|
1
|
Ren Y, Chen Y, Zheng W, Kong W, Liao Y, Zhang J, Wang M, Zeng T. The effect of GLP-1 receptor agonists on circulating inflammatory markers in type 2 diabetes patients: A systematic review and meta-analysis. Diabetes Obes Metab 2025. [PMID: 40230207 DOI: 10.1111/dom.16366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 03/11/2025] [Accepted: 03/13/2025] [Indexed: 04/16/2025]
Abstract
AIM To investigate whether the antidiabetic agent glucagon-like peptide-1 receptor agonists (GLP-1 RAs) can exert anti-inflammatory effects while lowering blood glucose, we performed a meta-analysis and systematic review. METHODS We searched 4 online databases (Medline, Embase, Cochrane Library and the Web of Science) for randomised controlled trials (RCTs) that examined changes after GLP-1RAs intervention in commonly accepted biomarkers of inflammation: C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), leptin, adiponectin, plasminogen activator inhibitor-1 (PAI-1), monocyte chemotactic protein-1(MCP-1) and advanced glycation end products (AGEs). RESULTS This meta-analysis included 52 eligible RCTs (n = 4734) with a median follow-up of 24 weeks, a mean age of 54.13 years, 44.46% females, body mass index (BMI) 29.80 kg/m2, glycated haemoglobin (HbA1c) 8.28% and diabetes duration 7.27 years. GLP-1 RAs treatment, compared to placebo or conventional diabetes therapies (including oral medicine and insulin), resulted in significant reductions in CRP, TNF-α, IL-6, IL-1β and leptin (standard mean difference [SMD] -0.63 [-1.03, -0.23]; SMD -0.92 [-1.57, -0.27]; SMD -0.76 [-1.32, -0.20], SMD -3.89 [-6.56, -1.22], SMD -0.67 [-1.09, -0.26], respectively), as well as significant increases in adiponectin (SMD 0.69 [0.19, 1.19]). CONCLUSIONS Our meta-analysis demonstrates that GLP-1 RAs exert significant anti-inflammatory effects in patients with T2DM. Our findings provide important insights that may guide the therapeutic application of GLP-1 RAs and inform the development of related therapies.
Collapse
Affiliation(s)
- Yifan Ren
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, China
- Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, China
| | - Yuzhang Chen
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, China
- Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, China
| | - Wenbin Zheng
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, China
- Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, China
| | - Wen Kong
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, China
- Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, China
| | - Yunfei Liao
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, China
- Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, China
| | - Jiaoyue Zhang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, China
- Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, China
| | - Meng Wang
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, China
- Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, China
| | - Tianshu Zeng
- Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Diabetes and Metabolic Disease Clinical Research Center of Hubei Province, Wuhan, China
- Hubei Key Laboratory of Metabolic Abnormalities and Vascular Aging, Wuhan, China
- Hubei Branch of National Center for Clinical Medical Research of Metabolic Diseases, Wuhan, China
| |
Collapse
|
|
2
|
An X, Sun W, Wen Z, Duan L, Zhang Y, Kang X, Ji H, Sun Y, Jiang L, Zhao X, Gao Q, Lian F. Comparison of the efficacy and safety of GLP-1 receptor agonists on cardiovascular events and risk factors: A review and network meta-analysis. Diabetes Obes Metab 2025; 27:1735-1751. [PMID: 39910752 DOI: 10.1111/dom.16228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 01/07/2025] [Accepted: 01/21/2025] [Indexed: 02/07/2025]
Abstract
OBJECTIVE This study aims to systematically evaluate and perform a systematic review and network meta-analysis comparing the comprehensive cardiovascular protective effects of various glucagon-like peptide-1 receptor agonists (GLP-1RAs), focusing on cardiovascular events and risk factors. METHODS We searched PubMed, Embase, Cochrane Library and Web of Science from inception to December 15, 2024. Included studies were published randomized controlled trials (RCTs) comparing GLP-1RAs to placebo or other GLP-1RAs. Missing data were standardized, and network meta-analysis was performed using Stata 17.0. Study heterogeneity, publication bias and evidence quality were assessed using the Cochrane Risk of Bias tool and Confidence in Network Meta-Analysis (CINeMA). RESULTS As of December 15, 2024, a total of 18 313 articles were retrieved. Based on the inclusion and exclusion criteria, 156 high-quality studies were included, incorporating 144 782 patients and 14 different GLP-1RAs. The network meta-analysis demonstrated low heterogeneity, ensuring the reliability of the results. Comprehensive analysis revealed the following: Efpeglenatide was the most effective in reducing major adverse cardiovascular events. Oral semaglutide shows more significant advantages in reducing all-cause mortality and cardiovascular mortality. Orforglipron excelled in glycaemic control and weight reduction. SC-Semaglutide showed the greatest efficacy in lowering both systolic blood pressure and diastolic blood pressure, Liraglutide showed the greatest efficacy in lowering total cholesterol, Noiiglutide in triglycerides and Taspoglutide in low-density lipoprotein cholesterol, but no GLP-1RAs in high-density lipoprotein cholesterol. GLP-1RAs did not significantly increase the incidence of adverse events, but Orforglipron and Taspoglutide significantly increased the incidence of gastrointestinal adverse events compared with placebo. CONCLUSION This study compared the cardiovascular benefits of different GLP-1RAs, including reductions in cardiovascular events and improvements in multiple cardiovascular risk factors. However, due to limitations in the quantity and quality of the included studies, the conclusions should be interpreted with caution. Future large-scale, high-quality clinical trials are needed to validate these findings and further optimize comprehensive cardiovascular management strategies for patients.
Collapse
Affiliation(s)
- Xuedong An
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - WenJie Sun
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhige Wen
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - LiYun Duan
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - YueHong Zhang
- Fangshan Hospital Beijing University of Chinese Medicine, Beijing, China
| | - Xiaomin Kang
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Hangyu Ji
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuting Sun
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Linlin Jiang
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Xuefei Zhao
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Qing Gao
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Fengmei Lian
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| |
Collapse
|
|
3
|
Qian Z, Cui F, Mao Z, Li Z, Yi X, Zhou J, Cao J, Li X. LINC-p21 Regulates Pancreatic β-Cell Function in Type 2 Diabetes Mellitus. Biochem Genet 2024:10.1007/s10528-024-10850-1. [PMID: 38864965 DOI: 10.1007/s10528-024-10850-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 05/23/2024] [Indexed: 06/13/2024]
Abstract
This study aimed to investigate the underlying mechanism and assess the biological role of long intergenic non-coding RNA (LINCRNA)-p21 in type 2 diabetes mellitus (T2DM). LINC-p21 and miR-335-3p expression levels were evaluated in blood from T2DM patients, healthy individuals, and mouse islet β-cell line MIN6 cells grown in a high glucose environment. Apoptosis-related proteins, iNOS, and IGF-1 were detected in vitro and in vivo. Bioinformatics was used to predict that miR-335-3p had complementary binding sites to IGF-1, and a dual-luciferase reporter confirmed the targeting link between LINC-p21 and miR-335-3p. LINC-p21 was highly expressed in the T2DM serum and cells, and LINC-p21 was significantly associated with T2DM prognosis. In vitro and in vivo dysfunction of β-cells was reduced by LINC-p21 knockdown. MiR-335-3p and IGF-1 may be potential targets of LINC-p21 and miR-335-3p, respectively, after the prediction of the target of LINC-p21 was verified by dual-luciferase assay. Anti-miR-335-3p made LINC-p21 knockdown function again; however, interference of IGF-1 mRNA restored the function of LINC-p21. The miR-335-3p/IGF-1 axis may have a role in the functional protection of pancreatic β-cells by LINC-p21 silencing, boosting insulin production, and slowing the course of diabetes.
Collapse
Affiliation(s)
- Zengkun Qian
- Department of Clinical Laboratory, Wuhu Hospital Affiliated to Anhui University of Science and Technology (The First People's Hospital of Wuhu), Wuhu, 241000, Anhui, China.
| | - Fan Cui
- Department of Clinical Laboratory, Wuhu Hospital Affiliated to Anhui University of Science and Technology (The First People's Hospital of Wuhu), Wuhu, 241000, Anhui, China
| | - Zheng Mao
- Department of Clinical Laboratory, Wuhu Hospital Affiliated to Anhui University of Science and Technology (The First People's Hospital of Wuhu), Wuhu, 241000, Anhui, China
| | - Zhen Li
- Department of Clinical Laboratory, Wuhu Hospital Affiliated to Anhui University of Science and Technology (The First People's Hospital of Wuhu), Wuhu, 241000, Anhui, China
| | - Xiayu Yi
- Department of Clinical Laboratory, Wuhu Hospital Affiliated to Anhui University of Science and Technology (The First People's Hospital of Wuhu), Wuhu, 241000, Anhui, China
| | - Jingjing Zhou
- Department of Clinical Laboratory, Wuhu Hospital Affiliated to Anhui University of Science and Technology (The First People's Hospital of Wuhu), Wuhu, 241000, Anhui, China
| | - Jinjin Cao
- Department of Clinical Laboratory, Wuhu Hospital Affiliated to Anhui University of Science and Technology (The First People's Hospital of Wuhu), Wuhu, 241000, Anhui, China
| | - Xiaoqin Li
- Department of Clinical Laboratory, Wuhu Hospital Affiliated to Anhui University of Science and Technology (The First People's Hospital of Wuhu), Wuhu, 241000, Anhui, China
| |
Collapse
|
|
4
|
Zhou Y, Suo W, Zhang X, Liang J, Zhao W, Wang Y, Li H, Ni Q. Targeting mitochondrial quality control for diabetic cardiomyopathy: Therapeutic potential of hypoglycemic drugs. Biomed Pharmacother 2023; 168:115669. [PMID: 37820568 DOI: 10.1016/j.biopha.2023.115669] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/23/2023] [Accepted: 10/06/2023] [Indexed: 10/13/2023] Open
Abstract
Diabetic cardiomyopathy is a chronic cardiovascular complication caused by diabetes that is characterized by changes in myocardial structure and function, ultimately leading to heart failure and even death. Mitochondria serve as the provider of energy to cardiomyocytes, and mitochondrial dysfunction plays a central role in the development of diabetic cardiomyopathy. In response to a series of pathological changes caused by mitochondrial dysfunction, the mitochondrial quality control system is activated. The mitochondrial quality control system (including mitochondrial biogenesis, fusion and fission, and mitophagy) is core to maintaining the normal structure of mitochondria and performing their normal physiological functions. However, mitochondrial quality control is abnormal in diabetic cardiomyopathy, resulting in insufficient mitochondrial fusion and excessive fission within the cardiomyocyte, and fragmented mitochondria are not phagocytosed in a timely manner, accumulating within the cardiomyocyte resulting in cardiomyocyte injury. Currently, there is no specific therapy or prevention for diabetic cardiomyopathy, and glycemic control remains the mainstay. In this review, we first elucidate the pathogenesis of diabetic cardiomyopathy and explore the link between pathological mitochondrial quality control and the development of diabetic cardiomyopathy. Then, we summarize how clinically used hypoglycemic agents (including sodium-glucose cotransport protein 2 inhibitions, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, thiazolidinediones, metformin, and α-glucosidase inhibitors) exert cardioprotective effects to treat and prevent diabetic cardiomyopathy by targeting the mitochondrial quality control system. In addition, the mechanisms of complementary alternative therapies, such as active ingredients of traditional Chinese medicine, exercise, and lifestyle, targeting mitochondrial quality control for the treatment of diabetic cardiomyopathy are also added, which lays the foundation for the excavation of new diabetic cardioprotective drugs.
Collapse
Affiliation(s)
- Yutong Zhou
- Guang'an Men Hospital, China Academy of Chinese Medicine, Beijing 100053, China
| | - Wendong Suo
- LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Xinai Zhang
- Guang'an Men Hospital, China Academy of Chinese Medicine, Beijing 100053, China
| | - Jiaojiao Liang
- Zhengzhou Shuqing Medical College, Zhengzhou 450064, China
| | - Weizhe Zhao
- College of Traditional Chinese Medicine, Beijing University of Traditional Chinese Medicine, Beijing 100105, China
| | - Yue Wang
- Capital Medical University, Beijing 100069, China
| | - Hong Li
- LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
| | - Qing Ni
- Guang'an Men Hospital, China Academy of Chinese Medicine, Beijing 100053, China.
| |
Collapse
|
|
5
|
Soejima H, Ogawa H, Morimoto T, Okada S, Matsumoto C, Nakayama M, Masuda I, Jinnouchi H, Waki M, Saito Y. Dipeptidyl peptidase-4 inhibitors reduce the incidence of first cardiovascular events in Japanese diabetic patients. Heart Vessels 2023; 38:1371-1379. [PMID: 37522902 DOI: 10.1007/s00380-023-02291-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 07/13/2023] [Indexed: 08/01/2023]
Abstract
BACKGROUND Dipeptidyl Peptidase-4 (DPP-4) inhibitors do not suppress cardiovascular events in diabetic patients with a history of cardiovascular disease. However, the effect of DPP-4 inhibitors on cardiovascular events in Japanese diabetic patients is unclear. Therefore, we investigated whether DPP-4 inhibitors alter the incidence of cardiovascular events in Japanese diabetic patients without a history of cardiovascular events. METHODS The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial was a multicenter, prospective, randomized, open label, blinded, end-point study conducted from 2002 to 2008. After completion of the JPAD trial, we followed up the patients until 2019. Patients who had had a cardiovascular event by the 2013 follow-up were excluded from the study. JPAD patients were divided into a DPP-4 group and a non-DPP-4 group based on whether they were taking DPP-4 inhibitors at the 2013 follow-up because few patients took DPP-4 inhibitors before 2013. We investigated the incidence of cardiovascular events consisting of coronary events, cerebrovascular events, heart failure requiring hospitalization, and aortic and peripheral vascular disease in 1099 JPAD patients until 2019. RESULTS During the observation period from 2013 to 2019, 37 (7%) first cardiovascular events occurred in the DPP-4 group (n = 518) and 66 (11%) in the non-DPP-4 group (n = 581). The incidence of cardiovascular events was significantly lower in the DPP-4 group than in the non-DPP-4 group (Log-Rank P = 0.0065). Cox proportional hazards model analysis revealed that the use of DPP-4 inhibitors (hazard ratio 0.65; 95% confidence interval 0.43-0.98; P = 0.038) was an independent factor after adjustment for age ≥ 65 years, hypertension, statin usage, and insulin usage. CONCLUSIONS Our findings have demonstrated that the use of DPP-4 inhibitors may be associated with a reduced incidence of first cardiovascular events in Japanese diabetic patients. The results require confirmation in randomized controlled trials.
