Rationale Use of GLP-1 Receptor Agonists in Patients with Type 1 Diabetes

Clinicians and patients are rapidly adapting GLP-1 receptor agonists as efficacious and safe therapeutic options for managing type 2 diabetes (T2DM). GLP-1 receptor agonists stimulate insulin production and secretion from the pancreatic β cells in a glucose-dependent manner, improve gastric emptying, favor weight reduction, and reduce postabsorptive glucagon secretion from pancreatic α cells. GLP-1 receptor activity is impaired in patients with T2DM. GLP-1 secretion and subsequent physiologic actions in patients with type 1 diabetes (T1DM) is ill-defined. Some researchers have suggested that the use of GLP-1 receptor agonists in T1DM may reduce excessive postprandial glucagon secretion allowing patients to reduce their total daily dose of exogenous insulin. Hypoglycemia risk may also be minimized in T1DM as glucagon counter-regulation can be preserved to some degree via the glucose-dependent action of the GLP-1 receptor agonists. This paper will consider the physiologic and pharmacologic benefits of adding GLP-1 receptor agonists to therapeutic regimens of patients with T1DM.     

Adverse Effects of GLP-1 Receptor Agonists

Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of injective anti-diabetic drugs that improve glycemic control and many other atherosclerosis-related parameters in patients with type 2 diabetes (T2D). However, the use of this relatively new class of drugs may be associated with certain adverse effects. Concerns have been expressed regarding the effects of these drugs on pancreatic and thyroid tissue, since animal studies and analyses of drug databases indicate an association of GLP-1 receptor agonists with pancreatitis, pancreatic cancer, and thyroid cancer. However, several meta-analyses failed to confirm a cause-effect relation between GLP-1 receptor agonists and the development of these adverse effects. One benefit of GLP-1 receptor agonists is that they do not cause hypoglycemia when combined with metformin or thiazolidinediones, but the dose of concomitant sulphonylurea or insulin may have to be decreased to reduce the risk of hypoglycemic episodes. On the other hand, several case reports have linked the use of these drugs, mainly exenatide, with the occurrence of acute kidney injury, primarily through hemodynamic derangement due to nausea, vomiting, and diarrhea. The most common symptoms associated with the use of GLP-1 receptor agonists are gastrointestinal symptoms, mainly nausea. Other common adverse effects include injection site reactions, headache, and nasopharyngitis, but these effects do not usually result in discontinuation of the drug. Current evidence shows that GLP-1 receptor agonists have no negative effects on the cardiovascular risk of patients with T2D. Thus, GLP-1 receptor agonists appear to have a favorable safety profile, but ongoing trials will further assess their cardiovascular effects. The aim of this review is to analyze critically the available data regarding adverse events of GLP-1 receptor agonists in different anatomic systems published in Pubmed and Scopus. Whenever possible, certain differences between GLP-1 receptor agonists are described. The review also provides the reader with structured data that compare the rates of the most common adverse effects for each of the various GLP-1 receptor agonists.     

Targeting Incretins in Type 2 Diabetes: Role of GLP-1 Receptor Agonists and DPP-4 Inhibitors

Until recently, the pathogenesis of type 2 diabetes mellitus (T2DM) has been conceptualized in terms of the predominant defects in insulin secretion and insulin action. It is now recognized that abnormalities in other hormones also contribute to the development of hyperglycemia. For example, the incretin effect, mediated by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), is attenuated in T2DM. Intravenous administration of GLP-1 ameliorates hyperglycemia in patients with T2DM, but an extremely short half-life limits its utility as a therapeutic agent. Strategies to leverage the beneficial effects of GLP-1 include GLP-1 receptor agonists or analogs or dipeptidyl peptidase-4 (DPP-4) inhibitors-agents that act by slowing the inactivation of endogenous GLP-1 and GIP. The GLP-1 agonist exenatide has been shown to improve HbA1c and decrease body weight. However, exenatide is limited by its relatively short pharmacologic half-life, various gastrointestinal (GI) side effects, and the development of antibodies. Studies of a long-acting exenatide formulation suggest that it has improved efficacy and also promotes weight loss. Another prospect is liraglutide, a once-daily human GLP-1 analog. In phase 2 studies, liraglutide lowered HbA1c by up to 1.7% and weight by approximately 3 kg, with apparently fewer GI side effects than exenatide. DPP-4 inhibitors such as sitagliptin and vildagliptin result in clinically significant reductions in HbA1c, and are weight neutral with few GI side effects. This review will provide an overview of current and emerging agents that augment the incretin system with a focus on the role of GLP-1 receptor agonists and DPP-4 inhibitors.     

