treat type 2 diabetes and the complexity of patients with this condition present a constant challenge when it comes to identifying the most appropriate treatment approach. The more recent glucagon-like peptide-1 receptor agonists (GLP-1RAs) are non-insulin injectable options for the management of type 2 diabetes. Effective at improving glycaemic control with a low intrinsic risk of hypoglycaemia and the potential for weight reduction, this agent class is an important addition to the prescribing armamentarium. However, understanding their place in therapy may prove confusing for many primary care practitioners, especially given the common belief that 'injectables' are a last-resort treatment option, which puts them at risk of being niched alongside insulin. This review summarises the clinical evidence for GLP-1RAs and how they compare to other glucose-lowering agents in managing type 2 diabetes. It also provides practical and case-driven opinions and recommendations on the optimal use of GLP-1RAs by discussing important patient factors and clinical considerations that will help to identify those who are most likely to benefit from this class of agents.Funding: Eli Lilly Australia.
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Affiliation(s)
- Roy Rasalam
- James Cook University, Douglas, QLD, Australia.
| | - John Barlow
- Bankstown Medical Centre, Bankstown, NSW, Australia
| | | | - Pat Phillips
- Queen Elizabeth Specialist Centre, Woodville South, SA, Australia
| | - Alan Wright
- Lakes Medical Centre, South Lake, WA, Australia
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31
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Pieber TR, Bode B, Mertens A, Cho YM, Christiansen E, Hertz CL, Wallenstein SOR, Buse JB. Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial. Lancet Diabetes Endocrinol 2019; 7:528-539. [PMID: 31189520 DOI: 10.1016/s2213-8587(19)30194-9] [Citation(s) in RCA: 181] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 05/08/2019] [Accepted: 05/08/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Oral semaglutide is the first oral formulation of a glucagon-like peptide-1 (GLP-1) receptor agonist developed for the treatment of type 2 diabetes. We aimed to compare the efficacy and safety of flexible dose adjustments of oral semaglutide with sitagliptin 100 mg. METHODS In this 52-week, multicentre, randomised, open-label, phase 3a trial, we recruited patients with type 2 diabetes from 81 sites in ten countries. Patients were eligible if they were aged 18 years or older (19 years or older in South Korea), had type 2 diabetes (diagnosed ≥90 days before screening), HbA1c of 7·5-9·5% (58-80 mmol/mol), and were inadequately controlled on stable daily doses of one or two oral glucose-lowering drugs (for 90 days or more before screening). Participants were randomly assigned (1:1) by use of an interactive web-response system, stratified by background glucose-lowering medication at screening, to oral semaglutide with flexible dose adjustments to 3, 7, or 14 mg once daily or sitagliptin 100 mg once daily. To approximate treatment individualisation in clinical practice, oral semaglutide dose could be adjusted on the basis of prespecified HbA1c and tolerability criteria. Two efficacy-related estimands were prespecified: treatment policy (regardless of treatment discontinuation or use of rescue medication) and trial product (on treatment and without use of rescue medication) for participants randomly assigned to treatment. The primary endpoint was achievement of HbA1c of less than 7% (53 mmol/mol) at week 52 and the confirmatory secondary efficacy endpoint was change in bodyweight from baseline to week 52. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02849080, and European Clinical Trials Database, EudraCT number 2015-005593-38, and an open-label extension is ongoing. FINDINGS Between Sept 20, 2016, and Feb 7, 2017, of 804 patients assessed for eligibility, 504 were eligible and randomly assigned to oral semaglutide (n=253) or sitagliptin (n=251). Most participants were male (285 [57%] of 504) with a mean age of 57·4 years (SD 9·9). All participants were given at least one dose of their allocated study drug except for one participant in the sitagliptin group. From a mean baseline HbA1c of 8·3% (SD 0·6%; 67 mmol/mol [SD 6·4]), a greater proportion of participants achieved an HbA1c of less than 7% with oral semaglutide than did with sitagliptin (treatment policy estimand: 58% [134 of 230] vs 25% [60 of 238]; and trial product estimand: 63% [123 of 196] vs 28% [52 of 184]). The odds of achieving an HbA1c of less than 7% was significantly better with oral semaglutide than sitagliptin (treatment policy estimand: odds ratio [OR] 4·40, 95% CI 2·89-6·70, p<0·0001; and trial product estimand: 5·54, 3·54-8·68, p<0·0001). The odds of decreasing mean bodyweight from baseline to week 52 were higher with oral semaglutide than with sitagliptin (estimated mean change in bodyweight, treatment policy estimand: -2·6 kg [SE 0·3] vs -0·7 kg [SE 0·2], estimated treatment difference [ETD] -1·9 kg, 95% CI -2·6 to -1·2; p<0·0001; and trial product estimand: -2·9 kg [SE 0·3] vs -0·8 kg [SE 0·3], ETD -2·2 kg, -2·9 to -1·5; p<0·0001). Adverse events occurred in 197 (78%) of 253 participants in the oral semaglutide group versus 172 (69%) of 250 in the sitagliptin group, and nausea was the most common adverse event with oral semaglutide (53 [21%]). Two deaths occurred in the sitagliptin group during the trial. INTERPRETATION Oral semaglutide, with flexible dose adjustment, based on efficacy and tolerability, provided superior glycaemic control and weight loss compared with sitagliptin, and with a safety profile consistent with subcutaneous GLP-1 receptor agonists. FUNDING Novo Nordisk A/S.
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Affiliation(s)
- Thomas R Pieber
- Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria.