Collapse
Affiliation(s)
- Hirofumi Soejima
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
- Health Care Center, Kumamoto University, Kumamoto, Japan.
| | | | - Takeshi Morimoto
- Department of Clinical Epidemiology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Sadanori Okada
- Department of Diabetes and Endocrinology, Nara Medical University, Kashihara, Japan
| | - Chisa Matsumoto
- Department of Cardiology, Center for Health Surveillance & Preventive Medicine, Tokyo Medical University Hospital, Tokyo, Japan
| | | | - Izuru Masuda
- Internal Medicine, Koseikai Clinic, Kyoto, Japan
| | - Hideaki Jinnouchi
- Department of Internal Medicine, Jinnouchi Hospital Diabetes Care Center, Kumamoto, Japan
| | - Masako Waki
- Food Safety Commission of Japan, Tokyo, Japan
| | | |
Collapse
|
|
6
|
Pham TK, Nguyen THT, Yi JM, Kim GS, Yun HR, Kim HK, Won JC. Evogliptin, a DPP-4 inhibitor, prevents diabetic cardiomyopathy by alleviating cardiac lipotoxicity in db/db mice. Exp Mol Med 2023; 55:767-778. [PMID: 37009790 PMCID: PMC10167305 DOI: 10.1038/s12276-023-00958-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 12/05/2022] [Accepted: 12/23/2022] [Indexed: 04/04/2023] Open
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors are glucose-lowering drugs for type 2 diabetes mellitus (T2DM). We investigated whether evogliptin® (EVO), a DPP-4 inhibitor, could protect against diabetic cardiomyopathy (DCM) and the underlying mechanisms. Eight-week-old diabetic and obese db/db mice were administered EVO (100 mg/kg/day) daily by oral gavage for 12 weeks. db/db control mice and C57BLKS/J as wild-type (WT) mice received equal amounts of the vehicle. In addition to the hypoglycemic effect, we examined the improvement in cardiac contraction/relaxation ability, cardiac fibrosis, and myocardial hypertrophy by EVO treatment. To identify the mechanisms underlying the improvement in diabetic cardiomyopathy by EVO treatment, its effect on lipotoxicity and the mitochondrial damage caused by lipid droplet accumulation in the myocardium were analyzed. EVO lowered the blood glucose and HbA1c levels and improved insulin sensitivity but did not affect the body weight or blood lipid profile. Cardiac systolic/diastolic function, hypertrophy, and fibrosis were improved in the EVO-treated group. EVO prevented cardiac lipotoxicity by reducing the accumulation of lipid droplets in the myocardium through suppression of CD36, ACSL1, FABP3, PPARgamma, and DGAT1 and enhancement of the phosphorylation of FOXO1, indicating its inhibition. The EVO-mediated improvement in mitochondrial function and reduction in damage were achieved through activation of PGC1a/NRF1/TFAM, which activates mitochondrial biogenesis. RNA-seq results for the whole heart confirmed that EVO treatment mainly affected the differentially expressed genes (DEGs) related to lipid metabolism. Collectively, these findings demonstrate that EVO improves cardiac function by reducing lipotoxicity and mitochondrial injury and provides a potential therapeutic option for DCM.
Collapse
Affiliation(s)
- Trong Kha Pham
- Cardiovascular and Metabolic Disease Center, Smart Marine Therapeutic Center, Department of Physiology, College of Medicine, Inje University, Busan, South Korea
- Department of Health Sciences and Technology, Graduate School, Inje University, Busan, South Korea
- University of Science, Vietnam National University, Hanoi, Vietnam
| | - To Hoai T Nguyen
- Cardiovascular and Metabolic Disease Center, Smart Marine Therapeutic Center, Department of Physiology, College of Medicine, Inje University, Busan, South Korea
- Department of Health Sciences and Technology, Graduate School, Inje University, Busan, South Korea
| | - Joo Mi Yi
- Department of Microbiology and Immunology, College of Medicine, Inje University, Busan, South Korea
| | - Gwang Sil Kim
- Division of Cardiology, Department of Internal Medicine, Sanggye Paik Hospital, Inje University, Seoul, South Korea
| | - Hyeong Rok Yun
- Cardiovascular and Metabolic Disease Center, Smart Marine Therapeutic Center, Department of Physiology, College of Medicine, Inje University, Busan, South Korea
| | - Hyoung Kyu Kim
- Cardiovascular and Metabolic Disease Center, Smart Marine Therapeutic Center, Department of Physiology, College of Medicine, Inje University, Busan, South Korea.
| | - Jong Chul Won
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Sanggye Paik Hospital, Cardiovascular and Metabolic Disease Center, College of Medicine, Inje University, Seoul, South Korea
| |
Collapse
|
|
7
|
Scheen AJ. Clinical pharmacology of antidiabetic drugs: What can be expected of their use? Presse Med 2023; 52:104158. [PMID: 36565754 DOI: 10.1016/j.lpm.2022.104158] [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: 11/07/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
The pharmacotherapy of type 2 diabetes mellitus (T2DM) has markedly evolved in the last two decades. Classical antidiabetic agents (sulphonylureas, metformin, insulin) are now in competition with new glucose-lowering medications. Alpha-glucosidase inhibitors and thiazolidinediones (glitazones) were not able to replace older agents, because of insufficient efficacy and/or poor tolerability/safety. In contrast, incretin-based therapies, both dipeptidyl peptidase-4 inhibitors (DPP-4is or gliptins, oral agents) and glucagon-like peptide-1 receptor agonists (GLP-1RAs, subcutaneous injections) are a major breakthrough in the management of T2DM. Because they are not associated with hypoglycaemia and weight gain, DPP-4is tend to replace sulphonylureas as add-on to metformin while GLP-1RAs tend to replace basal insulin therapy after failure of oral therapies. Furthermore, placebo-controlled cardiovascular outcome trials demonstrated neutrality for DPP-4is, but cardiovascular protection for GLP-1RAs in patients with T2DM at high cardiovascular risk. More recently sodium-glucose cotransporter 2 inhibitors (SGLT2is or gliflozins, oral agents) also showed cardiovascular protection, especially a reduction in hospitalization for heart failure, as well as a renal protection in patients with and without T2DM, at high cardiovascular risk, with established heart failure and/or with chronic kidney disease. Thus, GLP-1RAs and SGLT2is are now considered as preferred drugs in T2DM patients with or at high risk of atherosclerotic cardiovascular disease whereas SGLT2is are more specifically recommended in patients with or at risk of heart failure and renal (albuminuric) disease. The management of T2DM is moving from a glucocentric approach to a broader strategy focusing on all risk factors, including overweight/obesity, and to an organ-disease targeted personalized approach.
Collapse
Affiliation(s)
- André J Scheen
- Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium; Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium.
| |
Collapse
|
|
8
|
Maleksabet H, Rezaee E, Tabatabai SA. Host-Cell Surface Binding Targets in SARS-CoV-2 for Drug Design. Curr Pharm Des 2022; 28:3583-3591. [PMID: 36420875 DOI: 10.2174/1381612829666221123111849] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 08/20/2022] [Accepted: 08/31/2022] [Indexed: 11/27/2022]
Abstract
The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a major public health threat to all countries worldwide. SARS-CoV-2 interactions with its receptor are the first step in the invasion of the host cell. The coronavirus spike protein (S) is crucial in binding to receptors on host cells. Additionally, targeting the SARS-CoV-2 viral receptors is considered a therapeutic option in this regard. In this review of literature, we summarized five potential host cell receptors, as host-cell surface bindings, including angiotensin-converting enzyme 2 (ACE2), neuropilin 1 (NRP-1), dipeptidyl peptidase 4 (DPP4), glucose regulated protein-78 (GRP78), and cluster of differentiation 147 (CD147) related to the SARS-CoV-2 infection. Among these targets, ACE2 was recognized as the main SARS-CoV-2 receptor, expressed at a low/moderate level in the human respiratory system, which is also involved in SARS-CoV-2 entrance, so the virus may utilize other secondary receptors. Besides ACE2, CD147 was discovered as a novel SARS-CoV-2 receptor, CD147 appears to be an alternate receptor for SARSCoV- 2 infection. NRP-1, as a single-transmembrane glycoprotein, has been recently found to operate as an entrance factor and enhance SARS Coronavirus 2 (SARS-CoV-2) infection under in-vitro. DPP4, which was discovered as the first gene clustered with ACE2, may serve as a potential SARS-CoV-2 spike protein binding target. GRP78 could be recognized as a secondary receptor for SARS-CoV-2 because it is widely expressed at substantially greater levels, rather than ACE2, in bronchial epithelial cells and the respiratory mucosa. This review highlights recent literature on this topic.
Collapse
Affiliation(s)
- Hanieh Maleksabet
- Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elham Rezaee
- Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sayyed Abbas Tabatabai
- Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
9
|
da Cruz Freire JE, Júnior JEM, Pinheiro DP, da Cruz Paiva Lima GE, do Amaral CL, Veras VR, Madeira MP, Freire EBL, Ozório RG, Fernandes VO, Montenegro APDR, Montenegro RC, Colares JKB, Júnior RMM. Evaluation of the anti-diabetic drug sitagliptin as a novel attenuate to SARS-CoV-2 evidence-based in silico: molecular docking and molecular dynamics. 3 Biotech 2022; 12:344. [PMCID: PMC9640538 DOI: 10.1007/s13205-022-03406-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 09/30/2022] [Indexed: 11/09/2022] Open
Abstract
The current outbreak of COVID-19 cases worldwide has been responsible for a significant number of deaths, especially in hospitalized patients suffering from comorbidities, such as obesity, diabetes, hypertension. The disease not only has prompted an interest in the pathophysiology, but also it has propelled a massive race to find new anti-SARS-CoV-2 drugs. In this scenario, known drugs commonly used to treat other diseases have been suggested as alternative or complementary therapeutics. Herein we propose the use of sitagliptin, an inhibitor of dipeptidyl peptidase-4 (DPP4) used to treat type-II diabetes, as an agent to block and inhibit the activity of two proteases, 3CLpro and PLpro, related to the processing of SARS-CoV-2 structural proteins. Inhibition of these proteases may possibly reduce the viral load and infection on the host by hampering the synthesis of new viruses, thus promoting a better outcome. In silico assays consisting in the modeling of the ligand sitagliptin and evaluation of its capacity to interact with 3CLpro and PLpro through the prediction of the ligand bioactivity, molecular docking, overlapping of crystal structures, and molecular dynamic simulations were conducted. The experiments indicate that sitagliptin can interact and bind to both targets. However, this interaction seems to be stronger and more stable to 3CLpro (ΔG = −7.8 kcal mol−1), when compared to PLpro (ΔG = −7.5 kcal mol−1). This study suggests that sitagliptin may be suitable to treat COVID-19 patients, beyond its common use as an anti-diabetic medication. In vivo studies may further support this hypothesis.
Collapse
|
|
10
|
Scheen AJ. Glucose-lowering agents and risk of ventricular arrhythmias and sudden cardiac death: a comprehensive review ranging from sulphonylureas to SGLT2 inhibitors. DIABETES & METABOLISM 2022; 48:101405. [DOI: 10.1016/j.diabet.2022.101405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 10/17/2022] [Accepted: 10/17/2022] [Indexed: 11/05/2022]
|
|
11
|
Luo J, Feldman R, Rothenberger S, Korytkowski M, Fischer MA, Gellad WF. Incidence and Predictors of Primary Nonadherence to Sodium Glucose Co-transporter 2 Inhibitors and Glucagon-Like Peptide 1 Agonists in a Large Integrated Healthcare System. J Gen Intern Med 2022; 37:3562-3569. [PMID: 35048301 PMCID: PMC9585108 DOI: 10.1007/s11606-021-07331-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 12/14/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND Newer glucose-lowering drugs, including sodium glucose co-transporter 2 inhibitors (SGLT2i) and GLP-1 agonists, have a key role in the pharmacologic management of type 2 diabetes. No studies have measured primary nonadherence for these two drug classes, defined as when a medication is prescribed for a patient but ultimately not dispensed to them. OBJECTIVE To describe the incidence and predictors of primary nonadherence to SGLT2i (canagliflozin, empagliflozin) or GLP-1 agonists (dulaglutide, liraglutide, semaglutide) using a dataset that links electronic prescribing with health insurance claims. DESIGN AND PARTICIPANTS A retrospective cohort design using data of adult patients from a large health system who had at least one prescription order for a SGLT2i or GLP-1 agonist between 2012 and 2019. We used mixed-effects multivariable logistic regression to determine associations between sociodemographic, clinical, and provider variables and primary nonadherence. MAIN MEASURES Primary medication nonadherence, defined as no dispensed claim within 30 days of an electronic prescription order for any drug within each medication class. KEY RESULTS The cohort included 5146 patients newly prescribed a SGLT2i or GLP-1 agonist. The overall incidence of 30-day primary medication nonadherence was 31.8% (1637/5146). This incidence rate was 29.8% (n = 726) and 33.6% (n = 911) among those initiating a GLP-1 agonist and SGLT2i, respectively. Age ≥ 65 (aOR 1.37 (95% CI 1.09 to 1.72)), Black race vs White (aOR 1.29 (95% CI 1.02 to 1.62)), diabetic nephropathy (aOR 1.31 (95% CI 1.02 to 1.68)), and hyperlipidemia (aOR 1.18 (95% CI 1.01 to 1.39)) were associated with a higher odds of primary nonadherence. Female sex (aOR 0.86 (95% CI 0.75 to 0.99)), peripheral artery disease (aOR 0.73 (95% CI 0.56 to 0.94)), and having the index prescription ordered by an endocrinologist vs a primary care provider (aOR 0.76 (95% CI 0.61 to 0.95)) were associated with lower odds of primary nonadherence. CONCLUSIONS One third of patients prescribed SGLT2i or GLP-1 agonists in this sample did not fill their prescription within 30 days. Black race, male sex, older age, having greater baseline comorbidities, and having a primary care provider vs endocrinologist prescribe the index drug were associated with higher odds of primary nonadherence. Interventions targeting medication adherence for these newer drugs must consider primary nonadherence as a barrier to optimal clinical care.
