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The Safety and Extrapancreatic effects of GLP-1 on cardiovascular tissue, adipose tissue, liver, and kidney

GLP-1 receptors are widely expressed in CV, adipose, hepatic, and renal tissue. High-affinity GLP-1 receptors are present in autonomic nuclei that control CV functions, and have been isolated in rodent and human cardiomyocytes, endothelial cells, and vascular smooth muscle cells….

GLP-1 receptors are widely expressed in CV, adipose, hepatic, and renal tissue [80, 81]. High-affinity GLP-1 receptors are present in autonomic nuclei that control CV functions [91, 92], and have been isolated in rodent and human cardiomyocytes, endothelial cells, and vascular smooth muscle cells [23, 93].

Although the specific localization and functional relevance of those receptors has not been completely defined, it is noteworthy that mice lacking functional GLP-1 receptors have structural and functional cardiac abnormalities. These include diastolic dysfunction, alterations in resting heart rate, heart wall thickness, and abnormalities in the ratio of heart weight to body weight. Stimulation of central GLP-1 systems has been associated with activation of autonomic regulatory neurons and increased heart rate and blood pressure [91, 92, 95]. In a recent study, GLP-1-receptor activation improved survival after myocardial infarction (MI) in the normal and diabetic mouse heart. This finding suggests that GLP-1-receptor activation is accompanied by effects on the modulation of mediators important for cardiomyocyte survival, including peroxisome proliferator-activated receptors (PPAR)-β/δ, heme oxygenase (HO)-1, Akt, and glycogen synthase kinase (GSK)-3β [96].

GLP-1 receptor agonists appear to have CV effects independent of the autonomic nervous system, and even independent of known GLP-1 receptor-linked pathways [97]. Preclinical evidence suggests a novel two-pathway schema for the CV actions of GLP-1. One pathway depends on the GLP-1 receptor for glucose uptake, ischemic preconditioning, and mild vasodilatory actions. Another appears to involve GLP-1 receptor-independent effects on postischemic recovery of cardiac function and vasodilation [23, 48].

Recent studies suggest a role for GLP-1 as a cardioactive peptide, with demonstrable effects on contractility, cardiac output, arterial blood flow, and cardioprotection [23, 46, 4850, 98]. At supraphysiologic concentrations, GLP-1 behaves as a molecular signal, linking CV and metabolic functions in vivo. Treatment with GLP-1 at supraphysiologic concentrations resulted in increased femoral arterial blood flow correlated with whole-body insulin-stimulated glucose utilization. In a murine model, a strong correlation was observed between glucose utilization and blood flow rates. This correlation was not observed in experimental conditions where brain GLP-1 signaling was abolished in GLP-1-receptor knockout mice, and even more selectively, in mice whose brains were directly infused with a GLP-1 receptor antagonist [99]. GLP-1 has demonstrated an inotropic effect in dogs with heart failure [49, 100], and exerts salutary cardioprotective effects in patients with acute MI when administered as a 72-hour infusion following angioplasty [50]. Clinical studies, involving patients with type 2 diabetes and comorbid coronary artery disease, have shown that GLP-1 infusion improved endothelial function [93], and blood pressure and cardiac function in the immediate postoperative state after bypass surgery [98]. Recent in vitro studies indicate that GLP-1 attenuates tumor necrosis factor alpha (TNF-α)-induced expression of plasminogen activator inhibitor 1 (PAI-1) in vascular endothelial cells, suggesting a possible mechanism for observed ameliorative effects on endothelial dysfunction [101]. Of salient interest, studies have shown cardioprotective and vasodilatory actions of GLP-1 independent of the proposed GLP-1-receptor pathway. [23]

The beneficial effects of GLP-1 on CV parameters may also occur indirectly through GLP-1-mediated improvements in fatty free acid levels and glucose disposal. GLP-1 has been shown to stimulate lypolysis in rat [102] and human [103] adipocytes. In a small study of 20 patients with type 2 diabetes, a continuous 6-week infusion of GLP-1 produced reductions in fasting and 8-hour mean concentrations of free fatty acids [104]. There is preliminary evidence that GLP-1 suppresses endogenous glucose production under fasting conditions independently of its action on islet hormone secretion [105]. GLP-1 may also help to regulate glucose homeostasis via influencing islet cell hormone secretion and modulating gastric emptying. Also, it may have an impact on hepatic glucose production via stimulation of GLP-1 receptor in the arcuate [106]. D’Alessio et al. have postulated that GLP-1 facilitates enhanced glucose disposal in peripheral tissues independently of its effects on islet hormone secretions (insulin and glucagon) [107]. However, other studies have failed to demonstrate a GLP-1-mediated, insulin-independent effect on glucose disposal [107, 108].

