Glucagon-like peptide-1 receptor agonist (GLP-1RA) is a new class of hypoglycemic drugs in the treatment of type 2 diabetes mellitus (T2DM), which has been confirmed in recent years to not only significantly improve glucose metabolism disorders, but also have metabolic benefits other than hypoglycemic benefits such as weight loss, systolic blood pressure, and blood lipid profile. In addition, the Cardiovascular Outcomes Study (CVOT) demonstrated that GLP-1RA reduces major adverse cardiovascular events (MACE) in patients with diabetes associated with cardiovascular disease (CVD) or at high risk. In May 2024, the results of the landmark study, FLOW, were presented at the 61st Annual Meeting of the European Kidney Association (ERA) and simultaneously published in the New England Journal of Medicine (NEJM) [1], which provided direct evidence-based evidence for the renal benefits of GLP-1RA semaglutide 1.0 mg. GLP-1RA drugs transcend metabolism and have cardiorenal protective effects, and have once again become a new type of hypoglycemic drug that has attracted much attention.
In this paper, Professor Wu Yongjian from Fuwai Hospital, Chinese Academy of Medical Sciences is invited to review and sort out the evidence of multiple benefits of GLP-1RA, and interpret the latest FLOW study data, in order to help reduce the disease burden of T2DM complicated with CVD or chronic kidney disease (CKD) and improve the clinical outcomes of patients.
Resumes of experts
Prof. Wu Yongjian
He is a tenured professor and doctoral supervisor of Peking Union Medical College
Chief Physician of the Department of Cardiovascular Medicine, Fuwai Hospital, Chinese Academy of Medical Sciences
Director of the Coronary Heart Disease Center, Deputy Director of the Center for Structural Heart Disease, and Director of the Second Ward of Coronary Heart Disease
Member of the Academic Committee of Fuwai Hospital
He is also the director of the Department of Cardiology of Xiamen Hospital of Traditional Chinese Medicine
Director of Cardiopulmonary Rehabilitation Center, Beijing First Rehabilitation Hospital
Director of Cardiovascular Medicine Center of Linyi People's Hospital of Shandong Province
He is mainly engaged in the interventional treatment of coronary heart disease and geriatric valvular heart disease and related research
The main person in charge of the coronary heart disease intervention training base of the National Health Commission
He is one of the main clinical investigators of VENUS-A, the first generation of TAVR artificial interventional heart valve in China
Chinese Geriatric Heart Disease Research (CHINA-DVD) 牵头人
He is the chief expert of the innovative treatment technology project of transcatheter valvular heart disease of the Chinese Academy of Medical Sciences
He has successively undertaken 4 projects of the National Natural Science Foundation of China, 2 key projects of Beijing, 1 key project of the Capital Development Fund, 2 general projects, 1 medical and health science and technology innovation project of the Chinese Academy of Medical Sciences, 1 key research project of the Ministry of Science and Technology, and participated in 2 projects
在国际著名学术期刊JACC、Circulation Research等发表100余篇论文
The first person to complete the first prize of the Science and Technology Progress Award of the Ministry of Education
The first person to complete the second prize of the Chinese Medical Award
The first person to complete the first prize of Beijing Science and Technology Progress Award
He used to be the vice chairman of the Youth Committee of the Cardiovascular Disease Branch of the Chinese Medical Association
He is currently a member of the Cardiovascular Disease Branch of the Chinese Medical Association and the deputy head of the Atherosclerosis and Coronary Heart Disease Group
Member of the Standing Committee of the Cardiovascular Disease Branch of the Chinese Medical Doctor Association and head of the Structural Cardiology Group
Vice Chairman of the Cardiovascular Disease Branch of the Beijing Medical Association
He is the chairman-elect of the Cardiac Intervention and Rehabilitation Branch of the Chinese Rehabilitation Association
Chairman of the Cardiac Rehabilitation Branch of the World Federation of Chinese Medicine Associations
Member of the European Society of Cardiology (FESC)
Member of the American Society of Angiography and Interventional Imaging (FSCAI)
Member of the American College of Cardiology (FACC)
He is a member of the editorial board of Chinese Journal of Cardiovascular Diseases, Chinese Journal of Circulation, and Chinese Journal of Interventional Cardiology
He is the winner of the first Capital Gold Medal Good Doctor, the second National Famous Doctor and the third Bethune Nomination Award
Multiple benefits contribute to GLP-1RA's inclusion in the guidelines
Status elevation
01
Lowers blood sugar and improves other metabolic factors
GLP-1RA can promote insulin secretion, inhibit glucagon secretion in a glucose concentration-dependent manner, and can suppress appetite and delay gastric emptying, which can reduce blood sugar without increasing the risk of hypoglycemia. Since 2005, GLP-1RA such as exenatide, liraglutide, semaglutide and dulaglutide have been marketed at home and abroad as new hypoglycemic drugs. With the gradual deepening of research, GLP-1RA has been proven to be able to reduce body weight, reduce systolic blood pressure, and improve dyslipidemia while effectively lowering blood glucose. However, in the major guidelines before 2018, the diabetes management pathway was driven by glucose-lowering, emphasizing that the next level of treatment would only be considered if the blood glucose of a single drug did not meet the standard, and GLP-1RA was only in the recommended position of second-line hypoglycemic drugs.