Collapse
Affiliation(s)
- Jing Luo
- Division of General Internal Medicine, University of Pittsburgh School of Medicine, Pittsburg, PA, USA.
| | - Robert Feldman
- Division of General Internal Medicine, University of Pittsburgh School of Medicine, Pittsburg, PA, USA
| | - Scott Rothenberger
- Division of General Internal Medicine, University of Pittsburgh School of Medicine, Pittsburg, PA, USA
| | - Mary Korytkowski
- Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Michael A Fischer
- Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, Boston, MA, USA
| | - Walid F Gellad
- Division of General Internal Medicine, University of Pittsburgh School of Medicine, Pittsburg, PA, USA
- Center for Health Equity Research and Promotion, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA
| |
Collapse
|
|
12
|
Saher T, Al-Worafi YM, Iqbal MN, Wahid A, Iqbal Q, Khan A, Atif M, Ahmad N. Doctors' adherence to guidelines recommendations and glycaemic control in diabetic patients in Quetta, Pakistan: Findings from an observational study. Front Med (Lausanne) 2022; 9:978345. [PMID: 36388939 PMCID: PMC9661729 DOI: 10.3389/fmed.2022.978345] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 10/12/2022] [Indexed: 01/25/2024] Open
Abstract
Background Poor control of diabetes mellitus (DM) is partly attributed to doctors' poor adherence to guidelines. Objective To evaluate doctors' adherence to pharmacotherapeutic recommendations of DM management guidelines and factors associated with guidelines adherence and glycaemic control. Methods This prospective observational study included 30 doctors who were treating DM patients in their private clinics in Quetta, Pakistan. On visit 1, a total of 600 prescriptions written by 30 enrolled doctors (20 patients per doctor) were noted along with patients' sociodemographic and clinical characteristics. American Diabetes Association guidelines was used as a reference. The prescriptions noted were judged for guidelines compliance. Of 600 enrolled patients, 450 patients (15 patients per doctor) were followed for one more visit and included in final analysis. Glycated hemoglobin (HbA1c) level noted one visit 2 was related with the respective prescription on visit 1. Data were analyzed by SPSS (version 23). A p-value <0.05 was considered statistically significant. Results Patients received a median of two antidiabetic drugs (range: 1-5). A total of 73.1% patients were on polytherapy. Metformin was the most frequently prescribed (88.4%) antidiabetic followed by gliptins (46.2%). A total of 41.6% prescriptions were judged guidelines compliant. In multivariate binary logistic regressions (MVBLR) analysis, chronic kidney disease (CKD) (OR = 0.422) and polytherapy (OR = 0.367) had statistically significant negative associations (p-value <0.05) with guidelines' compliant prescriptions. The group of doctors comprised of specialists and consultants wrote significantly (p-value = 0.004) high number of guidelines adherent prescriptions (mean rank = 20.25) than the group comprised of medical officers (mean rank = 11.34). On visit 2, only 39.5% patients were on goal glycemic levels. In MVBLR analysis, suffering from dyslipidemia (OR = 0.134) and CKD (OR = 0.111), receiving sulfonylurea (OR = 0.156) and guidelines' compliant prescription (OR = 4.195) were significantly (p-value <0 .05) associated with glycemic control. Conclusion Although guidelines compliant prescriptions produced better glycemic control, but doctors' adherence to guidelines and glycemic control were poor. Polytherapy and CKD emerged as risk factors for guidelines divergent prescriptions. Dyslipidemia, CKD and reception of sulfonylureas had negative association with glycemic control.
Collapse
Affiliation(s)
- Tabassum Saher
- Department of Pharmacy Practice, Faculty of Pharmacy and Health Sciences, University of Baluchistan, Quetta, Pakistan
| | - Yaser Mohammed Al-Worafi
- Department of Clinical Sciences, College of Pharmacy, University of Science and Technology of Fujairah, Fujairah, United Arab Emirates
| | | | - Abdul Wahid
- Department of Pharmacy Practice, Faculty of Pharmacy and Health Sciences, University of Baluchistan, Quetta, Pakistan
| | - Qaiser Iqbal
- Department of Pharmaceutics, Faculty of Pharmacy and Health Sciences, University of Baluchistan, Quetta, Pakistan
| | - Asad Khan
- Department of Pharmacy Practice, Faculty of Pharmacy and Health Sciences, University of Baluchistan, Quetta, Pakistan
| | - Muhammad Atif
- Department of Pharmacy Practice, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
| | - Nafees Ahmad
- Department of Pharmacy Practice, Faculty of Pharmacy and Health Sciences, University of Baluchistan, Quetta, Pakistan
| |
Collapse
|
|
13
|
Davies MJ, Drexel H, Jornayvaz FR, Pataky Z, Seferović PM, Wanner C. Cardiovascular outcomes trials: a paradigm shift in the current management of type 2 diabetes. Cardiovasc Diabetol 2022; 21:144. [PMID: 35927730 PMCID: PMC9351217 DOI: 10.1186/s12933-022-01575-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 05/14/2022] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in patients with type 2 diabetes (T2D). Historical concerns about cardiovascular (CV) risks associated with certain glucose-lowering medications gave rise to the introduction of cardiovascular outcomes trials (CVOTs). Initially implemented to help monitor the CV safety of glucose-lowering drugs in patients with T2D, who either had established CVD or were at high risk of CVD, data that emerged from some of these trials started to show benefits. Alongside the anticipated CV safety of many of these agents, evidence for certain sodium-glucose transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have revealed potential cardioprotective effects in patients with T2D who are at high risk of CVD events. Reductions in 3-point major adverse CV events (3P-MACE) and CV death have been noted in some of these CVOTs, with additional benefits including reduced risks of hospitalisation for heart failure, progression of renal disease, and all-cause mortality. These new data are leading to a paradigm shift in the current management of T2D, with international guidelines now prioritising SGLT2 inhibitors and/or GLP-1 RAs in certain patient populations. However, clinicians are faced with a large volume of CVOT data when seeking to use this evidence base to bring opportunities to improve CV, heart failure and renal outcomes, and even reduce mortality, in their patients with T2D. The aim of this review is to provide an in-depth summary of CVOT data-crystallising the key findings, from safety to efficacy-and to offer a practical perspective for physicians. Finally, we discuss the next steps for the post-CVOT era, with ongoing studies that may further transform clinical practice and improve outcomes for people with T2D, heart failure or renal disease.
Collapse
Affiliation(s)
- Melanie J Davies
- Diabetes Research Centre, University of Leicester, Leicester, UK
- NIHR Leicester Biomedical Research Centre, Leicester, UK
- University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Heinz Drexel
- Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Landeskrankenhaus Feldkirch, Feldkirch, Austria
| | - François R Jornayvaz
- Service of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, WHO Collaborating Centre, Geneva University Hospital/Geneva University, Geneva, Switzerland
| | - Zoltan Pataky
- Service of Endocrinology, Diabetes, Nutrition and Therapeutic Patient Education, WHO Collaborating Centre, Geneva University Hospital/Geneva University, Geneva, Switzerland
| | - Petar M Seferović
- University of Belgrade, Faculty of Medicine, Belgrade, Serbia.
- Serbian Academy of Sciences and Arts, Belgrade, Serbia.
| | | |
Collapse
|
|
14
|
Liang J, Zhang L, Huang Z, He Y, Ling Y, Chen K, Ying M, Lin M, Li G, Liu J, Liu Y, Liang Y, Chen S, Hu Y. Implications of Malnutrition on Contrast-Associated Acute Kidney Injury in Young and Old Patients Undergoing Percutaneous Coronary Intervention: A Multicenter Prospective Cohort. Front Nutr 2022; 8:795068. [PMID: 35211494 PMCID: PMC8861456 DOI: 10.3389/fnut.2021.795068] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/21/2021] [Indexed: 01/01/2023] Open
Abstract
BackgroundThe relationship between malnutrition and the risk of contrast-associated acute kidney injury (CA-AKI) and the resulting prognosis in patients undergoing percutaneous coronary intervention (PCI) is still not well known.MethodsPatients undergoing PCI were consecutively enrolled in a multicenter study in China (NCT01402232), categorized by nutritional status (non-malnutrition, malnutrition) based on two different cut-off values (i.e., traditional threshold and the best cut-off value based on the receiver operating characteristic (ROC) curve) for the controlling nutritional status (CONUT) score. The primary endpoint was CA-AKI, diagnosed as a rise in serum creatinine >0.3 mg/dl or >50% than the baseline level occurring within 48 h after the intervention. The secondary endpoint was all-cause mortality. The relationships of malnutrition, CA-AKI, and all-cause mortality were examined using multivariate-adjusted logistic and Cox regression analyses, respectively.ResultsAmong 2,083 patients undergoing PCI (age: 62.8 ± 11.1 years; 79.0% men), 1,258 (60.4%) were malnourished. During hospitalization, 80 (3.8%) patients developed CA-AKI events. The incidence of CA-AKI in patients who did not have malnutrition (the non-malnutrition group) and those who did have malnutrition (the malnutrition group) was 1.7% and 5.25%, respectively. Patients with malnutrition had a 2-fold increased adjusted risk of CA-AKI compared to those with no malnutrition [adjusted odds ratio (aOR) (95% confidence interval CI): 2.41 (1.22 to 5.22)]. Malnutrition was associated with a 3-fold increased adjusted risk of CA-AKI in patients aged ≤ 75 years [N = 1,791, aOR (95% CI): 3.39 (1.46–9.25)]. Malnourished patients with CA-AKI had a higher risk of all-cause mortality than the others. Similar results were observed in the grouping of Supplemental Analyses based on the optimal cut-off value of the CONUT score identified by the ROC curve.ConclusionsMalnutrition is strongly associated with an increased risk of CA-AKI in both young and old patients undergoing PCI. Malnourished patients with CA-AKI had a significantly higher risk of all-cause mortality. Further studies are needed to prospectively assess the efficacy of nutritional interventions on outcomes in patients undergoing PCI.
Collapse
Affiliation(s)
- Jingjing Liang
- Department of Cardiology, Shunde Hospital, Southern Medical University, Foshan, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Lingyu Zhang
- Department of Cardiology, Maoming People's Hospital, Maoming, China
| | - Zhidong Huang
- Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yibo He
- Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yihang Ling
- Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Kai Chen
- Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Ming Ying
- Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Mengfei Lin
- Department of Cardiology, Maoming People's Hospital, Maoming, China
| | - Guode Li
- Department of Cardiology, Maoming People's Hospital, Maoming, China
| | - Jin Liu
- Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yong Liu
- Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yan Liang
- Department of Cardiology, Maoming People's Hospital, Maoming, China
- *Correspondence: Yan Liang
| | - Shiqun Chen
- Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- Shiqun Chen
| | - Yunzhao Hu
- Department of Cardiology, Shunde Hospital, Southern Medical University, Foshan, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
- Yunzhao Hu
| |
Collapse
|
|
15
|
Zein AFMZ, Raffaello WM. Dipeptidyl peptidase-4 (DPP-IV) inhibitor was associated with mortality reduction in COVID-19 - A systematic review and meta-analysis. Prim Care Diabetes 2022; 16:162-167. [PMID: 34952805 PMCID: PMC8666291 DOI: 10.1016/j.pcd.2021.12.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 12/06/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023]
Abstract
INTRODUCTION This systematic review and meta-analysis aimed to synthesize the latest evidence on the effect of dipeptidyl peptidase-4 (DPP-IV) inhibitor in patients with COVID-19. METHODS We performed a systematic literature search from the PubMed, Scopus, Embase, and Clinicaltrials.gov up until 15 July 2021. Studies that met the following criteria were included: prospective or retrospective observational studies or case series or randomized controlled trials (RCTs) reporting DPP-IV inhibitor use in patients with COVID-19 and mortality. The intervention group was patients receiving DPP-IV inhibitor. The control group was patients that did not receive DPP-IV inhibitor. The outcome was mortality reported as odds ratio (OR). RESULTS There were 11 studies consisting of 5950 patients in this meta-analysis. DPP-IV inhibitor use was associated with reduced mortality (OR 0.75 [0.56, 0.99], p = 0.043, I2: 42.9, p = 0.064) compared to those that did not receive DPP-IV inhibitor. Sensitivity analysis using the fixed-effect model (OR 0.75 [0.63, 0.88], p < 0.001, I2: 42.9, p = 0.064) also showed mortality benefit. The association between DPP-IV inhibitor and mortality was not significantly affected by age (p = 0.540), sex (p = 0.054), hypertension (p = 0.320), location (continent; p = 0.532), and retrospective/prospective nature of the study (p = 0.840). However, the association was affected by metformin (OR 1.03 [95% CI 1.01, 1.06], p = 0.010) and ACEI/ARB use (OR 1.06 [95% CI 1.02, 1.10], p = 0.004). CONCLUSION This meta-analysis showed that DPP-IV inhibitor was associated with reduced mortality in patients with COVID-19.
Collapse
Affiliation(s)
- Ahmad Fariz Malvi Zamzam Zein
- Department of Internal Medicine, Faculty of Medicine, Universitas Swadaya Gunung Jati, Cirebon, Indonesia; Department of Internal Medicine, Waled General Hospital, Cirebon, Indonesia.
| | | |
Collapse
|
|
16
|
Jiang C, Xie S, Yang G, Wang N. Spotlight on NLRP3 Inflammasome: Role in Pathogenesis and Therapies of Atherosclerosis. J Inflamm Res 2022; 14:7143-7172. [PMID: 34992411 PMCID: PMC8711145 DOI: 10.2147/jir.s344730] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammation is an intricate biological response of body tissues to detrimental stimuli. Cardiovascular disease (CVD) is the leading cause of death worldwide, and inflammation is well documented to play a role in the development of CVD, especially atherosclerosis (AS). Emerging evidence suggests that activation of the NOD-like receptor (NLR) family and the pyridine-containing domain 3 (NLRP3) inflammasome is instrumental in inflammation and may result in AS. The NLRP3 inflammasome acts as a molecular platform that triggers the activation of caspase-1 and the cleavage of pro-interleukin (IL)-1β, pro-IL-18, and gasdermin D (GSDMD). The cleaved GSDMD forms pores in the cell membrane and initiates pyroptosis, inducing cell death and the discharge of intracellular pro-inflammatory factors. Hence, the NLRP3 inflammasome is a promising target for anti-inflammatory therapy against AS. In this review, we systematically summarized the current understanding of the activation mechanism of NLRP3 inflammasome, and the pathological changes in AS involving NLRP3. We also discussed potential therapeutic strategies targeting NLRP3 inflammasome to combat AS.