| | - Bruce Bode
- Atlanta Diabetes Associates, Atlanta, GA, USA
| | - Ann Mertens
- Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Aging (CHROMETA), KU Leuven, Leuven, Belgium
| | - Young Min Cho
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | | | | | | | - John B Buse
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA
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Unger J, Allison DC, Carlton M, Lakkole K, Lowe D, Murphy G, Panda JK, Sargin M, Kaltoft M, Treppendahl MB, Zoghbi M, on behalf of the LIRA‐PRIME global panel. Trial design and baseline data for LIRA-PRIME: A randomized trial investigating the efficacy of liraglutide in controlling glycaemia in type 2 diabetes in a primary care setting. Diabetes Obes Metab 2019; 21:1543-1550. [PMID: 30828917 PMCID: PMC6617804 DOI: 10.1111/dom.13682] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 02/15/2019] [Accepted: 02/28/2019] [Indexed: 12/31/2022]
Abstract
AIMS Using a pragmatic approach, the LIRA-PRIME trial aims to address a knowledge gap by comparing efficacy in controlling glycaemia with glucagon-like peptide-1 analog liraglutide vs oral antidiabetic drugs (OADs) in patients with type 2 diabetes (T2D) uncontrolled with metformin monotherapy in primary care practice. We report the study design and patient baseline characteristics. MATERIALS AND METHODS This 104-week, two-arm, open-label, active-controlled trial is active in 219 primary care practices across nine countries. At screening, eligible patients with T2D were at least 18 years of age, had been using a stable daily dose of metformin ≥1500 mg or the maximum tolerated dose for ≥60 days, and had a glycated haemoglobin (HbA1c) of 7.5% to 9.0%, measured ≤90 days before screening. Patients were randomized (1:1) to liraglutide or OAD, both in addition to pre-trial metformin. Individual OADs were chosen by the treating physician based on local guidelines. The primary endpoint is time to inadequate glycaemic control, defined as HbA1c above 7.0% at two scheduled consecutive visits after the first 26 weeks of treatment. RESULTS The trial randomized 1997 patients with a mean (standard deviation) age of 56.9 (10.8) years, T2D duration of 7.2 (5.9) years (range, <1-47 years), and HbA1c of 8.2%. One-fifth of patients had a history of diabetes complications, and most were overweight (24.8%) or had obesity (65.3%). CONCLUSIONS This pragmatically designed, large-scale, multinational, randomized clinical trial will help guide treatment decisions for patients with T2D who are inadequately controlled with metformin monotherapy and treated in primary care.
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Affiliation(s)
- Jeff Unger
- Unger Concierge Primary Care Medical GroupRanch CucamongaCalifornia
| | | | - Melissa Carlton
- Physician Practice ResearchSentara Medical GroupNorfolkVirginia
| | | | - Derek Lowe
- Ocean West ResearchSurreyBritish ColumbiaCanada
| | - Gerri Murphy
- Commonwealth Medical ClinicMount PearlNewfoundlandCanada
| | | | - Mehmet Sargin
- Faculty of MedicineIstanbul Medeniyet UniversityIstanbulTurkey
| | | | | | - Marouan Zoghbi
- Middle East Institute of Health University HospitalBsalimLebanon
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Aim to normalize glucose levels and reduce cardiovascular mortality when managing type 2 diabetes in the elderly. DRUGS & THERAPY PERSPECTIVES 2019. [DOI: 10.1007/s40267-019-00619-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Rosenstock J, Allison D, Birkenfeld AL, Blicher TM, Deenadayalan S, Jacobsen JB, Serusclat P, Violante R, Watada H, Davies M. Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial. JAMA 2019; 321:1466-1480. [PMID: 30903796 PMCID: PMC6484814 DOI: 10.1001/jama.2019.2942] [Citation(s) in RCA: 280] [Impact Index Per Article: 46.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
IMPORTANCE Phase 3 trials have not compared oral semaglutide, a glucagon-like peptide 1 receptor agonist, with other classes of glucose-lowering therapy. OBJECTIVE To compare efficacy and assess long-term adverse event profiles of once-daily oral semaglutide vs sitagliptin, 100 mg added on to metformin with or without sulfonylurea, in patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, double-dummy, parallel-group, phase 3a trial conducted at 206 sites in 14 countries over 78 weeks from February 2016 to March 2018. Of 2463 patients screened, 1864 adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea were randomized. INTERVENTIONS Patients were randomized to receive once-daily oral semaglutide, 3 mg (n = 466), 7 mg (n = 466), or 14 mg (n = 465), or sitagliptin, 100 mg (n = 467). Semaglutide was initiated at 3 mg/d and escalated every 4 weeks, first to 7 mg/d then to 14 mg/d, until the randomized dosage was achieved. MAIN OUTCOMES AND MEASURES The primary end point was change in glycated hemoglobin (HbA1c), and the key secondary end point was change in body weight, both from baseline to week 26. Both were assessed at weeks 52 and 78 as additional secondary end points. End points were tested for noninferiority with respect to HbA1c (noninferiority margin, 0.3%) prior to testing for superiority of HbA1c and body weight. RESULTS Among 1864 patients randomized (mean age, 58 [SD, 10] years; mean baseline HbA1c, 8.3% [SD, 0.9%]; mean body mass index, 32.5 [SD, 6.4]; n=879 [47.2%] women), 1758 (94.3%) completed the trial and 298 prematurely discontinued treatment (16.7% for semaglutide, 3 mg/d; 15.0% for semaglutide, 7 mg/d; 19.1% for semaglutide, 14 mg/d; and 13.1% for sitagliptin). Semaglutide, 7 and 14 mg/d, compared with sitagliptin, significantly reduced HbA1c (differences, -0.3% [95% CI, -0.4% to -0.1%] and -0.5% [95% CI, -0.6% to -0.4%], respectively; P < .001 for both) and body weight (differences, -1.6 kg [95% CI, -2.0 to -1.1 kg] and -2.5 kg [95% CI, -3.0 to -2.0 kg], respectively; P < .001 for both) from baseline to week 26. Noninferiority of semaglutide, 3 mg/d, with respect to HbA1c was not demonstrated. Week 78 reductions in both end points were statistically significantly greater with semaglutide, 14 mg/d, vs sitagliptin. CONCLUSIONS AND RELEVANCE Among adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea, oral semaglutide, 7 mg/d and 14 mg/d, compared with sitagliptin, resulted in significantly greater reductions in HbA1c over 26 weeks, but there was no significant benefit with the 3-mg/d dosage. Further research is needed to assess effectiveness in a clinical setting. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02607865.