Preclinical and Clinical Data on Extraglycemic Effects of GLP-1 Receptor Agonists

The diverse actions of the incretin hormone glucagon-like peptide (GLP)-1 include insulinotropic, beta-cell preservative, cardioprotective and vasodilatory effects. This spectrum makes GLP-1 an appealing therapeutic option for patients with type 2 diabetes. However, its rapid metabolism by the enzyme dipeptidyl peptidase (DPP)-4 renders it impractical. Incretin-based analogues have been developed to extend endogenous GLP-1 action (GLP-1 receptor agonists) and to hamper its degradation (DPP-4 inhibitors). Evidence suggests that GLP-1 receptor agonists and DPP-4 inhibitors have different pharmacodynamic and pharmacokinetic effects. For example, GLP-1 receptor agonists deliver supraphysiologic levels of GLP-1 analogues designed to resist inactivation by DPP-4, whereas DPP-4 inhibition conserves native GLP-1 resulting in concentrations within the physiologic range. Furthermore, GLP-1 receptor agonists induce glucose-dependent insulin secretion, beta-cell protection, and other extraglycemic benefits such as weight loss and improvement in markers of cardiovascular risk. In contrast, DPP-4 inhibitors are weight neutral and have modest effects on glucose control. DPP-4 inhibition is dependent on the availability of endogenous GLP-1, which appears to be adversely affected by type 2 diabetes and its progression. Therefore, DPP-4 inhibitors may be better suited for patients with mild hyperglycemia without comorbidities. This review examines the present understanding of the pancreatic effects of endogenous GLP-1, and the extrapancreatic actions it exerts on human bodily systems. Also, it analyzes available preclinical and clinical data on incretin therapies with respect to glycemia, lipids, blood pressure, and weight.     

GLP-1 Receptor Agonists and Cardiovascular Disease: a Meta-Analysis of Recent Cardiac Outcome Trials

Purpose

The aim of this study is to examine the cardioprotective properties of Glucagon-like peptide-1 receptor agonist, a class of antihyperglycemic therapy, via meta-analysis of four recently published cardiovascular outcomes trials.

Methods

Meta-analysis was performed pooling data from the ELIXA, LEADER, SUSTAIN-6 and EXSCEL trials. A random effects model was used to generate risk ratio with 95% confidence interval for cardiovascular and safety outcomes.

Results

A total of 33,457 patients were included in the meta-analysis. Based on the study, GLP-1R agonists significantly reduced all-cause mortality (RR 0.89; 95% CI 0.82 to 0.96) and cardiovascular mortality (RR 0.88; 95% CI 0.80 to 0.97) when compared to placebo. When long-acting agents were analyzed alone, reduction in major adverse cardiac events (RR 0.88; 95% CI 0.81 to 0.97) and non-fatal strokes (RR 0.87; 95% CI 0.76 to 0.99) also showed significance.

Conclusion

Overall, GLP-1R agonists appear to have cardioprotective properties likely via modification of metabolic parameters such as glycemic control, weight loss, and improvement in blood pressure. Additional studies are warranted to compare cardiovascular outcomes among the different agents.

     

Possible Role of GLP-1 and Its Agonists in the Treatment of Type 1 Diabetes Mellitus

Unfortunately, the only approved medical treatment for type 1 diabetes mellitus (DM) is insulin, despite the fact that tight control cannot be reached without some serious side effects such as hypoglycemia and weight gain. More and more importance is now shifted towards developing new drugs that can reach a better glycemic control with lesser side effects. Some of these promising drugs are the glucagon-like peptides 1 (GLP-1) and their agonists, which have been FDA approved for the treatment of type 2 DM. The purpose of this article is to review all of the relevant literature on the potential role of GLP-1 in the treatment of type 1 DM. The major source of data acquisition included Medline search strategies, using the words "type 1 diabetes mellitus" and "GLP-1." Articles published in the last 20?years were screened. GLP-1 increases insulin secretion in humans with existing beta cells; it also decreases glucagon secretion, and blunts appetite. Of note, new animal studies demonstrate a role in beta cell-proliferation and decreased apoptosis. Because of all the effects mentioned above, GLP-1 seems to be a promising drug for type 1 DM treatment, but more studies are still needed before solid conclusions can be drawn.     