Collapse
Affiliation(s)
- Chunteng Jiang
- Department of Internal Medicine, The Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, People's Republic of China.,Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg-August-University of Göttingen, Göttingen, Lower Saxony, Germany
| | - Santuan Xie
- Department of Internal Medicine, The Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, People's Republic of China
| | - Guang Yang
- Department of Food Nutrition and Safety, School of Public Health, Dalian Medical University, Dalian, Liaoning, People's Republic of China
| | - Ningning Wang
- Department of Food Nutrition and Safety, School of Public Health, Dalian Medical University, Dalian, Liaoning, People's Republic of China
| |
Collapse
|
|
17
|
Prattichizzo F, de Candia P, Nicolucci A, Ceriello A. Elevated HbA1c levels in pre-Covid-19 infection increases the risk of mortality: A sistematic review and meta-analysis. Diabetes Metab Res Rev 2022; 38:e3476. [PMID: 34018307 PMCID: PMC8209812 DOI: 10.1002/dmrr.3476] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 05/12/2021] [Accepted: 05/17/2021] [Indexed: 01/08/2023]
Abstract
AIMS Diabetes is emerging as a risk factor for coronavirus disease (COVID)-19 prognosis. However, contradictory findings have been reported regarding the impact of glycaemic control on COVID-19 outcome. The aim of this meta-analysis was to explore the impact of hospital pre-admission or at-admission values of HbA1c on COVID-19 mortality or worsening in patients with diabetes. MATERIALS AND METHODS We searched PubMed, Embase and Scopus up to 30th December 2020. Eligibility criteria for study selection were the following: (1)enrolling patients with any form of diabetes mellitus and hospitalized for COVID-19 and (2) reporting data regarding HbA1c values before infection or at hospital admission in relation to COVID-19 mortality or worsening. Descriptive statistics, HbA1c values, odds ratios (ORs) and hazard ratios were extracted from seven observational studies and generic inverse variance (random effects) of OR was used to estimate the effect of HbA1c on COVID-19 outcome. RESULTS HbA1c was linearly associated with an increased COVID-19 mortality or worsening when considered as a continuous variable (OR 1.01 [1.01, 1.01]; p < 0.00001). Similarly, when analysing studies providing the number of events according to the degree of glycaemic control among various strata, a significantly increased risk was observed with poor glycaemic control (OR 1.15 [1.11, 1.19]; p < 0.00001), a result corroborated by sensitivity analysis. CONCLUSIONS Notwithstanding the large heterogeneity in study design and patients' characteristics in the few available studies, data suggest that patients with diabetes and poor glycaemic control before infection might have an increased risk of COVID-19 related mortality.
Collapse
Affiliation(s)
| | | | - Antonio Nicolucci
- Centre for Outcomes Research and Clinical Epidemiology (CORESEARCH)PescaraItaly
| | | |
Collapse
|
|
18
|
Abstract
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the general population. Energy metabolism disturbance is one of the early abnormalities in CVDs, such as coronary heart disease, diabetic cardiomyopathy, and heart failure. To explore the role of myocardial energy homeostasis disturbance in CVDs, it is important to understand myocardial metabolism in the normal heart and their function in the complex pathophysiology of CVDs. In this article, we summarized lipid metabolism/lipotoxicity and glucose metabolism/insulin resistance in the heart, focused on the metabolic regulation during neonatal and ageing heart, proposed potential metabolic mechanisms for cardiac regeneration and degeneration. We provided an overview of emerging molecular network among cardiac proliferation, regeneration, and metabolic disturbance. These novel targets promise a new era for the treatment of CVDs.
Collapse
Affiliation(s)
- Lu-Yun WANG
- Division of Cardiology, Tongji Hospital, Tongji Medical College and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, China
| | - Chen CHEN
- Division of Cardiology, Tongji Hospital, Tongji Medical College and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
19
|
Rezki A, Cosson E, Fysekidis M, Chiheb S, Vicaut E, Valensi P. Acute and long-term effects of saxagliptin on a set of cardiovascular targets measured at fasting and post-prandially in obese patients with impaired glucose tolerance: A placebo-controlled study. Nutr Metab Cardiovasc Dis 2021; 31:2945-2958. [PMID: 34420816 DOI: 10.1016/j.numecd.2021.06.017] [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: 12/05/2020] [Revised: 06/15/2021] [Accepted: 06/19/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND AND AIMS Studies of dipeptidyl peptidase inhibitors (DPP4is) report heterogeneous effects on cardiovascular targets in type 2 diabetes. This study aimed to investigate, in patients with impaired glucose tolerance (IGT), whether saxagliptin, a DPP4i, had beneficial cardiovascular effects at fasting and during the post-prandial state. METHODS AND RESULTS In this randomized, placebo-controlled, double-blind, single-center pilot exploratory study, we included obese individuals with IGT. Twenty-four individuals (BMI 36.8 ± 4.8 kg/m2) were randomized to receive for 12 weeks either saxagliptin 5 mg a day or placebo. They were explored before and after a standardized breakfast for biological markers; microcirculatory blood flow at baseline and after transcutaneous administration of acetylcholine (Periflux System 5000® PERIMED); post-occlusive digital reactive hyperhemia (Endopat2000®); pulse wave velocity, augmentation index, central pulse pressure and subendocardial viability ratio (Sphygmocor®); cardiac hemodynamic parameters and cardiovascular autonomic nervous system activity (Task force monitor®). The results of all the investigations were similar after breakfast in the two groups at Visit 1 (acute post-prandial effects, after the first tablet) and Visit 2 (long-term post-prandial effects), and at fasting at Visit 1 and 2 (long-term effects, after 12 weeks of treatment). Only at Visit 2 the decrease in cardiac vagal activity occurring after breakfast was more sustained in the saxagliptin group than in the placebo group (interaction between treatment and time effect: p = 0.016). CONCLUSION In obese patients with IGT, the effects of saxagliptin on the large set of cardiovascular parameters measured are neutral, except for a more marked post-prandial depression of vagal activity. CLINICAL TRIAL REGISTRATION NUMBER NCT01521312.
Collapse
Affiliation(s)
- Amel Rezki
- AP-HP, Department of Endocrinology-Diabetology-Nutrition, CRNH-IdF, CINFO, Paris 13 University, Jean Verdier Hospital, Bondy, France; Paris 13 University, Sorbonne Paris Cité, UMR U557 INSERM/U11125 INRA/CNAM/Université Paris13, Unité de Recherche Epidémiologique Nutritionnelle, Bobigny, France
| | - Emmanuel Cosson
- AP-HP, Department of Endocrinology-Diabetology-Nutrition, CRNH-IdF, CINFO, Paris 13 University, Jean Verdier Hospital, Bondy, France; Paris 13 University, Sorbonne Paris Cité, UMR U557 INSERM/U11125 INRA/CNAM/Université Paris13, Unité de Recherche Epidémiologique Nutritionnelle, Bobigny, France
| | - Marinos Fysekidis
- AP-HP, Department of Endocrinology-Diabetology-Nutrition, CRNH-IdF, CINFO, Paris 13 University, Jean Verdier Hospital, Bondy, France; Paris 13 University, Sorbonne Paris Cité, UMR U557 INSERM/U11125 INRA/CNAM/Université Paris13, Unité de Recherche Epidémiologique Nutritionnelle, Bobigny, France
| | - Sabrina Chiheb
- AP-HP, Department of Endocrinology-Diabetology-Nutrition, CRNH-IdF, CINFO, Paris 13 University, Jean Verdier Hospital, Bondy, France
| | - Eric Vicaut
- Université Denis Diderot, AP-HP Unité de Recherche Clinique St-Louis-Lariboisière, Paris, France
| | - Paul Valensi
- AP-HP, Department of Endocrinology-Diabetology-Nutrition, CRNH-IdF, CINFO, Paris 13 University, Jean Verdier Hospital, Bondy, France.
| |
Collapse
|
|
20
|
Scheen AJ. Efficacy / safety balance of DPP-4 inhibitors versus SGLT2 inhibitors in elderly patients with type 2 diabetes. DIABETES & METABOLISM 2021; 47:101275. [PMID: 34481962 DOI: 10.1016/j.diabet.2021.101275] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 08/07/2021] [Indexed: 12/14/2022]
Abstract
Dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium-glucose cotransporter type 2 inhibitors (SGLT2is) offer new options for the oral management of type 2 diabetes mellitus (T2DM), with the advantage in the elderly population to be devoid of a high risk of hypoglycaemia. SGLT2is have also shown benefits regarding cardiovascular (heart failure) and renal protection, including in patients with T2DM aged ≥ 65 years while DPP-4is have only proved cardiovascular and renal safety without superiority compared with placebo. The glucose-lowering efficacy of the two pharmacological classes is almost similar including in older patients with T2DM. However, the tolerance and safety profile may be highly different and overall more favourable with DPP-4is than with SGLT2is. Some adverse events have been reported with SGLT2is which may be more prevalent or severe in older patients than in younger patients. The present comprehensive review focuses on the benefit/risk balance in the elderly population with T2DM by comparing the profile of DPP-4is and SGLT2is regarding the following potential issues: metabolic disorders (hypoglycaemia and diabetic ketoacidosis); cardiac and vascular issues (atheromatous cardiovascular disease, heart failure, volume reduction hypotension, and lower limb amputations); renal endpoints including acute renal injury; risk of infections; digestive disorders; bone and skin adverse events; and cancer risk. Both DPP-4is and SGLT2is have their own advantages and disadvantages. Personalised treatment is recommended based upon the efficacy/safety profile of each drug class and individual patient characteristics that may be markedly different among the heterogeneous population of older individuals with T2DM.
Collapse
Affiliation(s)
- André J Scheen
- Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium; Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium.
| |
Collapse
|
|
21
|
Amatruda M, Gembillo G, Giuffrida AE, Santoro D, Conti G. The Aggressive Diabetic Kidney Disease in Youth-Onset Type 2 Diabetes: Pathogenetic Mechanisms and Potential Therapies. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:868. [PMID: 34577791 PMCID: PMC8467670 DOI: 10.3390/medicina57090868] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 08/21/2021] [Accepted: 08/22/2021] [Indexed: 02/07/2023]
Abstract
Youth-onset Type 2 Diabetes Mellitus (T2DM) represents a major burden worldwide. In the last decades, the prevalence of T2DM became higher than that of Type 1 Diabetes Mellitus (T1DM), helped by the increasing rate of childhood obesity. The highest prevalence rates of youth-onset T2DM are recorded in China (520 cases/100,000) and in the United States (212 cases/100,000), and the numbers are still increasing. T2DM young people present a strong hereditary component, often unmasked by social and environmental risk factors. These patients are affected by multiple coexisting risk factors, including obesity, hyperglycemia, dyslipidemia, insulin resistance, hypertension, and inflammation. Juvenile T2DM nephropathy occurs earlier in life compared to T1DM-related nephropathy in children or T2DM-related nephropathy in adult. Diabetic kidney disease (DKD) is T2DM major long term microvascular complication. This review summarizes the main mechanisms involved in the pathogenesis of the DKD in young population and the recent evolution of treatment, in order to reduce the risk of DKD progression.
Collapse
Affiliation(s)
- Michela Amatruda
- Unit of Pediatric Nephrology with Dialysis, AOU Policlinic G Martino, University of Messina, 98125 Messina, Italy;
| | - Guido Gembillo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (G.G.); (A.E.G.); (D.S.)
- Department of Biomedical and Dental Sciences and Morpho-functional Imaging, University of Messina, 98125 Messina, Italy
| | - Alfio Edoardo Giuffrida
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (G.G.); (A.E.G.); (D.S.)
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy; (G.G.); (A.E.G.); (D.S.)
| | - Giovanni Conti
- Unit of Pediatric Nephrology with Dialysis, AOU Policlinic G Martino, University of Messina, 98125 Messina, Italy;
| |
Collapse
|
|
22
|
Mansour SM, Aly S, Hassan SHM, Zaki HF. Protective effect of sitagliptin and whole-body γ-irradiation in diabetes-induced cardiac injury. Can J Physiol Pharmacol 2021; 99:676-684. [PMID: 33108742 DOI: 10.1139/cjpp-2020-0454] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Diabetes mellitus is associated with an increased risk of cardiac complications; this study aimed to investigate effect of sitagliptin (SITA) alone or combined with γ-irradiation on diabetes-associated cardiac injury. Rats were treated with SITA (100 mg/kg per day; p.o.) for 2 weeks followed by a single dose of whole-body γ-irradiation (3 Gy). Solitary administration of SITA or combined treatment with γ-irradiation succeeded to ameliorate the increase in serum levels of glucose, total cholesterol, triglycerides, creatine kinase-MB, and malondialdehyde, coupled by increased insulin and reduced glutathione levels. Their cardioprotective potential was confirmed through attenuating the apoptotic signaling by mitigating Bcl-2-associated X protein, caspase-3, and apoptosis-inducing factor expression, while augmenting the anti-apoptotic factors, B cell lymphoma-2 (Bcl-2), and heat shock protein 70 (HSP-70) in left ventricular tissue homogenates. These findings were supported histopathologically. In conclusion, treatment with SITA alone or combined with γ-irradiation may prove beneficial in diabetes-accompanied cardiac insult. This could be due to the crosstalk between the antioxidant, anti-apoptotic, and restoration of body's defense capacities.
Collapse
Affiliation(s)
- Suzan M Mansour
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
- Department of Pharmacology, Toxicology and Biochemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, Egypt
| | - Sara Aly
- Drug Radiation Research Department, National Centre for Radiation Research and Technology (NCRRT)-Atomic Energy Authority, Cairo, Egypt
| | - Seham H M Hassan
- Drug Radiation Research Department, National Centre for Radiation Research and Technology (NCRRT)-Atomic Energy Authority, Cairo, Egypt
| | - Hala F Zaki
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
| |
Collapse
|
|
23
|
Park SH, Jeong HE, Oh IS, Hong SM, Yu SH, Lee CB, Shin JY. Cardiovascular safety of evogliptin in patients with type 2 diabetes: A nationwide cohort study. Diabetes Obes Metab 2021; 23:1232-1241. [PMID: 33502058 DOI: 10.1111/dom.14330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/18/2021] [Accepted: 01/23/2021] [Indexed: 12/17/2022]
Abstract
AIM To assess whether the use of evogliptin, a novel dipeptidyl peptidase-4 inhibitor (DPP-4i), was associated with an increased risk of cardiovascular events compared with glimepiride in patients with type 2 diabetes (T2D). METHODS We conducted a population-based cohort study using South Korea's nationwide healthcare database from 1 January 2014 to 31 December 2018. We identified a base cohort of patients with T2D who newly initiated metformin monotherapy, from which we identified a study cohort of patients who either added or switched to glimepiride or DPP-4is (including evogliptin). Patients were followed up from initiation of DPP-4is or glimepiride until the earliest of either outcome occurrence or 31 December 2018. Our primary outcome was hospitalization or an emergency visit for cardiovascular events, a composite endpoint comprised of cerebrovascular events, heart failure, myocardial infarction, transient ischaemic attack, angina pectoris and revascularization procedures; secondary outcomes were the individual components of the primary outcome. A multivariable Cox proportional hazards model was used to estimate adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for the risk of study outcomes associated with evogliptin compared with glimepiride. RESULTS Our base and study cohorts had 317,307 and 128,788 patients, respectively, of which 100,038 were DPP-4i users (2946 were evogliptin users) and 28,750 were glimepiride users within the study cohort. The median follow-up was 195 days for evogliptin and 113 days for glimepiride users. Compared with glimepiride, evogliptin was associated with a reduced risk of the primary outcome (aHR 0.67, 95% CI 0.48-0.95) and cerebrovascular events (aHR 0.41, 95% CI 0.22-0.78) but showed non-significant associations for myocardial infarction (aHR 0.63, 95% CI 0.27-1.46), heart failure (aHR 0.35, 95% CI 0.09-1.47), transient ischaemic attack (aHR 0.23, 95% CI 0.03-1.72) and angina pectoris (aHR 1.35, 95% CI 0.82-2.21). CONCLUSIONS Findings from this population-based cohort study provide novel real-world evidence that the use of evogliptin, compared with glimepiride, did not increase the risk of cardiovascular events, including cerebrovascular events, myocardial infarction, heart failure, transient ischaemic attack and angina pectoris.