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Affiliation(s)
| | | | - Andreas L. Birkenfeld
- Department of Medicine III, Carl Gustav Carus University Hospital, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden, Helmholtz Center Munich at Technische Universität Dresden, Dresden, Germany
| | | | | | | | - Pierre Serusclat
- Endocrinology, Diabetology and Nutrition, Clinique Portes du Sud, Venissieux, France
| | - Rafael Violante
- Departamento Endocrinología, Instituto Mexicano del Seguro Social, Ciudad Madero, Mexico
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Melanie Davies
- Diabetes Research Centre, University of Leicester, Leicester, England
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Hussain M, Rafique MA, Iqbal J, Akhtar L. Effect of sitagliptin and glimepiride on C-reactive protein (CRP) in overweight Type-2 diabetic patients. Pak J Med Sci 2019; 35:383-387. [PMID: 31086519 PMCID: PMC6500845 DOI: 10.12669/pjms.35.2.645] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Objectives To compare the anti-inflammatory effect of sitagliptin and glimepiride by measuring CRP in overweight Type-2 diabetic patients. Methods This clinical trial was conducted at diabetic clinic of Islam Central Hospital, Sialkot over a period of six months from June to November 2017. A total of 110 overweight Type-2 diabetic patients were divided in to two groups. Group-A was given tablet sitagliptin 50mg while Group-B was given tablet glimepiride 2mg for a period of 12 weeks. The dose was titrated according to blood sugar level. The primary outcome was measuring changes in CRP while secondary outcomes was changes in BMI, blood sugar, HbA1C, lipid profile and CRP from baseline in both study group using SPSS 16. Results After 12 weeks treatment, body weight increased in glimepiride but slightly reduced in sitagliptin, however comparison between them was non significant (p=0.07). Although both groups reduced blood sugar and HbA1c but comparison between them was non significant (p=0.59 and p=0.17 respectively) value. However lipid profile improved significantly in sitagliptin vs. glimepiride group i.e total cholesterol (-25±32.5 vs +1.5±45.4 P=0.02) triglycerides (-19±44.6 vs-1.8±48.7 P=0.001) LDL- cholesterol (-10±22.4 vs-0.8±18.7 P=0.001) HDL-cholesterol (-2.6±6.2 vs 1.2±5.2 P=0.03).Sitagliptin significantly reduced CRP in comparison to glimepiride (-2.3±1.8 vs0.8±1.5 P=0.001). Conclusion Sitagliptin has strong anti inflammatory effect marked by reduction in CRP level in comparison to glimepiride in overweight type-2 diabetic patients. It also exerted beneficial effect on glycemic and lipid profiles.
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Affiliation(s)
- Mazhar Hussain
- Dr. Mazhar Hussain, MBBS, M.Phil (Pharmacology). Associate Professor of Pharmacology, Department of Pharmacology, Sheikh Zayed Medical College, Rahim Yar Khan, Punjab, Pakistan
| | - Muhammad Aamir Rafique
- Muhammad Aamir Rafique, MBBS, M.Phil (Pharmacology). Assistant Professor of Pharmacology, Department of Pharmacology, Islam Medical, Sialkot, Punjab, Pakistan
| | - Javed Iqbal
- Dr. Javed Iqbal, MBBS, FCPS (Medicine). Assistant Professor, Department of Medicine, Sheikh Zayed Medical College, Rahim Yar Khan, Punjab, Pakistan
| | - Lubna Akhtar
- Dr. Lubna Akhtar, MBBS, FCPS. (Gynae & Obs). Senior Demonstrator Pharmacology, Department of Pharmacology, Sheikh Zayed Medical College, Rahim Yar Khan, Punjab, Pakistan
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Gentilella R, Pechtner V, Corcos A, Consoli A. Glucagon-like peptide-1 receptor agonists in type 2 diabetes treatment: are they all the same? Diabetes Metab Res Rev 2019; 35:e3070. [PMID: 30156747 DOI: 10.1002/dmrr.3070] [Citation(s) in RCA: 158] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 07/30/2018] [Accepted: 08/18/2018] [Indexed: 02/06/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are an important class of drugs with a well-established efficacy and safety profile in patients with type 2 diabetes mellitus. Agents in this class are derived from either exendin-4 (a compound present in Gila monster venom) or modifications of human GLP-1 active fragment. Differences among these drugs in duration of action (ie, short-acting vs long-acting), effects on glycaemic control and weight loss, immunogenicity, tolerability profiles, and administration routes offer physicians several options when selecting the most appropriate agent for individual patients. Patient preference is also an important consideration. The aim of this review is to discuss the differences between and similarities of GLP-1 RAs currently approved for clinical use, focusing particularly on the properties characterising the single short-acting and long-acting GLP-1 RAs rather than on their individual efficacy and safety profiles. The primary pharmacodynamic difference between short-acting (ie, exenatide twice daily and lixisenatide) and long-acting (ie, albiglutide, dulaglutide, exenatide once weekly, liraglutide, and semaglutide) GLP-1 RAs is that short-acting agents primarily delay gastric emptying (lowering postprandial glucose) and long-acting agents affect both fasting glucose (via enhanced glucose-dependent insulin secretion and reduced glucagon secretion in the fasting state) and postprandial glucose (via enhanced postprandial insulin secretion and inhibition of glucagon secretion). Other advantages of long-acting GLP-1 RAs include smaller fluctuations in plasma drug concentrations, improved gastrointestinal tolerability profiles, and simpler, more convenient administration schedules (once daily for liraglutide and once weekly for albiglutide, dulaglutide, the long-acting exenatide formulation, and semaglutide), which might improve treatment adherence and persistence.
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Affiliation(s)
| | - Valeria Pechtner
- Lilly Diabetes, Eli Lilly and Company, Neuilly-sur-Seine, France
| | | | - Agostino Consoli
- Department of Medicine and Ageing Sciences and CeSI-Met, University D'Annunzio, Chieti, Italy
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Liu Y, Zhang X, Chai S, Zhao X, Ji L. Risk of Malignant Neoplasia with Glucagon-Like Peptide-1 Receptor Agonist Treatment in Patients with Type 2 Diabetes: A Meta-Analysis. J Diabetes Res 2019; 2019:1534365. [PMID: 31396537 PMCID: PMC6664552 DOI: 10.1155/2019/1534365] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 07/02/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Glucagon-like peptide-1 (GLP-1) receptor agonists are effective glucose-lowering drugs, but there is concern that they may increase the risk of malignant neoplasia. The present meta-analysis examined the safety of GLP-1 receptor agonists with regard to malignant neoplasia. METHODS We analyzed data from randomized controlled trials with a minimum duration of 24 weeks that assessed the incidence of neoplasms in type 2 diabetes patients receiving GLP-1 receptor agonists compared with placebo or other hypoglycemic drugs. We searched the MEDLINE, Embase, and Cochrane databases with a language restriction of English through October 1, 2018, and carried out a meta-analysis of the available trial data using a fixed effects model to calculate odds ratios (ORs) for neoplasia. RESULTS Thirty-four relevant articles, providing data for 50452 patients, were included in the meta-analysis. Compared with the incidence of malignant neoplasia with placebo or other interventions, no increase in malignant neoplasm formation was observed with the use of GLP-1 receptor agonists (OR 1.04, 95% confidence interval (CI) 0.94-1.15; p = 0.46), liraglutide (OR 1.08, 95% CI 0.91-1.27; p = 0.38), exenatide (OR 1.00, 95% CI 0.86-1.16; p = 1.00), semaglutide (OR 0.89, 95% CI 0.35-2.22; p = 0.80), or albiglutide (OR 1.07, 95% CI 0.23-4.88; p = 0.93). A subanalysis of trials lasting longer than 3 years also showed no increase in the neoplasia risk with GLP-1 receptor agonist use (OR 1.03, 95% CI 0.92-1.15; p = 0.60). Between-trial statistical heterogeneity was low for all comparisons. CONCLUSION GLP-1 receptor agonists can be used without safety concerns related to malignant neoplasia in patients with type 2 diabetes.