PCI术前后 GLP-1受体激动剂治疗对ST段抬高心肌梗死心肌保护作用

心肌细胞凋亡的激活决定最终的心肌梗死（myocardial infarction,MI）大小、心室重构以及死亡率[1]。过去10年间,基础研究报道了葡萄糖一胰岛素一钾输液具有抗细胞凋亡作用。有些临床试验利用此输液来治疗sT段抬高心肌梗死。但因大部分试验中发现疗效欠佳或无效而在临床上停止使用此疗法[2]。     

氯沙坦对Ⅱ型糖尿病肾病患者的肾脏和心血管疾病的影响

背景　糖尿病肾病可导致终末期肾病 ,阻断肾素 -血管紧张素系统可以减慢Ⅰ型糖尿病肾病患者病情的恶化 ,但尚未在Ⅱ型糖尿病病人中得到同样的结果。本文作者评价ＡｎｇⅡ受体拮抗剂对Ⅱ型糖尿病肾病的作用 ,还将评价氯沙坦对心血管疾病、尿蛋白和肾病恶化发病率和死亡率的影响。方法　一项多国、双盲、随机、安慰剂对照研究中 ,评价ＡｎｇⅡ受体拮抗剂氯沙坦对Ⅱ型糖尿病肾病患者的肾保护作用。在 2 8个国家 2 5 0个研究中心 ,共有 15 13例Ⅱ型糖尿病肾病患者参与此项研究。在为期 6周的筛选期间 ,病人仍接受常规的抗高血压治疗 ,并根据尿蛋…     

GLP‐1 Receptor Agonists: Effects on Cardiovascular Risk Reduction

Comorbid obesity, dyslipidemia, and hypertension place patients with type 2 diabetes (T2DM) at greatly increased risk of cardiovascular (CV) disease‐related morbidity and mortality. An urgent need exists for effective treatment for patients with T2DM that encompasses glycemic control, weight loss, and reduction in CV risk factors. The glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) liraglutide and exenatide are incretin‐based antidiabetes agents. This review examines CV‐associated effects of liraglutide and exenatide in animal models and clinical trials with patients with T2DM. Studies support the effectiveness of GLP‐1 RAs in reducing hyperglycemia. Further, GLP‐1 RAs represent a significant advance in T2DM treatment because they uniquely affect a broad array of CV risk factors through significant weight and systolic blood pressure reduction, improved lipid levels, and possibly, as shown in in vitro studies and animal models, through direct effects on cardiac myocytes and endothelium.     

2022 Canadian Cardiovascular Society Guideline for Use of GLP-1 Receptor Agonists and SGLT2 Inhibitors for Cardiorenal Risk Reduction in Adults

This guideline synthesizes clinical trial data supporting the role of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors (SGLT2i) for treatment of heart failure (HF), chronic kidney disease, and for optimizing prevention of cardiorenal morbidity and mortality in patients with type 2 diabetes. It is on the basis of a companion systematic review and meta-analysis guided by a focused set of population, intervention, control, and outcomes (PICO) questions that address priority cardiorenal end points. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system and a modified Delphi process were used. We encourage comprehensive assessment of cardiovascular (CV) patients with routine measurement of estimated glomerular filtration rate, urinary albumin-creatinine ratio, glycosylated hemoglobin (A1c), and documentation of left ventricular ejection fraction (LVEF) when evaluating symptoms of HF. For patients with HF, we recommend integration of SGLT2i with other guideline-directed pharmacotherapy for the reduction of hospitalization for HF when LVEF is > 40% and for the reduction of all-cause and CV mortality, hospitalization for HF, and renal protection when LVEF is ≤ 40%. In patients with albuminuric chronic kidney disease, we recommend integration of SGLT2i with other guideline-directed pharmacotherapy to reduce all-cause and CV mortality, nonfatal myocardial infarction, and hospitalization for HF. We provide recommendations and algorithms for the selection of glucagon-like peptide-1 receptor agonists and SGLT2i for patients with type 2 diabetes and either established atherosclerotic CV disease or risk factors for atherosclerotic CV disease to reduce all-cause and CV mortality, nonfatal stroke, and for the prevention of hospitalization for HF and decline in renal function. We offer practical advice for safe use of these diabetes-associated agents with profound cardiorenal benefits.     