Collapse
Affiliation(s)
- So-Hee Park
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| | - Han Eol Jeong
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| | - In-Sun Oh
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
| | - Sang-Mo Hong
- Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Republic of Korea
| | - Sung Hoon Yu
- Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Republic of Korea
| | - Chang Beom Lee
- Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Republic of Korea
| | - Ju-Young Shin
- School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
- Department of Clinical Research Design & Evaluation, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Republic of Korea
| |
Collapse
|
|
24
|
Nusca A, Tuccinardi D, Pieralice S, Giannone S, Carpenito M, Monte L, Watanabe M, Cavallari I, Maddaloni E, Ussia GP, Manfrini S, Grigioni F. Platelet Effects of Anti-diabetic Therapies: New Perspectives in the Management of Patients with Diabetes and Cardiovascular Disease. Front Pharmacol 2021; 12:670155. [PMID: 34054542 PMCID: PMC8149960 DOI: 10.3389/fphar.2021.670155] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 04/16/2021] [Indexed: 12/14/2022] Open
Abstract
In type 2 diabetes, anti-thrombotic management is challenging, and current anti-platelet agents have demonstrated reduced efficacy. Old and new anti-diabetic drugs exhibited—besides lowering blood glucose levels—direct and indirect effects on platelet function and on thrombotic milieu, eventually conditioning cardiovascular outcomes. The present review summarizes existing evidence on the effects of glucose-lowering agents on platelet properties, addressing pre-clinical and clinical research, as well as drug–drug interactions with anti-platelet agents. We aimed at expanding clinicians’ understanding by highlighting new opportunities for an optimal management of patients with diabetes and cardiovascular disease. We suggest how an improvement of the thrombotic risk in this large population of patients may be achieved by a careful and tailored combination of anti-diabetic and anti-platelet therapies.
Collapse
Affiliation(s)
- Annunziata Nusca
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Dario Tuccinardi
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Silvia Pieralice
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Sara Giannone
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Myriam Carpenito
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Lavinia Monte
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Mikiko Watanabe
- Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, Rome, Italy
| | - Ilaria Cavallari
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Ernesto Maddaloni
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Gian Paolo Ussia
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Silvia Manfrini
- Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| | - Francesco Grigioni
- Unit of Cardiac Sciences, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy
| |
Collapse
|
|
25
|
Current Pharmacological Intervention and Medical Management for Diabetic Kidney Transplant Recipients. Pharmaceutics 2021; 13:pharmaceutics13030413. [PMID: 33808901 PMCID: PMC8003701 DOI: 10.3390/pharmaceutics13030413] [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] [Received: 02/28/2021] [Revised: 03/16/2021] [Accepted: 03/16/2021] [Indexed: 01/02/2023] Open
Abstract
Hyperglycemia after kidney transplantation is common in both diabetic and non-diabetic patients. Both pretransplant and post-transplant diabetes mellitus are associated with increased kidney allograft failure and mortality. Glucose management may be challenging for kidney transplant recipients. The pathophysiology and pattern of hyperglycemia in patients following kidney transplantation is different from those with type 2 diabetes mellitus. In patients with pre-existing and post-transplant diabetes mellitus, there is limited data on the management of hyperglycemia after kidney transplantation. The following article discusses the nomenclature and diagnosis of pre- and post-transplant diabetes mellitus, the impact of transplant-related hyperglycemia on patient and kidney allograft outcomes, risk factors and potential pathogenic mechanisms of hyperglycemia after kidney transplantation, glucose management before and after transplantation, and modalities for prevention of post-transplant diabetes mellitus.
Collapse
|
|
26
|
Scheen AJ. DPP-4 inhibition and COVID-19: From initial concerns to recent expectations. DIABETES & METABOLISM 2021; 47:101213. [PMID: 33249199 PMCID: PMC7690941 DOI: 10.1016/j.diabet.2020.11.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 11/15/2020] [Indexed: 12/18/2022]
Abstract
Dipeptidyl peptidase-4 inhibitors (DPP-4is) have gained a key place in the management of type 2 diabetes mellitus (T2DM) essentially because of their good safety profile even in the frail population. DPP-4, originally known as 'T-cell antigen CD26', is expressed in many immune cells and regulates their functions, so the initial concern over the use of DPP-4is was the possible increased susceptibility to infections. Furthermore, because of the high affinity between human DPP-4 and the spike (S) receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it was suspected that this virus, responsible for coronavirus disease 2019 (COVID-19), might be able to use the DPP-4 enzyme as a functional receptor to gain entry into the host. However, DPP-4is also exert anti-inflammatory effects, which could be beneficial in patients exposed to cytokine storms due to COVID-19. Yet, when observational (mostly retrospective) studies compared clinical outcomes in DPP-4i users vs non-users among diabetes patients with COVID-19, the overall results regarding the risk of progression towards more severe forms of the disease and mortality were heterogeneous, thereby precluding any definite conclusions. Nevertheless, new expectations have arisen following recent reports of significant reductions in admissions to intensive care units and mortality in DPP-4i users. However, given the limitations inherent in such observational studies, any available results should be considered, at best, as hypothetical and only suggestive of potentially substantial benefits with DPP-4is in diabetes patients with COVID-19. While the safe use of DPP-4is in COVID-19 patients appears to be an acceptable hypothesis, all such positive findings still need to be confirmed in randomized controlled trials (a few of which are currently ongoing) before any recommendations can be made for clinical practice.
Collapse
Affiliation(s)
- André J Scheen
- Division of Diabetes, Nutrition and Metabolic Disorders, CHU Liège, Liège, Belgium; Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), Liège University, Liège, Belgium.
| |
Collapse
|
|
27
|
Santos-Pardo I, Lagerqvist B, Ritsinger V, Witt N, Norhammar A, Nyström T. Risk of stent failure in patients with diabetes treated with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors: A nationwide observational study. Int J Cardiol 2021; 330:23-29. [PMID: 33621623 DOI: 10.1016/j.ijcard.2021.02.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 01/07/2021] [Accepted: 02/03/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Incretins are a group of glucose-lowering drugs with favourable cardiovascular (CV) effects against neoatherosclerosis. Incretins' potential effect in stent failure is unknown. The aim of this study is to determine if incretin treatment decreases the risk of stent-thrombosis (ST), and/or in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) with implanted drug-eluting stents (DES). METHODS Observational study including all diabetes patients who underwent PCI with DES in Sweden from 2007 to 2017. By merging 5 national registers, the information on patient characteristics, outcomes and drug dispenses was retrieved. Cox regression analysis with estimated hazard ratios (HRs) adjusted for confounders with 95% confidence intervals (CIs) was used to analyse for the occurrence of ST/ISR, and major adverse cardiovascular events (MACE). A subgroup analysis for the type of incretin treatment was performed. RESULTS In total 18,505 diabetes patients (30% women) underwent PCI, and 32,463 DES were implanted. Of those, 10% (3449 DES in 1943 patients) were treated with incretins. Median follow-up time was 995 days (Control Group) vs. 771 days (Incretin Group). No significant difference in the risk of ST/ISR was found neither for the main study group (HR:0.98 95% CI:0.80-1.19) nor for the subgroups. No reduction of the risk of MACE (HR:0.96 95% CI:0.88-1.06) was observed. There was a 26% lower risk for CV death in favour of incretin treated patients (HR:0.74 95% CI:0.57-0.95). CONCLUSION In diabetes patients who underwent PCI incretin treatment was not associated with lower risk of stent failure, but with lower risk of CV death.
Collapse
Affiliation(s)
- Irene Santos-Pardo
- Department of Clinical Science and Education, Karolinska Institutet, Unit of Cardiology, Södersjukhuset, Stockholm, Sweden.
| | - Bo Lagerqvist
- Department of Medical Sciences, Cardiology Unit and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
| | - Viveca Ritsinger
- Department of Medicine K2, Unit of Cardiology, Karolinska Institutet, Stockholm, Sweden; Department of Research and Development, Region Kronoberg, Växjö, Sweden
| | - Nils Witt
- Department of Clinical Science and Education, Karolinska Institutet, Unit of Cardiology, Södersjukhuset, Stockholm, Sweden
| | - Anna Norhammar
- Department of Medicine K2, Unit of Cardiology, Karolinska Institutet, Stockholm, Sweden; Capio S:t Görans Hospital, Stockholm, Sweden
| | - Thomas Nyström
- Department of Clinical Science and Education, Karolinska Institutet, Unit of Internal Medicine, Södersjukhuset, Stockholm, Sweden
| |
Collapse
|
|
28
|
Nistala R, Meuth AI, Smith C, An J, Habibi J, Hayden MR, Johnson M, Aroor A, Whaley-Connell A, Sowers JR, McKarns SC, Bender SB. DPP4 inhibition mitigates ANG II-mediated kidney immune activation and injury in male mice. Am J Physiol Renal Physiol 2021; 320:F505-F517. [PMID: 33522410 DOI: 10.1152/ajprenal.00565.2020] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Recent evidence suggests that dipeptidyl peptidase-4 (DPP4) inhibition with saxagliptin (Saxa) is renoprotective under comorbid conditions associated with activation of the renin-angiotensin-aldosterone system (RAAS), such as diabetes, obesity, and hypertension, which confer a high cardiovascular risk. Immune system activation is now recognized as a contributor to RAAS-mediated tissue injury, and, importantly, immunomodulatory effects of DPP4 have been reported. Accordingly, we examined the hypothesis that DPP4 inhibition with Saxa attenuates angiotensin II (ANG II)-induced kidney injury and albuminuria via attenuation of immune activation in the kidney. To this end, male mice were infused with either vehicle or ANG II (1,000 ng/kg/min, s.c.) for 3 wk and received either placebo or Saxa (10 mg/kg/day, p.o.) during the final 2 wk. ANG II infusion increased kidney, but not plasma, DPP4 activity in vivo as well as DPP4 activity in cultured proximal tubule cells. The latter was prevented by angiotensin receptor blockade with olmesartan. Further, ANG II induced hypertension and kidney injury characterized by mesangial expansion, mitochondrial damage, reduced brush border megalin expression, and albuminuria. Saxa inhibited DPP4 activity ∼50% in vivo and attenuated ANG II-mediated kidney injury, independent of blood pressure. Further mechanistic experiments revealed mitigation by Saxa of proinflammatory and profibrotic mediators activated by ANG II in the kidney, including CD8+ T cells, resident macrophages (CD11bhiF4/80loLy6C-), and neutrophils. In addition, Saxa improved ANG II suppressed anti-inflammatory regulatory T cell and T helper 2 lymphocyte activity. Taken together, these results demonstrate, for the first time, blood pressure-independent involvement of renal DPP4 activation contributing to RAAS-dependent kidney injury and immune activation.NEW & NOTEWORTHY This work highlights the role of dipeptidyl peptidase-4 (DPP4) in promoting ANG II-mediated kidney inflammation and injury. Specifically, ANG II infusion in mice led to increases in blood pressure and kidney DPP4 activity, which then led to activation of CD8+ T cells, Ly6C- macrophages, and neutrophils and suppression of anti-inflammatory T helper 2 lymphocytes and regulatory T cells. Collectively, this led to kidney injury, characterized by mesangial expansion, mitochondrial damage, and albuminuria, which were mitigated by DPP4 inhibition independent of blood pressure reduction.
Collapse
Affiliation(s)
- Ravi Nistala
- Divisions of Nephrology and Hypertension, University of Missouri School of Medicine, Columbia, Missouri.,Diabetes and Cardiovascular Center, University of Missouri School of Medicine, Columbia, Missouri.,Department of Research, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri
| | - Alex I Meuth
- Diabetes and Cardiovascular Center, University of Missouri School of Medicine, Columbia, Missouri.,Department of Research, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri.,Department of Biomedical Sciences, University of Missouri, Columbia, Missouri
| | - Cassandra Smith
- Diabetes and Cardiovascular Center, University of Missouri School of Medicine, Columbia, Missouri.,Department of Research, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri.,Divisions of Endocrinology and Metabolism, Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri
| | - Jianzhong An
- Divisions of Nephrology and Hypertension, University of Missouri School of Medicine, Columbia, Missouri.,Diabetes and Cardiovascular Center, University of Missouri School of Medicine, Columbia, Missouri.,Department of Research, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri
| | - Javad Habibi
- Diabetes and Cardiovascular Center, University of Missouri School of Medicine, Columbia, Missouri.,Department of Research, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri.,Divisions of Endocrinology and Metabolism, Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri
| | - M R Hayden
- Diabetes and Cardiovascular Center, University of Missouri School of Medicine, Columbia, Missouri.,Department of Research, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri.,Divisions of Endocrinology and Metabolism, Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri
| | - Megan Johnson
- Diabetes and Cardiovascular Center, University of Missouri School of Medicine, Columbia, Missouri.,Divisions of Endocrinology and Metabolism, Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri
| | - Annayya Aroor
- Diabetes and Cardiovascular Center, University of Missouri School of Medicine, Columbia, Missouri.,Department of Research, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri.,Divisions of Endocrinology and Metabolism, Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri
| | - Adam Whaley-Connell
- Divisions of Nephrology and Hypertension, University of Missouri School of Medicine, Columbia, Missouri.,Diabetes and Cardiovascular Center, University of Missouri School of Medicine, Columbia, Missouri.,Department of Research, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri
| | - James R Sowers
- Diabetes and Cardiovascular Center, University of Missouri School of Medicine, Columbia, Missouri.,Department of Research, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri.,Divisions of Endocrinology and Metabolism, Department of Medicine, University of Missouri School of Medicine, Columbia, Missouri.,Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
| | - Susan C McKarns
- Departments of Microbiology and Immunology and Surgery, University of Missouri School of Medicine, Columbia, Missouri
| | - Shawn B Bender
- Department of Research, Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri.,Department of Biomedical Sciences, University of Missouri, Columbia, Missouri.,Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
| |
Collapse
|
|
29
|
Demarchi A, Somaschini A, Cornara S, Androulakis E. Peripheral Artery Disease in Diabetes Mellitus: Focus on Novel Treatment Options. Curr Pharm Des 2020; 26:5953-5968. [PMID: 33243109 DOI: 10.2174/1389201021666201126143217] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 08/09/2020] [Indexed: 02/07/2023]
Abstract
Diabetes mellitus (DM) and peripheral artery disease (PAD) are two clinical entities closely associated. They share many pathophysiological pathways such as inflammation, endothelial dysfunction, oxidative stress and pro-coagulative unbalance. Emerging data focusing on agents targeting these pathways may be promising. Moreover, due to the increased cardiovascular risk, there is a growing interest in cardiovascular and "pleiotropic" effects of novel glucose lowering drugs. This review summarizes the main clinical features of PAD in patients, the diagnostic process and current medical/interventional approaches, ranging from "classical treatment" to novel agents.