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Affiliation(s)
- Yufang Liu
- Department of Endocrinology, Peking University International Hospital, Beijing 102206, China
| | - Xiaomei Zhang
- Department of Endocrinology, Peking University International Hospital, Beijing 102206, China
| | - Sanbao Chai
- Department of Endocrinology, Peking University International Hospital, Beijing 102206, China
| | - Xin Zhao
- Department of Endocrinology, Peking University International Hospital, Beijing 102206, China
| | - Linong Ji
- Department of Endocrinology, Peking University People's Hospital, Beijing 100044, China
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Avgerinos I, Karagiannis T, Malandris K, Liakos A, Mainou M, Bekiari E, Matthews DR, Tsapas A. Glucagon-like peptide-1 receptor agonists and microvascular outcomes in type 2 diabetes: A systematic review and meta-analysis. Diabetes Obes Metab 2019; 21:188-193. [PMID: 30058208 DOI: 10.1111/dom.13484] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 07/19/2018] [Accepted: 07/24/2018] [Indexed: 12/29/2022]
Abstract
We conducted a systematic review and meta-analysis of randomized controlled trials to assess the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on microvascular endpoints in adult patients with type 2 diabetes. We included 60 studies with 60 077 patients. GLP-1 RAs marginally reduced urinary albumin-to-creatinine ratio compared with placebo or other antidiabetic agents (weighted mean difference - 2.55 mg/g; 95% confidence interval [CI] -4.37 to -0.73 and -5.52; -10.89 to -0.16, respectively) and had no clinically relevant effect on change in estimated glomerular filtration rate. Treatment with GLP-1 RAs did not increase incidence of diabetic retinopathy, macular oedema, retinal detachment and retinal haemorrhage, irrespective of comparator. Nevertheless, incidence of vitreous haemorrhage was higher in subjects treated with GLP-1 RAs compared with placebo (odds ratios 1.93; 95% CI 1.09 to 3.42). In conclusion, GLP-1 RAs are safe regarding nephropathy- and retinopathy-related outcomes. Caution may be warranted for incidence of vitreous haemorrhage. The low overall quality of evidence highlights the need for consistent assessment and reporting of microvascular endpoints in future trials.
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Affiliation(s)
- Ioannis Avgerinos
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Thomas Karagiannis
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Konstantinos Malandris
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Aris Liakos
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Maria Mainou
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eleni Bekiari
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Diabetes Centre, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - David R Matthews
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK
- Harris Manchester College, University of Oxford, Oxford, UK
| | - Apostolos Tsapas
- Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Diabetes Centre, Second Medical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Harris Manchester College, University of Oxford, Oxford, UK
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Manolis AA, Manolis TA, Manolis AS. Cardiovascular Safety of Antihyperglycemic Agents: “Do Good or Do No Harm”. Drugs 2018; 78:1567-1592. [DOI: 10.1007/s40265-018-0985-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Bretón‐Romero R, Weisbrod RM, Feng B, Holbrook M, Ko D, Stathos MM, Zhang J, Fetterman JL, Hamburg NM. Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus. J Am Heart Assoc 2018; 7:e009379. [PMID: 30371206 PMCID: PMC6222937 DOI: 10.1161/jaha.118.009379] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 07/27/2018] [Indexed: 02/06/2023]
Abstract
Background Prior studies have shown that nutrient excess induces endoplasmic reticulum ( ER ) stress in nonvascular tissues from patients with diabetes mellitus ( DM ). ER stress and the subsequent unfolded protein response may be protective, but sustained activation may drive vascular injury. Whether ER stress contributes to endothelial dysfunction in patients with DM remains unknown. Methods and Results To characterize vascular ER stress, we isolated endothelial cells from 42 patients with DM and 37 subjects without DM. Endothelial cells from patients with DM displayed higher levels of ER stress markers compared with controls without DM. Both the early adaptive response, evidenced by higher phosphorylated protein kinase-like ER eukaryotic initiation factor-2a kinase and inositol-requiring ER-to-nucleus signaling protein 1 ( P=0.02, P=0.007, respectively), and the chronic ER stress response evidenced by higher C/ EBP α-homologous protein ( P=0.02), were activated in patients with DM . Higher inositol-requiring ER-to-nucleus signaling protein 1 activation was associated with lower flow-mediated dilation, consistent with endothelial dysfunction ( r=0.53, P=0.02). Acute treatment with liraglutide, a glucagon-like peptide 1 receptor agonist, reduced p-inositol-requiring ER-to-nucleus signaling protein 1 ( P=0.01), and the activation of its downstream target c-jun N-terminal kinase ( P=0.025) in endothelial cells from patients with DM . Furthermore, liraglutide restored insulin-stimulated endothelial nitric oxide synthase activation in patients with DM ( P=0.019). Conclusions In summary, our data suggest that ER stress contributes to vascular insulin resistance and endothelial dysfunction in patients with DM . Further, we have demonstrated that liraglutide ameliorates ER stress, decreases c-jun N-terminal kinase activation and restores insulin-mediated endothelial nitric oxide synthase activation in endothelial cells from patients with DM .