胰高血糖素样肽-1受体激动剂的心血管作用

胰高血糖素样肽-1受体激动剂胰高血糖素样肽-1、Exenatide和Liraglutide是理想的降糖药物。近几年的研究显示,这些药物除降糖作用以外还有心血管保护作用,包括降低血压、改善左心室功能和血管内皮功能、保护缺血损伤的心肌细胞等。现对胰高血糖素样肽-1受体激动剂的心血管作用最新研究进展进行综述。     

Cardiovascular Disease Morbidity and Mortality in Patients with Type 1 Diabetes Mellitus

There is an increased risk of cardiovascular disease (CVD) mortality and morbidity in patients with type 1 diabetes mellitus compared with the general population as shown by epidemiologic studies measuring cardiovascular endpoints, as well as by autopsy, angiographic, and coronary calcification studies. Most of the excess CVD risk associated with type 1 diabetes is concentrated in the subset of approximately 35% of patients who develop diabetic nephropathy (after 20 years of diabetes duration), who also typically have dyslipidemias, elevated blood pressure, and hyperglycemia, factors contributing to CVD. For reasons that remain speculative, the relative risks from CVD are higher in women than in men with type 1 diabetes compared with the general population, which effectively eliminates the gender differences in CVD. As in the general population and in patients with type 2 diabetes, education and lifestyle changes, interventions to reduce hyperglycemia, blood pressure, micro-albuminuria, lipid control, and the use of aspirin are important management areas in order to reduce the increased risk of CVD. Whether management with aspirin and statins should be started in type 1 diabetic patients at a younger age or at a lower risk score than in the general population is still under investigation. There is a need for a better understanding of the pathophysiology of vascular complications in type 1 diabetes, more specific risk engines in type 1 diabetes, and accurate estimations of the absolute and relative risk for CVD in order to improve management of CVD in these high-risk patients.     

Cardiovascular Characterization of DA-1 and DA-2 Dopamine Receptor Agonists in Anesthetized Rats

This report summarizes studies aimed to characterize pharmacologically, hemodynamically and biochemically DA-1 (fenoldopam) and DA-2 (quinpirole) dopamine receptor agonists in anesthetized rats. Fenoldopam (20 μg/kg/min i.v. over 15 min) and quinpirole (10 μg/kg/min i.v. over 15 min) share the common property of decreasing mean carotid artery blood pressure by lowering peripheral vascular resistance. Fenoldopam increased mesenteric and renal blood flows whereas quinpirole decreased the former blood flow, but enhanced the latter. These effects of quinpirole were antagonized selectively by S-sulpiride, but not SCH 23390; however, with fenoldopam the reverse was found. In chlorisondamine-pretreated rats with blood pressure supported by vasopressin, fenoldopam, but not quinpirole, caused hypotension. In nephrectomized rats, the blood pressure effects of fenoldopam (assessed as area under the infusion time-response curve) were more pronounced than in sham-operated controls. The hypotensive effects due to an i.v. bolus injection of fenoldopam, but not to acetylcholine, histamine, salbutamol or quinpirole, were significantly inhibited in rats pretreated with an infusion of fenoldopam. In pithed rats, quinpirole reduced the pressor responses to electrical stimulation of the spinal cord without affecting those to exogenous norepinephrine, angiotensin 11 or 5-hydroxytryptamine which, on the contrary, were inhibited by fenoldopam. The plasma renin activity (in intact rats) was reduced by quinpirole, but elevated by fenoldopam. The latter effect also occurred in pithed rats and was blocked by SCH 23390. Quinpirole lowered heart rate, whilst fenoldopam produced tachycardia. These effects of quinpirole and fenoldopam were significantly inhibited by S-sulpiride and SCH 23390, respectively. In chlorisondamine-pretreated rats quinpirole failed to change heart rate     

The Safety and Efficacy of GLP-1 Receptor Agonists in Heart Failure Patients: A Systematic Review and Meta-Analysis

Evaluation of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) usage in heart failure (HF) patients with or without type 2 diabetes mellitus (T2DM) could be proven to be a critical breakthrough in treatment options available for these patients. Our study focuses on understanding the safety and efficacy of GLP-1 RAs in this patient population by pooling the data from 9 randomized controlled trials (RCTs) comprising 871 subjects. As compared with the placebo, GLP-1 RAs did not improve major adverse cardiovascular events (MACE) which include cardiovascular (CV) mortality and heart failure (HF) hospitalizations, our primary outcome. CV mortality (RR = 1.03, 95% CI = 0.56-1.88, P = 0.92) and HF hospitalizations (RR = 1.18, 95%CI = 0.93-1.51, P = 0.18). Similarly, GLP-1 RAs did not improve our secondary findings of left ventricular ejection fraction (LVEF) and 6-minute walk test (6MWT). LVEF (RR = 1.96, 95%CI = ?0.16-4.07, P = 0.07) or 6 MWT (RR = 8.43, 95% CI = ?2.69-19.56, P = 0.14). This meta-analysis shows that GLP-1 RAs do not improve cardiovascular outcomes in HF patients with or without T2DM.