Collapse
Affiliation(s)
| | - Alberto Somaschini
- Adult Intensive Care Unit, Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom
| | | | - Emmanuel Androulakis
- Adult Intensive Care Unit, Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom
| |
Collapse
|
|
30
|
Siasos G, Bletsa E, Stampouloglou PK, Paschou SA, Oikonomou E, Tsigkou V, Antonopoulos AS, Vavuranakis M, Tousoulis D. Novel Antidiabetic Agents: Cardiovascular and Safety Outcomes. Curr Pharm Des 2020; 26:5911-5932. [PMID: 33167826 DOI: 10.2174/1381612826666201109110107] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Accepted: 08/22/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Concerns of elevated cardiovascular risk with some anti-diabetic medications warranted trials on the cardiovascular outcome to demonstrate cardiovascular safety of newly marketed anti-diabetic drugs. Although these trials were initially designed to evaluate safety, some of these demonstrated significant cardiovascular benefits. PURPOSE OF REVIEW We reviewed the cardiovascular and safety outcomes of novel antidiabetic agents in patients with type 2 diabetes and established cardiovascular disease or at high risk of it. We included the outcomes of safety trials, randomized controlled trials, meta-analysis, large cohort studies, and real-world data, which highlighted the cardiovascular profile of DPP-4is, GLP-1RAs and SGLT-2is. CONCLUSION Although DPP-4is demonstrated non-inferiority to placebo, gaining cardiovascular safety, as well market authorization, SGLT-2is and most of the GLP-1RAs have shown impressive cardiovascular benefits in patients with T2D and established CVD or at high risk of it. These favorable effects of novel antidiabetic agents on cardiovascular parameters provide novel therapeutic approaches in medical management, risk stratification and prevention.
Collapse
Affiliation(s)
- Gerasimos Siasos
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Evanthia Bletsa
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiota K Stampouloglou
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Stavroula A Paschou
- Division of Endocrinology and Diabetes, "Aghia Sophia" Hospital, Medical School, National and Kapodistrian University of Athens, Greece
| | - Evangelos Oikonomou
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Vasiliki Tsigkou
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Alexios S Antonopoulos
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Manolis Vavuranakis
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Tousoulis
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| |
Collapse
|
|
31
|
Kim EH, Kim SS, Kim DJ, Choi YS, Lee CW, Ku BJ, Cha KS, Song KH, Kim DK, Kim IJ. A prospective cohort study on effects of gemigliptin on cardiovascular outcomes in patients with type 2 diabetes (OPTIMUS study). Sci Rep 2020; 10:19033. [PMID: 33149182 PMCID: PMC7642439 DOI: 10.1038/s41598-020-75594-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 09/25/2020] [Indexed: 12/04/2022] Open
Abstract
This study was performed to evaluate the long-term cardiovascular safety of gemigliptin in patients with type 2 diabetes mellitus (T2DM). After screening, eligible patients with T2DM were enrolled, received gemigliptin, and were followed up for a median of 2.50 years. The primary outcome was a composite of confirmed cardiovascular death, nonfatal myocardial infarction, or nonfatal ischemic stroke (3-point major adverse cardiovascular event [MACE]). The key secondary outcomes were incidence of all-cause mortality and any other cardiovascular events. A total of 5179 patients were included in the study and 5113 were treated with gemigliptin. Overall, the primary outcome occurred in 26 patients within 12 months (estimated incidence by Cox proportional hazard model 0.49%, 95% CI 0.29–0.69%) and in 54 patients within 54 months (estimated incidence from Cox proportional hazard model 1.35%, 95% CI 0.92–1.77%). During the study period, the incidence rates of each component of the primary composite outcome were 0.04% (0.2 events per 1000 person-years) for cardiovascular death, 0.51% (2.2 events per 1000 person-years) for nonfatal myocardial infarction, and 0.61% (2.5 events per 1000 person-years) for nonfatal ischemic stroke. The incidence of all-cause mortality was 0.82% (3.2 events per 1000 person-years) and the incidences of other cardiovascular events were all less than 0.3%. In conclusion, T2DM patients who received gemigliptin exhibited a low incidence of the primary composite MACE and all-cause mortality. Therefore, the use of gemigliptin is expected to be safe without an increase in cardiovascular risk. Trial registration: The study was registered at ClinicalTrials.gov (identifier: NCT02290301).
Collapse
Affiliation(s)
- Eun Heui Kim
- Department of Internal Medicine, and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Sang Soo Kim
- Department of Internal Medicine, and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Dong Jun Kim
- Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Republic of Korea
| | - Young Sik Choi
- Department of Internal Medicine, Kosin University College of Medicine, Busan, Republic of Korea
| | - Chang Won Lee
- Department of Internal Medicine, Busan St. Mary's Hospital, Busan, Republic of Korea
| | - Bon Jeong Ku
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Kwang Soo Cha
- Department of Internal Medicine, and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Kee Ho Song
- Division of Endocrinology and Metabolism, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Republic of Korea
| | - Dae Kyeong Kim
- Department of Internal Medicine, Inje University Busan Paik Hospital, Busan, Republic of Korea
| | - In Joo Kim
- Department of Internal Medicine, and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea. .,Department of Internal Medicine, Pusan National University Hospital, 179, Gudeok-ro, Seo-gu, Busan, Republic of Korea.
| |
Collapse
|
|
32
|
Wilcox T, De Block C, Schwartzbard AZ, Newman JD. Diabetic Agents, From Metformin to SGLT2 Inhibitors and GLP1 Receptor Agonists: JACC Focus Seminar. J Am Coll Cardiol 2020; 75:1956-1974. [PMID: 32327107 PMCID: PMC7219531 DOI: 10.1016/j.jacc.2020.02.056] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 02/25/2020] [Accepted: 02/28/2020] [Indexed: 12/11/2022]
Abstract
Given the intersection between diabetes mellitus and cardiovascular disease (CVD), pharmacologic agents used to treat type 2 diabetes mellitus must show cardiovascular safety. Comorbid conditions, including heart failure and chronic kidney disease, are increasingly prevalent in patients with diabetes; therefore, they also play a large role in drug safety. Although biguanides, sulfonylurea, glitazones, and dipeptidyl peptidase 4 inhibitors have variable effects on cardiovascular events, sodium glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists have consistently shown safety and reduction in cardiovascular events in patients with established CVD. These medications are becoming essential tools for cardioprotection for patients with diabetes and CVD. They may also have roles in primary prevention and renal protection. This paper will review the cardiovascular impact, adverse effects, and possible mechanisms of action of pharmacologic agents used to treat patients with type 2 diabetes.
Collapse
Affiliation(s)
- Tanya Wilcox
- Department of Medicine, Division of Cardiology, New York University School of Medicine, New York, New York
| | - Christophe De Block
- Department of Endocrinology, Diabetology & Metabolism, University of Antwerp-Antwerp University Hospital, Antwerp, Belgium
| | - Arthur Z Schwartzbard
- Department of Medicine, Division of Cardiology, New York University School of Medicine, New York, New York; Center for the Prevention of CVD, Department of Medicine, Division of Cardiology, New York University School of Medicine, New York, New York
| | - Jonathan D Newman
- Department of Medicine, Division of Cardiology, New York University School of Medicine, New York, New York; Center for the Prevention of CVD, Department of Medicine, Division of Cardiology, New York University School of Medicine, New York, New York.
| |
Collapse
|
|
33
|
Paschou SA, Siasos G, Bletsa E, Stampouloglou PK, Oikonomou E, Antonopoulos AS, Batzias K, Tsigkou V, Mourouzis K, Vryonidou A, Tentolouris N, Vavouranakis M, Tousoulis D. The Effect of DPP-4i on Endothelial Function and Arterial Stiffness in Patients with Type 2 Diabetes: A Systematic Review of Randomized Placebo-controlled Trials. Curr Pharm Des 2020; 26:5980-5987. [PMID: 32303166 DOI: 10.2174/1381612826666200417153241] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 03/25/2020] [Indexed: 12/31/2022]
Abstract
We systematically reviewed the literature regarding the impact of dipeptidyl peptidase-4 inhibitors (DPP-4i) on vascular function, including endothelial function and arterial stiffness, as predictors of atherosclerosis progression and cardiovascular disease in patients with type 2 diabetes mellitus (T2DM). We searched PubMed in order to identify clinical trials that investigated the effect of DPP-4i on vascular function in patients with T2DM when compared with placebo. Although 168 articles were initially found, only 6 studies (total 324 patients) investigated the effect of DPP-4i in comparison with placebo, specifically linagliptin and sitagliptin, and satisfied the inclusion criteria. There are scarce data to indicate that linagliptin may enhance endothelial function and exert a slight beneficial effect on arterial wall properties. Sitagliptin seems to have a neutral effect on these variables. Further trials are needed to elucidate the topic. The standards of reporting were in accordance with the PRISMA guidelines.
Collapse
Affiliation(s)
- Stavroula A Paschou
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Gerasimos Siasos
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Evanthia Bletsa
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiota K Stampouloglou
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Evangelos Oikonomou
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Alexios S Antonopoulos
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos Batzias
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Vasiliki Tsigkou
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos Mourouzis
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Andromachi Vryonidou
- Department of Endocrinology and Diabetes, Hellenic Red Cross Hospital, Athens, Greece
| | - Nikolaos Tentolouris
- First Department of Propaedeutic and Internal Medicine, Diabetes Center, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Manolis Vavouranakis
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Tousoulis
- First Department of Cardiology, "Hippokration" General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| |
Collapse
|
|
34
|
Imaging of Atherosclerosis with 18F-FDG PET. Clin Nucl Med 2020. [DOI: 10.1007/978-3-030-39457-8_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
|
|
35
|
Kaku K, Kisanuki K, Shibata M, Oohira T. Benefit-Risk Assessment of Alogliptin for the Treatment of Type 2 Diabetes Mellitus. Drug Saf 2019; 42:1311-1327. [PMID: 31654243 PMCID: PMC6834733 DOI: 10.1007/s40264-019-00857-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The dipeptidyl peptidase-4 inhibitor (DPP-4i) alogliptin is an oral, antidiabetic treatment that is approved in many countries to treat patients with type 2 diabetes mellitus (T2DM), including the USA, Europe, and Japan. Alogliptin is efficacious both as monotherapy and as add-on/combination therapy with other commonly prescribed T2DM treatments, such as metformin and pioglitazone. Overall, alogliptin is well-tolerated in patients with T2DM, including older patients, those with renal and/or hepatic impairment, and those at high risk of cardiovascular events. There is a low risk of hypoglycemia, weight gain, acute pancreatitis, and gastrointestinal adverse events with alogliptin treatment, as demonstrated in long-term trials (lasting up to 4.5 years) and in a real-world setting. Additionally, alogliptin has a generally favorable or similar safety profile in comparison to other antidiabetic agents (metformin, thiazolidinediones, sulfonylureas, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, α-glucosidase inhibitors, and insulin). However, further evaluation would be required to determine the mechanism and effect of alogliptin on heart failure, bullous pemphigoid, and inflammatory bowel disease. Of note, due to the ethnic diversity in the epidemiology of T2DM, alogliptin has been shown to be more efficacious in Asian patients than in non-Asian patients with T2DM, but with a similar tolerability profile. These data indicate that DPP-4is, including alogliptin, are important treatment options, especially for Asian patients with T2DM, for whom they have potential as a first-line therapy. This benefit-risk assessment aims to place alogliptin within the current armamentarium of T2DM and aid physicians when choosing optimal diabetes treatment for their patients.
Collapse
Affiliation(s)
- Kohei Kaku
- Department of Medicine, Kawasaki Medical School, 577 Matsushima, Okayama, 701-0192, Japan.
| | - Koichi Kisanuki
- Japan Medical Office, Takeda Pharmaceutical Company Limited, 1-1, Doshomachi 4-chome, Chuo-ku, Osaka, 540-8645, Japan
| | - Mari Shibata
- Global Patient Safety Evaluation Japan, Pharmacovigilance Department, Takeda Pharmaceutical Company Limited, 1-1, Doshomachi 4-chome, Chuo-ku, Osaka, 540-8645, Japan
| | - Takashi Oohira
- Global Patient Safety Evaluation Japan, Pharmacovigilance Department, Takeda Pharmaceutical Company Limited, 1-1, Doshomachi 4-chome, Chuo-ku, Osaka, 540-8645, Japan
| |
Collapse
|
|
36
|
Sharma A, Verma S. Mechanisms by Which Glucagon-Like-Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors Reduce Cardiovascular Risk in Adults With Type 2 Diabetes Mellitus. Can J Diabetes 2019; 44:93-102. [PMID: 31882322 DOI: 10.1016/j.jcjd.2019.09.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 09/09/2019] [Indexed: 02/06/2023]
Abstract
The growing global burden of type 2 diabetes mellitus confers significant morbidity and mortality in addition to significant cost to local health-care systems. In recent years, 2 classes of therapies have shown some promise in reducing the risk of adverse cardiovascular (CV) events: 1) glucagon-like-peptide-1 (GLP-1) receptor agonists and 2) sodium-glucose cotransporter-2 (SGLT-2) inhibitors. The mechanisms whereby these therapies reduce the risk of adverse CV outcomes are emerging. Both classes of therapies have overlapping yet distinct mechanisms of action. GLP-1 receptor agonists appear to target the incretin axis, inhibit gastric mobility pathways, modify CV risk factors through weight reduction, induce protection of ischemia/reperfusion injury and improve endothelial dysfunction. In comparison, SGLT-2 inhibitors appear to improve ventricular loading conditions, reduce sympathetic nervous system activation, reduce cardiac fibrosis, reduce renal hypoxia and renal-cardiac signalling, reduce left ventricular mass and improve cardiac energetics. In this review, we summarize the potential mechanisms whereby GLP-1 receptor agonists and SGLT-2 inhibitors improve CV outcomes in patients with type 2 diabetes and highlight evidence for their use in populations without diabetes.