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Affiliation(s)
- Rosa Bretón‐Romero
- Whitaker Cardiovascular InstituteBoston University School of MedicineBostonMA
| | - Robert M. Weisbrod
- Whitaker Cardiovascular InstituteBoston University School of MedicineBostonMA
| | - Bihua Feng
- Whitaker Cardiovascular InstituteBoston University School of MedicineBostonMA
| | - Monika Holbrook
- Whitaker Cardiovascular InstituteBoston University School of MedicineBostonMA
| | - Darae Ko
- Whitaker Cardiovascular InstituteBoston University School of MedicineBostonMA
| | - Mary M. Stathos
- Whitaker Cardiovascular InstituteBoston University School of MedicineBostonMA
| | - Ji‐Yao Zhang
- Whitaker Cardiovascular InstituteBoston University School of MedicineBostonMA
| | | | - Naomi M. Hamburg
- Whitaker Cardiovascular InstituteBoston University School of MedicineBostonMA
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Overbeek JA, Bakker M, van der Heijden AAWA, van Herk-Sukel MPP, Herings RMC, Nijpels G. Risk of dipeptidyl peptidase-4 (DPP-4) inhibitors on site-specific cancer: A systematic review and meta-analysis. Diabetes Metab Res Rev 2018; 34:e3004. [PMID: 29573125 DOI: 10.1002/dmrr.3004] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 01/03/2018] [Accepted: 03/12/2018] [Indexed: 12/19/2022]
Abstract
The long-term impact of dipeptidyl peptidase-4 (DPP-4) inhibition is unknown, and there are concerns about the influence of DPP-4 inhibition on carcinogenesis of the pancreas and thyroid. As DPP-4 is a rather unselective enzyme present in many tissues, we focused on all specific cancer types. PubMed and EMBASE were searched between January 2005 and April 2017 to identify studies comparing DPP-4 inhibitors with either placebo or active drugs on cancer risk. Studies were included if they reported on at least one specific cancer outcome and had a follow-up of at least 1 year after start of drug use. Methodological quality of the studies was assessed by the Cochrane Collaboration's tool and the Newcastle-Ottawa Scale. Twenty-five studies met the inclusion criteria (12 randomized controlled trials and 13 observational studies). Sample sizes of the DPP-4 inhibitor groups ranged from 29 to 8212 patients for randomized controlled trials and from 2422 to 71 137 patients for observational studies. Mean age ranged from 51 to 76 years, and mean follow-up was 1.5 years. None of the pooled (sensitivity) analyses, except the observational studies studying breast cancer (hazard ratio [95% CI]: 0.76 [0.60-0.96]), showed evidence for an association between DPP-4 inhibitors and site-specific cancer. Also for pancreatic and thyroid cancer, no statistically significant risk was found. Based on the current literature, it is not possible to conclude whether DPP-4 inhibitors were associated with an increased risk of site-specific cancer. Future studies should address the methodological limitations and follow patients for a longer period to determine the long-term cancer risk of DPP-4 inhibitors.
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Affiliation(s)
- Jetty A Overbeek
- Department of General Practice and Elderly Care Medicine, Amsterdam Public Health Research Institute, VU University Medical Centre, Amsterdam, Netherlands
- PHARMO Institute for Drug Outcomes Research, Utrecht, Netherlands
| | - Marina Bakker
- PHARMO Institute for Drug Outcomes Research, Utrecht, Netherlands
| | - Amber A W A van der Heijden
- Department of General Practice and Elderly Care Medicine, Amsterdam Public Health Research Institute, VU University Medical Centre, Amsterdam, Netherlands
| | - Myrthe P P van Herk-Sukel
- Department of Internal Medicine and Dermatology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Ron M C Herings
- PHARMO Institute for Drug Outcomes Research, Utrecht, Netherlands
- Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, Netherlands
| | - Giel Nijpels
- Department of General Practice and Elderly Care Medicine, Amsterdam Public Health Research Institute, VU University Medical Centre, Amsterdam, Netherlands
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Li Q, Ganguly R, Ganz ML, Gamble C, Dang-Tan T. Real-World Clinical Effectiveness and Cost Savings of Liraglutide Versus Sitagliptin in Treating Type 2 Diabetes for 1 and 2 Years. Diabetes Ther 2018; 9:1279-1293. [PMID: 29744818 PMCID: PMC5984935 DOI: 10.1007/s13300-018-0432-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Indexed: 12/28/2022] Open
Abstract
INTRODUCTION This study compared the clinical and economic outcomes of long-term use of liraglutide versus sitagliptin for the treatment of type 2 diabetes (T2DM) in real-world practice in the USA. METHODS We identified adult patients (≥ 18 years old) with T2DM who initiated liraglutide or sitagliptin in 2010-2014 using a large claims database. Quarterly glycemic control measures and annual healthcare costs were assessed during the 1st and 2nd years of persistent medication use. Their associations with medication use (liraglutide or sitagliptin) were estimated using multivariable regression models adjusted for patient demographic and clinical characteristics. RESULTS A total of 3113 patients persistently used liraglutide (N = 493) or sitagliptin (N = 2620) for ≥ 1 year [mean age (standard deviation, SD): 53 (8.5) vs. 56 (9.7) years; 48.3% vs. 62.3% males; both p < 0.05]; 911 (including 113 liraglutide users) were persistent users for ≥ 2 years. During the 1st-year follow-up, liraglutide users (versus sitagliptin users, after adjustment) experienced larger glycated hemoglobin (HbA1c) reductions from baseline (ranging from 0.34%-point in quarter 1 to 0.21%-point in quarter 4); higher likelihoods of obtaining HbA1c reductions of ≥ 1%-points or ≥ 2%-points [odds ratios (ORs) range 1.47-2.04]; and higher likelihoods of reaching HbA1c goals of < 6.5% or < 7% (ORs range 1.51-2.12) (all p < 0.05). Liraglutide users also experienced HbA1c reductions from baseline in the 2nd-year follow-up (0.53-0.33%-point, all p < 0.05). Although liraglutide users incurred higher healthcare costs than sitagliptin users during the 1st-year follow-up, they had $2674 (per patient) lower all-cause medical costs (adjusted cost ratio: 0.67, p < 0.05) and similar total costs (all-cause and diabetes-related) in the 2nd year. CONCLUSION Long-term use of liraglutide for 1 or 2 years was associated with better glycemic control than using sitagliptin. Savings in medical costs were realized for liraglutide users during the 2nd year of persistent treatment, which offset differences in pharmacy costs. FUNDING Novo Nordisk Inc.