Intravenous infusion of GLP-1 revealed renal-protective properties, including enhanced sodium excretion and reduction in hyperfiltration associated with kidney damage [109]. The antihypertensive effects of GLP-1 observed in salt-sensitive Dahl S rats, coupled with reductions in renal and cardiac end organ damage, has been attributed to the GLP-1-dependent increase in salt and water excretion [110].

Beyond glucose control: preclinical and clinical effects of GLP-1 receptor agonists on lipid and cardiovascular biomarkers

Recognition of the sustained insulinotropic and glucagon-lowering activity of GLP-1 has fostered interest in the use of GLP-1 receptor agonists for the treatment of patients with type 2 diabetes. GLP-1-based therapy could be especially valuable in patients with comorbid overweight/obesity and/or CVD. Observations elucidating a role for GLP-1 in the potentiation of glucose-dependent insulin secretion have been followed by clinical trials. They confirm the efficacy of GLP-1 receptor agonists in controlling the glycemic disorders associated with type 2 diabetes. Similarly, in vivo and small proof-of-concept studies confirming the extrapancreatic actions of endogenous GLP-1 have provided the rationale for investigations of the extrapancreatic effects of GLP-1-based therapeutics.

Safety of GLP-1 analogues

Antiexenatide antibodies have been found in 27% to 49% of patients treated with exenatide [3133, 134, 135]. Of the 6% who developed high-titer antiexenatide antibodies, approximately half showed an attenuated glycemic response [112]. Likely due to its closer homology to human GLP-1, liraglutide is associated with antiliraglutide antibodies in up to 13% of patients treated [2730].

Nausea may be frequently observed with exenatide (incidence 3%-51%), although it typically subsides within 8 weeks of therapy initiation [3133, 136]. Incidence of nausea is less frequent with liraglutide (11%-40%) and tends to abate within 4 weeks [2530].

A number of cases of acute pancreatitis have been reported in patients with type 2 diabetes treated with exenatide. The exenatide product label cautions vigilance for signs and symptoms of acute pancreatitis [112]. A claims-based safety surveillance system report assessing the risk of acute pancreatitis with either exenatide or sitagliptin found no risk differential between the two therapies [137]. Currently available clinical trial data indicate that the incidence rate among subjects using liraglutide or a comparable product is in line with what one would expect in any type 2 diabetes population [2530]. It is important to note that patients with type 2 diabetes have a three-times higher risk of developing pancreatitis than the general population [138]. To date, the number of pancreatitis cases is not sufficiently high to determine whether there is an association between the development of acute pancreatitis and liraglutide treatment [139, 140].

In preclinical rodent studies, liraglutide induced calcitonin-producing cell (c-cell) hyperplasia, c-cell adenoma, and, at the highest doses, c-cell carcinoma. Similar findings did not occur in nonhuman primates at an exposure of 60-fold that of the human dose of 1.8 mg. The cumulative data suggest that rodent c-cells are sensitive to activation by GLP-1 agonists, but human and nonhuman primate c-cells not [139, 140].

Conclusions

In recent years, research into type 2 diabetes has generated a wealth of discoveries concerning the pleiotropic effects of GLP-1. The research initiatives revealed an activity profile beyond the stimulation of insulin secretion. The profile includes actions potentiating the secretory activity, proliferation and preservation of the β-cell, as well as cardioprotective actions.

GLP-1 appears to have broader biological action on the pancreas and on extrapancreatic tissues than previously expected. Indeed, the results of recent preliminary investigations suggest that the cardioprotective effects of GLP-1 may manifest via two distinct pathways. One dependent on the GLP-1 receptor for glucose uptake, mild vasodilatory effects, and ischemic preconditioning. Another is accompanied by actions on postischemic recovery of vasodilation and cardiac function independent of the GLP-1 receptor [23].

Limited data exist on the question whether GLP-1 receptor agonists affect strong end points such as CVD morbidity and mortality. However, it is evident that GLP-1 receptor agonists may have other CV, CNS, and gastointestinal consequences than DPP-4 inhibitors. The latter prolongs the activity of native GLP-1, but secretion and bioactivity is progressively impaired in type 2 diabetes. The pleiotropic effects of GLP-1 receptor agonists may benefit patients with type 2 diabetes with hypertension, dyslipidemia, and other risk factors for CV disease, such as overweight/obesity. Further studies in GLP-1 receptor agonists assessing surrogate parameters, and strong end point studies, are warranted to support promising but preliminary emerging evidence to date.

Rev Diabet Stud, 2009, 6(4):247-259
 
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