Collapse
Affiliation(s)
- Abhinav Sharma
- Division of Cardiology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Subodh Verma
- Division of Cardiac Surgery, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
| |
Collapse
|
|
37
|
de Boer SA, Heerspink HJL, Lefrandt JD, Hovinga-de Boer MC, van Roon AM, Juárez Orozco LE, Glaudemans AWJM, Kamphuisen PW, Slart RHJA, Mulder DJ. Effect of Linagliptin on Arterial 18F-Fluorodeoxyglucose Positron Emission Tomography Uptake: A Randomized Controlled Trial (RELEASE). J Am Coll Cardiol 2019; 69:1097-1098. [PMID: 28231936 DOI: 10.1016/j.jacc.2016.12.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 12/15/2016] [Accepted: 12/19/2016] [Indexed: 11/30/2022]
|
|
38
|
Akoumianakis I, Antoniades C. Impaired Vascular Redox Signaling in the Vascular Complications of Obesity and Diabetes Mellitus. Antioxid Redox Signal 2019; 30:333-353. [PMID: 29084432 DOI: 10.1089/ars.2017.7421] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Significance: Oxidative stress, a crucial regulator of vascular disease pathogenesis, may be involved in the vascular complications of obesity, systemic insulin resistance (IR), and diabetes mellitus (DM). Recent Advances: Excessive production of reactive oxygen species in the vascular wall has been linked with vascular disease pathogenesis. Recent evidence has revealed that vascular redox state is dysregulated in cases of obesity, systemic IR, and DM, potentially participating in the well-known vascular complications of these disease entities. Critical Issues: The detrimental effects of obesity and the metabolic syndrome on vascular biology have been extensively described at a clinical level. Further, vascular oxidative stress has often been associated with the presence of obesity and IR as well as with a variety of detrimental vascular phenotypes. However, the mechanisms of vascular redox state regulation under conditions of obesity and systemic IR, as well as their clinical relevance, are not adequately explored. In addition, the notion of vascular IR, and its relationship with systemic parameters of obesity and systemic IR, is not fully understood. In this review, we present all the important components of vascular redox state and the evidence linking oxidative stress with obesity and IR. Future Directions: Future studies are required to describe the cellular effects and the translational potential of vascular redox state in the context of vascular disease. In addition, further elucidation of the direct vascular effects of obesity and IR is required for better management of the vascular complications of DM.
Collapse
Affiliation(s)
- Ioannis Akoumianakis
- Division of Cardiovascular Medicine, University of Oxford , Oxford, United Kingdom
| | | |
Collapse
|
|
39
|
Whang A, Nagpal R, Yadav H. Bi-directional drug-microbiome interactions of anti-diabetics. EBioMedicine 2019; 39:591-602. [PMID: 30553752 PMCID: PMC6354569 DOI: 10.1016/j.ebiom.2018.11.046] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 11/13/2018] [Accepted: 11/21/2018] [Indexed: 12/18/2022] Open
Abstract
Type 2 diabetes (T2D) has become a global epidemic. Although several drugs are available to manage T2D, problems associated with person-to-person variability in drug efficacy and potential side-effects remain unresolved. Owing to the emerging role of the gut microbiome in obesity and T2D, the interaction between gut microbes and anti-diabetic drugs and its influence on drugs' functions remains of immediate research interest. On one hand, drugs can manipulate gut microbiome composition and metabolic capacity. Conversely, the metabolic activities of the microbiome and its metabolites can also influence drug metabolism and effects. Hence, understanding this bi-directional drug-microbiome interaction and how it influences the clinical outcomes of antidiabetic drugs can pave the way to develop next-generation strategies to ameliorate diabetes. This review presents evidences demonstrating the putative interactions between anti-diabetic drugs and the gut microbiome, and discusses the potential of microbiome modulators to manipulate drug-microbiome interactions and the drug metabolism.
Collapse
Affiliation(s)
- Andrew Whang
- Department of Internal Medicine- Molecular Medicine, Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Ravinder Nagpal
- Department of Internal Medicine- Molecular Medicine, Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Hariom Yadav
- Department of Internal Medicine- Molecular Medicine, Department of Microbiology and Immunology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
| |
Collapse
|
|
40
|
Sarkar J, Nargis T, Tantia O, Ghosh S, Chakrabarti P. Increased Plasma Dipeptidyl Peptidase-4 (DPP4) Activity Is an Obesity-Independent Parameter for Glycemic Deregulation in Type 2 Diabetes Patients. Front Endocrinol (Lausanne) 2019; 10:505. [PMID: 31402899 PMCID: PMC6670725 DOI: 10.3389/fendo.2019.00505] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 07/11/2019] [Indexed: 12/13/2022] Open
Abstract
Background: Increase in circulating dipeptidyl peptidase-4 (DPP4) activity and levels has been reported to associate both with hyperglycemia and obesity. Here we aim to decipher the role of enhanced plasma DPP4 activity in obese type 2 diabetes (T2DM) patients. Materials and methods: Plasma DPP4 levels and activity were measured in obese and non-obese newly diagnosed T2DM patients (n = 123). Visceral and subcutaneous adipose tissue DPP4 expression and activity were determined in 43 obese subjects (T2DM = 21 and non-T2DM = 22). 20 subjects undergoing Mini-Gastric Bypass (MGB) surgery were followed up over 4-6 weeks for plasma DPP4. Results: Plasma DPP4 levels and activity both were increased in T2DM patients compared to control group. However, DPP4 levels and not DPP4 activity were increased in obese T2DM patients compared to non-obese T2DM (62.49 ± 26.27 μg/ml vs. 48.4 ± 30.98 μg/ml, respectively, p = 0.028). DPP4 activity in visceral adipose tissue (VAT) from obese T2DM and obese non-T2DM groups were similar (5.05 ± 3.96 nmol/min/ml vs. 5.83 ± 4.13 nmol/min/ml respectively, p = 0.548) in spite of having increased DPP4 expression in the obese T2DM group. Moreover, in obese patients, plasma DPP4 levels and activity did not show any significant change after weight reduction and glycemic control following MGB surgery. Conclusion: Enhanced plasma DPP4 activity in T2DM occurs independently of obesity. Thus, adipose derived DPP4 may not be playing any significant role in glycemic deregulation in obese T2DM patients.
Collapse
Affiliation(s)
- Jit Sarkar
- Division of Cell Biology and Physiology, Indian Institute of Chemical Biology (CSIR), Kolkata, India
- Academy of Scientific and Innovative Research, Ghaziabad, India
- Community Health Program, SWANIRVAR, North 24 Parganas, India
| | - Titli Nargis
- Division of Cell Biology and Physiology, Indian Institute of Chemical Biology (CSIR), Kolkata, India
| | - Om Tantia
- Department of Minimal Access & Bariatric Surgery, ILS Hospitals, Kolkata, India
| | - Sujoy Ghosh
- Department of Endocrinology and Metabolism, Institute of Postgraduate Medical Education and Research, Kolkata, India
| | - Partha Chakrabarti
- Division of Cell Biology and Physiology, Indian Institute of Chemical Biology (CSIR), Kolkata, India
- Academy of Scientific and Innovative Research, Ghaziabad, India
- *Correspondence: Partha Chakrabarti
| |
Collapse
|
|
41
|
Santucci C, Franchi M, Staszewsky L, La Vecchia C, Latini R, Merlino L, Corrao G, Bosetti C. Incretin-based drugs and hospitalization for heart failure in the clinical practice: A nested case-control study. Diabetes Res Clin Pract 2018; 146:172-179. [PMID: 30332619 DOI: 10.1016/j.diabres.2018.10.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 10/01/2018] [Accepted: 10/11/2018] [Indexed: 12/28/2022]
Abstract
BACKGROUND AND AIMS There are concerns that incretin-based antidiabetic drugs - including dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists - increase the risk of hospitalization for heart failure (HF). To further analyse this issue, we conducted a nested case-control study within a cohort of antidiabetic users in a real world setting. METHODS AND RESULTS Within a cohort of 133,639 subjects with a first prescription of an antidiabetic drug (new-users) between 2010 and 2016 in Lombardy, Italy, and were followed-up to 2016, we identified 4057 subjects with a first hospitalization for HF and 80,450 controls matched on sex, age, and date of cohort-entry. The multivariate odds ratios (ORs) of HF in relation to current use of incretin-based drugs as compared to current use of two or more oral antidiabetics was 1.06 (95% confidence interval, CI, 0.83-1.35), with no evidence of a trend in risk with increasing duration of use. The corresponding ORs were 1.10 (95% CI 0.85-1.41) for DPP-4 inhibitors and 0.84 (95% CI 0.48-1.47) for GLP-1 receptor agonists. Estimates were consistent in various sensitivity analyses. CONCLUSIONS This study indicates that incretin-based drugs are not associated with an increased risk of hospitalization for HF, thus providing further reassurance on the cardiovascular safety of these antidiabetic drugs in the clinical practice.
Collapse
Affiliation(s)
- C Santucci
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - M Franchi
- National Centre for Healthcare Research & Pharmacoepidemiology, University of Milano-Bicocca, Milan, Italy; Laboratory of Healthcare Research & Pharmacoepidemiology, Unit of Biostatistics, Epidemiology and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy
| | - L Staszewsky
- Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - C La Vecchia
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - R Latini
- Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - L Merlino
- Unità Organizzativa Governo dei Dati, delle Strategie e Piani del Sistema Sanitario, Regione Lombardia, Milan, Italy
| | - G Corrao
- National Centre for Healthcare Research & Pharmacoepidemiology, University of Milano-Bicocca, Milan, Italy; Laboratory of Healthcare Research & Pharmacoepidemiology, Unit of Biostatistics, Epidemiology and Public Health, Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy
| | - C Bosetti
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
| |
Collapse
|
|
42
|
Scheen AJ. Effects of glucose-lowering agents on surrogate endpoints and hard clinical renal outcomes in patients with type 2 diabetes. DIABETES & METABOLISM 2018; 45:110-121. [PMID: 30477733 DOI: 10.1016/j.diabet.2018.10.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 09/17/2018] [Accepted: 10/08/2018] [Indexed: 12/12/2022]
Abstract
Diabetic kidney disease (DKD) represents an enormous burden in patients with type 2 diabetes mellitus (T2DM). Preclinical studies using most glucose-lowering agents have suggested renal-protective effects, but the proposed mechanisms of renoprotection have yet to be defined, and the promising results from experimental studies remain to be translated into human clinical findings to improve the prognosis of patients at risk of DKD. Also, it is important to distinguish effects on surrogate endpoints, such as decreases in albuminuria and estimated glomerular filtration rate (eGFR), and hard clinical endpoints, such as progression to end-stage renal disease (ESRD) and death from renal causes. Data regarding insulin therapy are surprisingly scarce, and it is nearly impossible to separate the effects of better glucose control from those of insulin per se, whereas favourable preclinical data with metformin, thiazolidinediones and dipeptidyl peptidase (DPP)-4 inhibitors are plentiful, and positive effects have been observed in clinical studies, at least for surrogate endpoints. The most favourable renal results have been reported with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter type-2 inhibitors (SGLT2is). Significant reductions in both albuminuria and eGFR decline have been reported with these classes of glucose-lowering medications compared with placebo and other glucose-lowering agents. Moreover, in large prospective cardiovascular outcome trials using composite renal outcomes as secondary endpoints, both GLP-1RAs and SGLT2is added to standard care reduced renal outcomes combining persistent macro-albuminuria, doubling of serum creatinine, progression to ESRD and kidney-related death; however, to date, only SGLT2is have been clearly shown to reduce such hard clinical outcomes. Yet, as the renoprotective effects of SGLT2is and GLP-1RAs appear to be independent of glucose-lowering activity, the underlying mechanisms are still a matter of debate. For this reason, further studies with renal outcomes as primary endpoints are now awaited in T2DM patients at high risk of DKD, including trials evaluating the potential add-on benefits of combined GLP-1RA-SGLT2i therapies.
Collapse
Affiliation(s)
- A J Scheen
- Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium; Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU de Liège, Liège, Belgium.
| |
Collapse
|
|
43
|
Noels H, Theelen W, Sternkopf M, Jankowski V, Moellmann J, Kraemer S, Lehrke M, Marx N, Martin L, Marx G, Jankowski J, Goetzenich A, Stoppe C. Reduced post-operative DPP4 activity associated with worse patient outcome after cardiac surgery. Sci Rep 2018; 8:11820. [PMID: 30087386 PMCID: PMC6081383 DOI: 10.1038/s41598-018-30235-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 07/19/2018] [Indexed: 01/04/2023] Open
Abstract
Cardiac surgery with cardiopulmonary bypass (CPB) triggers myocardial ischemia/reperfusion injury contributing to organ dysfunction. Preclinical studies revealed that dipeptidyl peptidase (DPP4) inhibition is protective during myocardial infarction. Here, we assessed for the first time the relation of peri-operative DPP4-activity in serum of 46 patients undergoing cardiac surgery with patients' post-operative organ dysfunction during intensive care unit (ICU) stay. Whereas a prior myocardial infarction significantly reduced pre-operative DDP4-activity, patients with preserved left ventricular function showed an intra-operative decrease of DPP4-activity. The latter correlated with aortic cross clamping time, indicative for the duration of surgery-induced myocardial ischemia. As underlying mechanism, mass-spectrometry revealed increased DPP4 oxidation by cardiac surgery, with DPP4 oxidation reducing DPP4-activity in vitro. Further, post-operative DPP4-activity was negatively correlated with the extent of post-operative organ injury as measured by SAPS II and SOFA scoring, circulating levels of creatinine and lactate, as well as patients' stay on the ICU. In conclusion, cardiac surgery reduces DPP4-activity through oxidation, with low post-operative DPP4-activity being associated with organ dysfunction and worse outcome of patients during the post-operative ICU stay. This likely reflects the severity of myocardial ischemia/reperfusion injury and may suggest potential beneficial effects of anti-oxidative treatments during cardiac surgery.