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Affiliation(s)
- Qian Li
- Evidera, 500 Totten Pond Road, 5th Floor, Waltham, MA, 02451, USA.
| | - Rahul Ganguly
- Novo Nordisk Inc, 800 Scudders Mill Road, Plainsboro, NJ, 08536, USA
| | - Michael L Ganz
- Evidera, 500 Totten Pond Road, 5th Floor, Waltham, MA, 02451, USA
| | - Cory Gamble
- Novo Nordisk Inc, 800 Scudders Mill Road, Plainsboro, NJ, 08536, USA
| | - Tam Dang-Tan
- Novo Nordisk Inc, 800 Scudders Mill Road, Plainsboro, NJ, 08536, USA
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Tran S, Retnakaran R, Zinman B, Kramer CK. Efficacy of glucagon-like peptide-1 receptor agonists compared to dipeptidyl peptidase-4 inhibitors for the management of type 2 diabetes: A meta-analysis of randomized clinical trials. Diabetes Obes Metab 2018; 20 Suppl 1:68-76. [PMID: 29364587 DOI: 10.1111/dom.13137] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 10/18/2017] [Accepted: 10/20/2017] [Indexed: 12/13/2022]
Abstract
AIMS Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are both incretin-based therapies for type 2 diabetes (T2DM) but have distinct efficacy and side effect profiles. We thus performed a systematic review and meta-analysis to compare the effects of GLP-1 agonists to DPP-4 inhibitors on glycaemic control, weight and incidence of adverse events in adults with T2DM. We also sought to determine whether there was any additional effect in switching from DPP-4 inhibitor to GLP-1 agonist. MATERIALS AND METHODS We systematically searched PubMed, Embase and ClinicalTrials.gov for (1) randomized controlled trials (RCTs) comparing any GLP-1 agonist to any DPP-4 inhibitor and (2) interventional studies where a DPP-4 inhibitor was switched to a GLP-1 agonist. We assessed pooled data using random-effects model (CRD42017057115). RESULTS The pooled analysis of 13 RCTs (n = 4330) showed that, compared to DPP-4 inhibitors, GLP-1 agonists yielded a greater mean reduction in glycated haemoglobin (HbA1c) of -0.41% (95% CI -0.53 to -0.30) and in weight of -2.15 kg (-3.04 to -1.27). GLP-1 agonists were associated with greater likelihood of gastrointestinal side effects with no increased risk of hypoglycaemia. In 5 interventional studies (n = 433), switching from DPP-4 inhibitor to GLP-1 agonist yielded further mean reduction in HbA1c of -0.69% (-1.03 to -0.35) and in weight of -2.25 kg (-3.12 to -1.38). CONCLUSIONS GLP-1 agonists yield greater reduction in HbA1c and weight as compared to DPP-4 inhibitors, with increased incidence of gastrointestinal symptoms but not hypoglycaemia. Replacing a DPP-4 inhibitor with GLP-1 agonist provides additional benefits in glycaemic control and weight loss.
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Affiliation(s)
- Susan Tran
- Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Canada
| | - Ravi Retnakaran
- Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Canada
- Division of Endocrinology, University of Toronto, Toronto, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
| | - Bernard Zinman
- Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Canada
- Division of Endocrinology, University of Toronto, Toronto, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
| | - Caroline K Kramer
- Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Canada
- Division of Endocrinology, University of Toronto, Toronto, Canada
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Mabilleau G, Gobron B, Bouvard B, Chappard D. Incretin-based therapy for the treatment of bone fragility in diabetes mellitus. Peptides 2018; 100:108-113. [PMID: 29412811 DOI: 10.1016/j.peptides.2017.12.008] [Citation(s) in RCA: 7] [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] [Received: 09/27/2017] [Revised: 12/06/2017] [Accepted: 12/07/2017] [Indexed: 12/23/2022]
Abstract
Bone fractures are common comorbidities of type 2 diabetes mellitus (T2DM). Bone fracture incidence seems to develop due to increased risk of falls, poor bone quality and/or anti-diabetic medications. Previously, a relation between gut hormones and bone has been suspected. Most recent evidences suggest indeed that two gut hormones, namely glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), may control bone remodeling and quality. The GIP receptor is expressed in bone cells and knockout of either GIP or its receptor induces severe bone quality alterations. Similar alterations are also encountered in GLP-1 receptor knock-out animals associated with abnormal osteoclast resorption. Some GLP-1 receptor agonist (GLP-1RA) have been approved for the treatment of type 2 diabetes mellitus and although clinical trials may not have been designed to investigate bone fracture, first results suggest that GLP-1RA may not exacerbate abnormal bone quality observed in T2DM. The recent design of double and triple gut hormone agonists may also represent a suitable alternative for restoring compromised bone quality observed in T2DM. However, although most of these new molecules demonstrated weight loss action, little is known on their bone safety. The present review summarizes the most recent findings on peptide-based incretin therapy and bone physiology.
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Affiliation(s)
- Guillaume Mabilleau
- GEROM-LHEA UPRES EA4658, University of Angers, Institut de Biologie en Santé, Angers, France; SCIAM, University of Angers, Institut de Biologie en Santé, Angers, France; Bone Pathology Unit, Angers University Hospital, Angers, France.
| | - Benoît Gobron
- GEROM-LHEA UPRES EA4658, University of Angers, Institut de Biologie en Santé, Angers, France; Rheumatology Department, Angers University Hospital, Angers, France
| | - Béatrice Bouvard
- GEROM-LHEA UPRES EA4658, University of Angers, Institut de Biologie en Santé, Angers, France; Rheumatology Department, Angers University Hospital, Angers, France
| | - Daniel Chappard
- GEROM-LHEA UPRES EA4658, University of Angers, Institut de Biologie en Santé, Angers, France; SCIAM, University of Angers, Institut de Biologie en Santé, Angers, France; Bone Pathology Unit, Angers University Hospital, Angers, France
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Baptista A, Teixeira I, Romano S, Carneiro AV, Perelman J. The place of DPP-4 inhibitors in the treatment algorithm of diabetes type 2: a systematic review of cost-effectiveness studies. THE EUROPEAN JOURNAL OF HEALTH ECONOMICS : HEPAC : HEALTH ECONOMICS IN PREVENTION AND CARE 2017; 18:937-965. [PMID: 27752788 DOI: 10.1007/s10198-016-0837-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 09/30/2016] [Indexed: 06/06/2023]
Abstract
OBJECTIVE To conduct a systematic review of cost-effectiveness, cost-utility, and cost-benefit studies of DPP-4 inhibitors for diabetes treatment versus other antidiabetics. METHODS Three investigators searched the CRD York, Tufts CEA Registry, and MEDLINE databases through 2015. We reviewed all potentially relevant titles and abstracts, and screened full-text articles, according to inclusion criteria. We established a quality score for each study based on a 35-item list. RESULTS A total of 295 studies were identified, of which 20 were included. The average quality score was 0.720 on a 0-1 scale. All studies were performed in high- and middle-income countries, using a 3rd-party payer perspective and randomized clinical trials to measure effectiveness. Sitagliptin, saxagliptin and vildagliptin had an ICER below 25,000 €/QALY, as second-line and as add-ons to metformin, in comparison to sulfonylureas. When compared with sitagliptin, liraglutide (GLP-1 receptor agonist) had an ICER of up to 22,724 €/QALY for the 1.2-mg dosage, and up to 32,869 €/QALY for the 1.8-mg dosage. Insulin glargine was dominant when compared with sitagliptin. CONCLUSIONS According to the WHO threshold applied to the country and year of each study, DPP-4 inhibitors were highly cost-effective as second-line, as add-ons to metformin, in comparison with sulfonylureas. More recent therapies (GLP-1 receptor agonists and insulin glargine) were highly cost-effective in comparison to DPP-4 inhibitors. These results were obtained, however, on the basis of a limited number of studies, relying on the same few clinical trials, and financed by manufacturers. Further independent research is needed to confirm these findings.