Cardiovascular benefits
SINCE 2015, THE RESULTS OF LARGE-SCALE CVOT STUDIES SUCH AS LEADER [2], SUSTAIN 6 [3], AND REWIND [4] HAVE SUCCESSIVELY CONFIRMED THAT GLP-1RA SUCH AS LIRAGLUTIDE, SEMAGLUTIDE, AND DULAGLUTIDE HAVE CLEAR CARDIOVASCULAR BENEFITS, AND CAN REDUCE THE RISK OF 3P-MAME (composite endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in patients with T2DM combined with CVD or high-risk patients. The main mechanism is derived from the effects of improving oxidative stress, anti-inflammatory, improving vascular endothelial function and vasomotor function, and anti-atherosclerosis. Since 2018, the major guidelines have begun to shift from hypoglycemic to individualized treatment, and GLP-1RA, which has cardiovascular benefits, is recommended for patients with T2DM and cardiovascular disease. Since 2019, cardiovascular guidelines have begun recommending the initiation of GLP-1RA, which has cardiovascular benefits, independent of glycemic control, in patients with T2DM and ASCVD or at high risk [5]; Since 2022, GLP-1RA has also been recommended in the American Diabetes Association (ADA) guidelines for patients with T2DM with ASCVD/high-risk factors [6].
03Potential kidney benefits
IN ADDITION TO CARDIOVASCULAR OUTCOMES, THE LEADER, SUSTAIN 6, REWIND AND OTHER STUDIES EXPLORED THE EFFECT OF GLP-1RA ON THE RISK OF DEVELOPING COMPOSITE ENDPOINTS OF THE KIDNEY, SUCH AS NEW-ONSET PERSISTENT MASSIVE PROTEINURIA, PERSISTENT DOUBLING OF SERUM CREATININE LEVELS, END-STAGE RENAL DISEASE, OR THE NEED FOR ONGOING RENAL REPLACEMENT THERAPY. In the LEADER study, liraglutide reduced the renal composite endpoint by 22% [7]. In a post-hoc analysis of the SUSTAIN 6 study, semaglutide significantly reduced the risk of renal composite events by up to 36% and delayed the decline in eGFR and proteinuria in patients with T2DM [3]. These results suggest a potential renal benefit for GLP-1RA, but GLP-1RA has not been included in the guidelines for first-line use of GLP-1RA in diabetes mellitus and CKD because the evidence is from cardiovascular outcome studies (CVOT), where renal endpoint events are analysed as a secondary endpoint in these studies, and because not all patients with CKD are in the population, there is a lack of direct renal outcome studies [8].
The FLOW study provides multiple benefits for GLP-1RA
A new certificate has been added
The FLOW study, the first renal outcome study of GLP-1RA semaglutide injection 1.0 mg in patients with diabetes mellitus and CKD, was a double-blind, randomized, placebo-controlled phase III clinical trial involving 3533 patients with a median follow-up of 3.4 years. substantial decline in renal function and renal or cardiovascular death) (Figure 1).
Figure 1: FLOW study design
（T2DM：2型糖尿病；HbA1c：糖化血红蛋白；eGFR：估算肾小球滤过率; GLP-1RA：胰高血糖素样肽-1受体激动剂；RAAS：肾素-血管紧张素-醛固酮系统；UACR：尿白蛋白肌酐比）
The results showed that with a median follow-up of 3.4 years, the primary endpoint was met: the semaglutide group significantly reduced the risk of major renal events by 24%, and the primary endpoint risk reduction was co-driven by all components, with both the renal and cardiovascular event components contributing to the risk reduction (Figure 2). Subgroup analysis of the primary endpoint showed that baseline age, sex, body mass index (BMI), course of disease, estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), cardiovascular history, and concomitant medications did not affect the combined renal benefit of semaglutide injection[1].
Figure 2: Primary endpoint of the FLOW study[1]
（CI：置信区间；NNT：需要治疗患者数; CV：心血管；eGFR：估算肾小球滤过率；HR：风险比）
At the same time, all three confirmatory secondary endpoints were positive: compared with the placebo group, the semaglutide group had a smaller slope of eGFR, with an annual change rate of 1.16 ml/min/1.73 m2, which reduced the rate of eGFR decline; The risk of MACE and the risk of all-cause mortality were significantly reduced by 18% and 20%, respectively (Figure 3). In addition, semaglutide was shown to be safe and well tolerated throughout the study.