Collapse
Affiliation(s)
- Heidi Noels
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
| | - Wendy Theelen
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - Marieke Sternkopf
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - Vera Jankowski
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - Julia Moellmann
- Department of Internal Medicine I-Cardiology, University Hospital Aachen, Aachen, Germany
| | - Sandra Kraemer
- Department of Thoracic, Cardiac and Vascular Surgery, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - Michael Lehrke
- Department of Internal Medicine I-Cardiology, University Hospital Aachen, Aachen, Germany
| | - Nikolaus Marx
- Department of Internal Medicine I-Cardiology, University Hospital Aachen, Aachen, Germany
| | - Lukas Martin
- Department of Intensive Care Medicine, University Hospital, RWTH Aachen University, Aachen, Germany
| | - Gernot Marx
- Department of Intensive Care Medicine, University Hospital, RWTH Aachen University, Aachen, Germany
| | - Joachim Jankowski
- Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, RWTH Aachen University, Aachen, Germany.,Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
| | - Andreas Goetzenich
- Department of Thoracic, Cardiac and Vascular Surgery, University Hospital Aachen, RWTH Aachen University, Aachen, Germany
| | - Christian Stoppe
- Department of Intensive Care Medicine, University Hospital, RWTH Aachen University, Aachen, Germany.
| |
Collapse
|
|
44
|
Fleenor BS, Ouyang A, Olver TD, Hiemstra JA, Cobb MS, Minervini G, Emter CA. Saxagliptin Prevents Increased Coronary Vascular Stiffness in Aortic-Banded Mini Swine. Hypertension 2018; 72:466-475. [PMID: 29891647 DOI: 10.1161/hypertensionaha.118.10993] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 02/25/2018] [Accepted: 05/14/2018] [Indexed: 01/09/2023]
Abstract
Increased peripheral conduit artery stiffness has been shown in patients with heart failure (HF) with preserved ejection fraction. However, it is unknown whether this phenomenon extends to the coronary vasculature. HF with preserved ejection fraction may be driven, in part, by coronary inflammation, and inhibition of the enzyme DPP-4 (dipeptidyl-peptidase 4) reduces inflammation and oxidative stress. The purpose of this study was to determine the effect of saxagliptin-a DPP-4 inhibitor-on coronary stiffness in aortic-banded mini swine. We hypothesized saxagliptin would prevent increased coronary artery stiffness in a translational swine model with cardiac features of HF with preserved ejection fraction by inhibiting perivascular adipose tissue inflammation. Yucatan mini swine were divided into 3 groups: control, aortic-banded untreated HF, and aortic-banded saxagliptin-treated HF. Ex vivo mechanical testing was performed on the left circumflex and right coronary arteries, and advanced glycation end product, NF-κB (nuclear factor-κB), and nitrotyrosine levels were measured. An increase in the coronary elastic modulus of HF animals was associated with increased vascular advanced glycation end products, NF-κB, and nitrotyrosine levels compared with control and prevented by saxagliptin treatment. Aortas from healthy mice were treated with media from swine perivascular adipose tissue culture to assess its role on vascular stiffening. Conditioned media from HF and saxagliptin-treated HF animals increased mouse aortic stiffness; however, only perivascular adipose tissue from the HF group showed increased advanced glycation end products and NF-κB levels. In conclusion, our data show increased coronary conduit vascular stiffness was prevented by saxagliptin and associated with decreased advanced glycation end products, NF-κB, and nitrotyrosine levels in a swine model with potential relevance to HF with preserved ejection fraction.
Collapse
Affiliation(s)
- Bradley S Fleenor
- From the Human Performance Laboratory, School of Kinesiology, Ball State University, Muncie, IN (B.S.F.)
| | - An Ouyang
- Department of Kinesiology and Health Promotion, University of Kentucky, Lexington (A.O.)
| | - T Dylan Olver
- Department of Biomedical Science, University of Missouri, Columbia (T.D.O., J.A.H., M.S.C., C.A.E.)
| | - Jessica A Hiemstra
- Department of Biomedical Science, University of Missouri, Columbia (T.D.O., J.A.H., M.S.C., C.A.E.)
| | - Melissa S Cobb
- Department of Biomedical Science, University of Missouri, Columbia (T.D.O., J.A.H., M.S.C., C.A.E.)
| | | | - Craig A Emter
- Department of Biomedical Science, University of Missouri, Columbia (T.D.O., J.A.H., M.S.C., C.A.E.)
| |
Collapse
|
|
45
|
Abstract
PURPOSE OF REVIEW Type 2 diabetes mellitus (T2DM) is associated with increased coronary heart disease (CHD) morbidity and mortality. These patients are also more prone to heart failure, arrhythmias and sudden cardiac death. Furthermore, coronary interventions performed in such high-risk patients have worse outcomes. In this narrative review, we discuss the role of diabetic dyslipidaemia on the risk of CHD in patients with T2DM. The effects of hypolipidaemic, antihypertensive and antidiabetic drugs on lipid and glucose metabolism in T2DM are also considered. RECENT FINDINGS Among CHD risk factors, diabetic dyslipidaemia characterized by moderately elevated low-density lipoprotein (LDL) cholesterol, increased triglycerides and small, dense LDL particles as well as decreased high-density lipoprotein cholesterol levels may contribute to the increased CHD risk associated with T2DM. Hypolipidaemic, antihypertensive and antidiabetic drugs can affect lipid and glucose parameters thus potentially influencing CHD risk. Such drugs may improve not only the quantity, but also the quality of LDL as well as postprandial lipaemia. SUMMARY Current data highlight the importance of treating diabetic dyslipidaemia in order to minimize CHD risk. Both fasting and postprandial lipids are influenced by drugs in patients with T2DM; physicians should take this into consideration in clinical decision making.
Collapse
|
|
46
|
Abstract
Cardiovascular disease (CVD) is a major challenge in the management of type 2 diabetes mellitus. Glucose-lowering agents that reduce the risk of major cardiovascular events would be considered a major advance, as recently reported with liraglutide and semaglutide, 2 glucagon-like peptide-1 receptor agonists, and with empagliflozin and canagliflozin, 2 SGLT-2 (sodium-glucose cotransporter type 2) inhibitors, but not with DPP-4 (dipeptidyl peptidase-4) inhibitors. The present review is devoted to CV effects of new oral glucose-lowering agents. DPP-4 inhibitors (gliptins) showed some positive cardiac and vascular effects in preliminary studies, and initial data from phase 2 to 3 clinical trials suggested a reduction in major cardiovascular events. However, subsequent CV outcome trials with alogliptin, saxagliptin, and sitagliptin showed noninferiority but failed to demonstrate any superiority compared with placebo in patients with type 2 diabetes mellitus and high CV risk. An unexpected higher risk of hospitalization for heart failure was reported with saxagliptin. SGLT-2 inhibitors (gliflozins) promote glucosuria, thus reducing glucose toxicity and body weight, and enhance natriuresis, thus lowering blood pressure. Two CV outcome trials in type 2 diabetes mellitus patients mainly in secondary prevention showed remarkable positive results. Empagliflozin in EMPA-REG-OUTCOME (EMPAgliflozin Cardiovascular OUTCOME Events in Type 2 Diabetes Mellitus Patients) reduced major cardiovascular events, CV mortality, all-cause mortality, and hospitalization for heart failure. In CANVAS (Canagliflozin Cardiovascular Assessment Study), the reduction in CV mortality with canagliflozin failed to reach statistical significance despite a similar reduction in major cardiovascular events. The underlying protective mechanisms of SGLT-2 inhibitors remain unknown and both hemodynamic and metabolic explanations have been proposed. CVD-REAL studies (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors; with the limitation of an observational approach) suggested that these favorable results may be considered as a class effect shared by all SGLT-2 inhibitors (including dapagliflozin) and be extrapolated to a larger population of patients with type 2 diabetes mellitus in primary prevention. Ongoing CV outcome trials with other DPP-4 (linagliptin) and SGLT-2 (dapagliflozin, ertugliflozin) inhibitors should provide additional information about CV effects of both pharmacological classes.
Collapse
Affiliation(s)
- André J Scheen
- From the Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Belgium (A.J.S.)
- Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM), University of Liège, Belgium (A.J.S.)
| |
Collapse
|
|
47
|
Ojeda-Montes MJ, Gimeno A, Tomas-Hernández S, Cereto-Massagué A, Beltrán-Debón R, Valls C, Mulero M, Pujadas G, Garcia-Vallvé S. Activity and selectivity cliffs for DPP-IV inhibitors: Lessons we can learn from SAR studies and their application to virtual screening. Med Res Rev 2018; 38:1874-1915. [PMID: 29660786 DOI: 10.1002/med.21499] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 02/06/2018] [Accepted: 03/02/2018] [Indexed: 12/13/2022]
Abstract
The inhibition of dipeptidyl peptidase-IV (DPP-IV) has emerged over the last decade as one of the most effective treatments for type 2 diabetes mellitus, and consequently (a) 11 DPP-IV inhibitors have been on the market since 2006 (three in 2015), and (b) 74 noncovalent complexes involving human DPP-IV and drug-like inhibitors are available at the Protein Data Bank (PDB). The present review aims to (a) explain the most important activity cliffs for DPP-IV noncovalent inhibition according to the binding site structure of DPP-IV, (b) explain the most important selectivity cliffs for DPP-IV noncovalent inhibition in comparison with other related enzymes (i.e., DPP8 and DPP9), and (c) use the information deriving from this activity/selectivity cliff analysis to suggest how virtual screening protocols might be improved to favor the early identification of potent and selective DPP-IV inhibitors in molecular databases (because they have not succeeded in identifying selective DPP-IV inhibitors with IC50 ≤ 100 nM). All these goals are achieved with the help of available homology models for DPP8 and DPP9 and an analysis of the structure-activity studies used to develop the noncovalent inhibitors that form part of some of the complexes with human DPP-IV available at the PDB.
Collapse
Affiliation(s)
- María José Ojeda-Montes
- Research Group in Cheminformatics & Nutrition, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Campus de Sescelades, Tarragona, Spain
| | - Aleix Gimeno
- Research Group in Cheminformatics & Nutrition, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Campus de Sescelades, Tarragona, Spain
| | - Sarah Tomas-Hernández
- Research Group in Cheminformatics & Nutrition, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Campus de Sescelades, Tarragona, Spain
| | - Adrià Cereto-Massagué
- Research Group in Cheminformatics & Nutrition, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Campus de Sescelades, Tarragona, Spain
| | - Raúl Beltrán-Debón
- Research Group in Cheminformatics & Nutrition, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Campus de Sescelades, Tarragona, Spain
| | - Cristina Valls
- Research Group in Cheminformatics & Nutrition, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Campus de Sescelades, Tarragona, Spain
| | - Miquel Mulero
- Research Group in Cheminformatics & Nutrition, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Campus de Sescelades, Tarragona, Spain
| | - Gerard Pujadas
- Research Group in Cheminformatics & Nutrition, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Campus de Sescelades, Tarragona, Spain.,EURECAT, TECNIO, CEICS, Avinguda Universitat 1, Reus, Spain
| | - Santiago Garcia-Vallvé
- Research Group in Cheminformatics & Nutrition, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Campus de Sescelades, Tarragona, Spain.,EURECAT, TECNIO, CEICS, Avinguda Universitat 1, Reus, Spain
| |
Collapse
|
|
48
|
Abstract
INTRODUCTION Dipeptidyl peptidase-4 inhibitors (DPP-4is) are generally considered as glucose-lowering agents with a safe profile in type 2 diabetes. AREAS COVERED An updated review of recent safety data from randomised controlled trials, observational studies, meta-analyses, pharmacovigilance reports regarding alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin, with a special focus on risks of hypoglycemia, pancreatitis and pancreatic cancer, major cardiovascular events, hospitalisation for heart failure and other new safety issues, such as bone fractures and arthralgia. The safety of DPP-4i use in special populations, elderly patients, patients with renal impairment, liver disease or heart failure, will also be discussed. EXPERT OPINION The good tolerance/safety profile of DPP-4is has been largely confirmed, including in more fragile populations, with no gastrointestinal adverse effects and a minimal risk of hypoglycemia. DPP-4is appear to be associated with a small increased incidence of acute pancreatitis in placebo-controlled trials, although most observational studies are reassuring. Most recent studies with DPP-4is do not confirm the increased risk of hospitalisation for heart failure reported with saxagliptin in SAVOR-TIMI 53, but further post-marketing surveillance is still recommended. New adverse events have been reported such as arthralgia, yet a causal relationship remains unclear.
Collapse
Affiliation(s)
- André Jacques Scheen
- a Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine , CHU Sart Tilman, University of Liège , Liège , Belgium.,b Division of Clinical Pharmacology , Center for Interdisciplinary Research on Medicines (CIRM) , Liège , Belgium
| |
Collapse
|
|
49
|
Estrogen and DPP4 inhibitor, but not metformin, exert cardioprotection via attenuating cardiac mitochondrial dysfunction in obese insulin-resistant and estrogen-deprived female rats. Menopause 2018; 23:894-902. [PMID: 27326818 DOI: 10.1097/gme.0000000000000640] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
OBJECTIVE Cardiac function was markedly compromised in obese insulin-resistant and estrogen-deprived rats. Metformin and dipeptidyl peptidase-4 inhibitor (vildagliptin) were reported to improve cardiac function in insulin-resistant rats. Their effects on the heart under estrogen-deprived conditions are, however, unknown. Therefore, the effects of metformin, vildagliptin, and estrogen on the cardiac function in estrogen-deprived insulin-resistant female rats were investigated. METHODS Bilateral ovariectomized female rats (n = 48) were divided to be fed with either a normal diet (ND) or a high-fat diet (HFD) for 12 weeks. Then, both ND- and HFD-fed groups were subdivided to receive a vehicle, estrogen (50 μg/kg), metformin (30 mg/kg), or vildagliptin (3 mg/kg) for 4 weeks (n = 6/group). Heart rate variability, echocardiography, metabolic and biochemical parameters, cardiac function, and mitochondrial function were determined. Sham-operated female rats (n = 6) were used as a control. RESULTS Both ND- and HFD-fed ovariectomized rats developed insulin resistance, depressed heart rate variability, and decreased cardiac contractility. Although treatment with metformin, vildagliptin, and estrogen improved metabolic status and cardiac function, only estrogen and vildagliptin improved diastolic blood pressure and left ventricular ±dP/dt, and also reduced mitochondrial impairment, apoptosis, and oxidative stress in HD-fed ovariectomized rats. CONCLUSIONS Treatment with estrogen and vildagliptin provided more beneficial effects in the inhibition of oxidative stress, apoptosis, and cardiac mitochondrial dysfunction, and preserved cardiac contractile performance in estrogen-deprived insulin-resistant female rats.
Collapse
|
|
50
|
Affiliation(s)
- André J Scheen
- Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège B-4000, Belgium; and the Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège B-4000, Belgium
| |
Collapse
|