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Affiliation(s)
- Alexandre Baptista
- Unit of Epidemiology of the Faculty of Medicine of Lisbon, Edifício Egas Moniz, Faculdade de Medicina da Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028, Lisbon, Portugal.
| | - Inês Teixeira
- Centre for Health Evaluation and Research (CEFAR), National Association of Pharmacies Group, R. Marechal Saldanha, 1., 1249-069, Lisbon, Portugal
| | - Sónia Romano
- Centre for Health Evaluation and Research (CEFAR), National Association of Pharmacies Group, R. Marechal Saldanha, 1., 1249-069, Lisbon, Portugal
| | - António Vaz Carneiro
- Center for Evidence-Based Medicine (CEMBE) of the Faculty of Medicine at the University of Lisbon, Faculdade de Medicina da Universidade de Lisboa, Av. Professor Egas Moniz, 1649-028, Lisbon, Portugal
| | - Julian Perelman
- Escola Nacional de Saúde Pública and Centro de Investigação em Saúde Pública, Universidade Nova de Lisboa, Avenida Padre Cruz, 1600-5605, Lisbon, Portugal
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Li M, Yang Y, Jiang D, Ying M, Wang Y, Zhao R. Efficacy and safety of liraglutide versus sitagliptin both in combination with metformin in patients with type 2 diabetes: A systematic review and meta-analysis. Medicine (Baltimore) 2017; 96:e8161. [PMID: 28953663 PMCID: PMC5626306 DOI: 10.1097/md.0000000000008161] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 08/30/2017] [Accepted: 09/01/2017] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The aim of this systematic review was to evaluate the efficacy and safety of liraglutide versus sitagliptin both in combination with metformin in patients with type 2 diabetes and provide reference basis for rational use of clinical drugs. METHODS Several databases were searched, including Web of science, PubMed, Cochrane library, CNKI, and Wanfang database. Only randomized controlled trials (RCTs) of liraglutide versus sitagliptin both in combination with metformin up to 31 August 2016 were included. Data were extracted independently by 2 reviewers, and a fixed or random effects model were used to analyze outcomes that were expressed as odds ratio (OR) or mean difference (MD) and 95% confidence intervals (95% CIs) for different situations. RESULTS Five RCTs involving 1440 participants were included. Compared with sitagliptin combination with metformin group, participants' treatment with 1.2 mg and 1.8 mg liraglutide with metformin could significantly lower the level of glycosylated hemoglobin (HbA1c) (P < .00001, MD = -0.35, 95% CI -0.51 to -0.20). Moreover, patients with 1.8 mg liraglutide group had significant body weight loss (P < .00001, MD = -1.12, 95% CI -1.54 to -0.70). However, there were no obvious differences in cutting down the systolic blood pressure and diastolic blood pressure between liraglutide-metformin and sitagliptin-metformin groups. The incidence of gastrointestinal problems was significantly higher than sitagliptin with metformin groups. CONCLUSION The results of this meta-analysis indicated that Liraglutide added on to metformin therapy could significantly lower the level of HbA1c and increase body weight loss. Meanwhile, the adverse reactions such as gastrointestinal problems were common in the liraglutide treatment group. Thus, this will provide an important reference for the treatment of patients with type 2 diabetes.
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Affiliation(s)
- Mingxing Li
- Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou
| | - Yi Yang
- Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou
| | - Deqi Jiang
- Department of Biopharmaceutical, Yulin Normal University, Yulin
| | - Miaofa Ying
- Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou
| | - Yong Wang
- Department of Pharmacy, Zhu Jiang Hospital, Southern Medical University, Guangzhou, China
| | - Rui Zhao
- Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou
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Tonouchi R, Mine Y, Aoki M, Okuno M, Suzuki J, Urakami T. Efficacy and safety of alogliptin in a pediatric patient with maturity-onset diabetes of the young type 1. Clin Pediatr Endocrinol 2017; 26:183-188. [PMID: 28804210 PMCID: PMC5537215 DOI: 10.1297/cpe.26.183] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 03/13/2017] [Indexed: 12/30/2022] Open
Abstract
The first-line pharmacological treatment for patients with maturity-onset diabetes of the
young type 1 (MODY1) and maturity-onset diabetes of the young type 3 (MODY3) are
sulfonylureas (SUs) or insulin. However, several reports have suggested the possibility of
using incretin-associated drugs, including dipeptidyl-peptidase-4 (DPP-4) inhibitors, for
the treatment of patients with these types of MODY. Here we report a case of a pediatric
patient with MODY1 who was successfully treated with a DPP-4 inhibitor, alogliptin. A
13-yr-old Japanese girl with diabetes was initially treated with insulin for 5 mo. After
diagnosis of MODY1, confirmed via a genetic analysis, treatment was changed from insulin
to alogliptin. SUs were prescribed temporarily, but monotherapy with alogliptin finally
resulted in good glycemic control. After changing to alogliptin, the patient maintained
optimal glycemic control with glycated hemoglobin levels of 6.3–7.0% while maintaining
substantial β-cell function. No adverse events associated with alogliptin were observed.
These results suggest that DPP-4 inhibitors may be a potential treatment for patients with
MODY1 at the early stage of the disease when residual insulin secretion is still being
sustained.