Figure 3: Results of three confirmatory secondary endpoints of the FLOW study[1]
(CI: Confidence Interval; NNT: number of patients requiring treatment; CV: cardiovascular; eGFR: estimation of glomerular filtration rate; HR: risk ratio; MACE: major adverse cardiovascular events; ETD: Estimated Treatment Difference)
Unlike CVOT studies such as SUSTAIN 6, the FLOW study is a renal outcome study, and all the patients enrolled are patients with diabetes mellitus and CKD, and the main focus is on the occurrence of hard endpoint events with kidney outcomes, and 93% of the patients in the study are at high or very high risk of CKD, with a high risk of deterioration of kidney function, and a higher risk of renal failure and cardiovascular events. Semaglutide's effect on delaying renal failure and declining kidney function, reducing the risk of cardiovascular events and mortality is more valuable for improving the clinical outcomes of these patients. In addition, more than 95% of patients in the FLOW study were treated with renin-angiotensin-aldosterone system (RAAS) inhibitors and 15.6% with sodium-glucose cotransporter 2 inhibitors (SGLT2i), which clearly confirmed that semaglutide can reduce the risk of renal events, MACE, and all-cause mortality in addition to the above-mentioned standard drugs for T2DM and CKD. These results fully demonstrate the potential of semaglutide in reducing residual risk, and GLP-1RA is expected to be one of the first-line treatments for the management of diabetes mellitus and CKD.
At the just-concluded 2024 ADA Annual Meeting, the results of a pre-defined secondary analysis of the FLOW study were presented in subgroups with or without SGLT2i: semaglutide primary endpoint and confirmatory secondary endpoint benefit were not significantly different between the two groups (both > 0.05 p-values) [9]. In addition, the FLOW study has a series of pre-specified or non-pre-scheduled post-hoc analyses to explore the benefits of semaglutide in different baseline subgroups, which will be presented at international conferences such as the 2024 European Annual Meeting of Cardiology (ESC) and the Annual Meeting of the European Association for the Study of Diabetes (EASD), which will provide more detailed evidence support for the renal benefits of semaglutide, and the results are very promising.
The FLOW study helps open a new chapter in the management of cardiorenal metabolic syndrome (CKM).
In October 2023, the American Heart Association (AHA) President's proposal proposed the "concept of cardiovascular-renal-metabolic syndrome (CKM)," which described the complex relationship and interaction between CVD, CKD, and cardiovascular disease, and recommended early prevention and comprehensive intervention for the three diseases (Figure 3). The Chair suggested emphasizing the important role of drugs with multiple benefits such as GLP-1RA and SGLT2i in the management of CKM, because in addition to the comprehensive regulation of metabolic abnormalities such as blood glucose and obesity, they can also play a role in improving cardiorenal outcomes, which is in line with the concept of co-management of multiple diseases, so it has become the preferred drug for the comprehensive management of CKM.
Figure 4: Key points of CKM staging and management [11]
The results of the FLOW study of semaglutide confirmed that on the basis of standard treatment in patients with T2DM and CKD, it can further reduce the risk of renal failure, cardiovascular events and death in patients with different baseline characteristics, delay the decline of eGFR, provide strong evidence-based evidence for the renal benefit of GLP-1RA in diabetic patients, and provide a new treatment option for delaying the progression of renal failure and reducing the risk of cardiorenal events in patients with CKD. For the management of CKM, GLP-1RA has been shown to improve metabolism and exert cardiovascular protective effects, and the evidence of direct renal benefit provided by the FLOW study will strengthen the multiple benefits of GLP-1RA in the high-quality management of CKM, help improve the prognosis of patients in an all-round way, and open a new chapter in the comprehensive management of CKM.
brief summary
As a new hypoglycemic drug, GLP-1RA has become a first-line drug recommendation for patients with diabetes mellitus and cardiovascular disease or high-risk patients who can improve multiple metabolic risk factors and have cardiovascular benefits. The results of the FLOW study provide evidence of the direct benefit of semaglutide in reducing the risk of cardiorenal events in patients with diabetes mellitus and CKD, adding new evidence to the multiple benefits of GLP-1RA. The concept of CKM emphasizes the co-management of multiple diseases, and drugs such as GLP-1RA, which has both metabolic and cardiac and renal benefit evidence, are the preferred drugs for CKM management. The publication of the results of the FLOW study and its post-hoc analysis will strengthen the position of GLP-1RA in the integrated management of CKM and open a new chapter in the co-management of diabetes, CVD and CKD.
bibliography
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