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Affiliation(s)
- Ryosuke Tonouchi
- Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan
| | - Yusuke Mine
- Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan
| | - Masako Aoki
- Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan
| | - Misako Okuno
- Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan
| | - Junichi Suzuki
- Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan
| | - Tatsuhiko Urakami
- Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan
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Gadde KM, Vetter ML, Iqbal N, Hardy E, Öhman P, on behalf of the DURATION‐NEO‐2 study investigators. Efficacy and safety of autoinjected exenatide once-weekly suspension versus sitagliptin or placebo with metformin in patients with type 2 diabetes: The DURATION-NEO-2 randomized clinical study. Diabetes Obes Metab 2017; 19:979-988. [PMID: 28205322 PMCID: PMC5485171 DOI: 10.1111/dom.12908] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 02/06/2017] [Accepted: 02/13/2017] [Indexed: 12/12/2022]
Abstract
AIMS Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors treat type 2 diabetes through incretin-signaling pathways. This study compared the efficacy and safety of the glucagon-like peptide-1 receptor agonist exenatide once-weekly (Miglyol) suspension for autoinjection (QWS-AI) with the dipeptidyl peptidase-4 inhibitor sitagliptin or placebo. MATERIALS AND METHODS In this open-label, multicentre study of patients with type 2 diabetes who had suboptimal glycaemic control on metformin monotherapy, 365 patients were randomized to receive exenatide 2.0 mg QWS-AI, sitagliptin 100 mg once daily or oral placebo (3:2:1 ratio). The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to 28 weeks. RESULTS At 28 weeks, exenatide QWS-AI significantly reduced HbA1c from baseline compared to sitagliptin (-1.13% vs -0.75% [baseline values, 8.42% and 8.50%, respectively]; P = .02) and placebo (-0.40% [baseline value, 8.50%]; P = .001). More exenatide QWS-AI-treated patients achieved HbA1c <7.0% than did sitagliptin- or placebo-treated patients (43.1% vs 32.0% and 24.6%; both P < .05). Exenatide QWS-AI and sitagliptin reduced fasting plasma glucose from baseline to 28 weeks (-21.3 and -11.3 mg/dL) vs placebo (+9.6 mg/dL), with no significant difference between the 2 active treatments. Body weight decreased with both active treatments (-1.12 and -1.19 kg), but not with placebo (+0.15 kg). No improvement in blood pressure was observed in any group. The most common adverse events with exenatide QWS-AI were gastrointestinal events and injection-site reactions. CONCLUSIONS This study demonstrated that exenatide QWS-AI reduced HbA1c more than sitagliptin or placebo and was well tolerated.
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Affiliation(s)
- Kishore M. Gadde
- Pennington Biomedical Research CenterLouisiana State UniversityBaton RougeLouisiana
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Liu J, Li L, Deng K, Xu C, Busse JW, Vandvik PO, Li S, Guyatt GH, Sun X. Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis. BMJ 2017; 357:j2499. [PMID: 28596247 PMCID: PMC5463186 DOI: 10.1136/bmj.j2499] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/11/2017] [Indexed: 02/05/2023]
Abstract
Objective To assess the impact of incretin based treatment on all cause mortality in patients with type 2 diabetes.Design Systematic review and meta-analysis of randomised trials.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov.Eligibility criteria Randomised controlled trials that compared glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors with placebo or active anti-diabetic drugs in patients with type 2 diabetes.Data collection and analysis Paired reviewers independently screened citations, assessed risk of bias of included studies, and extracted data. Peto's method was used as the primary approach to pool effect estimates from trials, sensitivity analyses were carried out with other statistical approaches, and meta-regression was applied for six prespecified hypotheses to explore heterogeneity. The GRADE approach was used to rate the quality of evidence.Results 189 randomised controlled trials (n=155 145) were included, all of which were at low to moderate risk of bias; 77 reported no events of death and 112 reported 3888 deaths among 151 614 patients. Meta-analysis of 189 trials showed no difference in all cause mortality between incretin drugs versus control (1925/84 136 v 1963/67 478; odds ratio 0.96, 95% confidence interval 0.90 to 1.02, I2=0%; risk difference 3 fewer events (95% confidence interval 7 fewer to 1 more) per 1000 patients over five years; moderate quality evidence). Results suggested the possibility of a mortality benefit with GLP-1 agonists but not DPP-4 inhibitors, but the subgroup hypothesis had low credibility. Sensitivity analyses showed no important differences in the estimates of effects.Conclusions Current evidence does not support the suggestion that incretin based treatment increases all cause mortality in patients with type 2 diabetes. Further studies are warranted to examine if the effect differs between GLP-1 agonists versus DPP-4 inhibitors.
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Affiliation(s)
- Jiali Liu
- Chinese Evidence-based Medicine Centre and CREAT Group, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Centre, Chengdu, 610041, Sichuan, China
| | - Ling Li
- Chinese Evidence-based Medicine Centre and CREAT Group, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Centre, Chengdu, 610041, Sichuan, China
| | - Ke Deng
- Chinese Evidence-based Medicine Centre and CREAT Group, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Centre, Chengdu, 610041, Sichuan, China
| | - Chang Xu
- Chinese Evidence-based Medicine Centre and CREAT Group, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Centre, Chengdu, 610041, Sichuan, China
| | - Jason W Busse
- Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON L8S 4K1, Canada
- Department of Anesthesia, McMaster University, Hamilton, ON L8S 4K1, Canada
- Michael G DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Per Olav Vandvik
- Norwegian Knowledge Centre for the Health Services, N-0130 Oslo, Norway
- Department of Medicine, Innlandet Hospital Trust, 2819 Gjøvik, Norway
| | - Sheyu Li
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Gordon H Guyatt
- Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON L8S 4K1, Canada
- Department of Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Xin Sun
- Chinese Evidence-based Medicine Centre and CREAT Group, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Centre, Chengdu, 610041, Sichuan, China
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St Onge E, Miller S, Clements E, Celauro L, Barnes K. The Role of Glucagon-like Peptide-1 Receptor Agonists in the Treatment of Type 2 Diabetes. J Transl Int Med 2017; 5:79-89. [PMID: 28721339 PMCID: PMC5506406 DOI: 10.1515/jtim-2017-0015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The role of GLP-1 agonists in the treatment of type 2 diabetes have been shown to be viable options for add-on therapy in diabetic patients, as well as potential monotherapy options. With six available GLP-1 agents, and new combination products in the pipeline, they are a promising drug class for type 2 diabetic patients, especially due to their extended dosing interval and potential weight loss benefits.
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Affiliation(s)
- Erin St Onge
- University of Florida, College of Pharmacy, Florida, USA
| | - Shannon Miller
- University of Florida, College of Pharmacy, Florida, USA
| | | | | | - Ke’la Barnes
- Florida Hospital Celebration Health, Florida, USA
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