Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: Systematic review and meta-analysis

Warwick Medical School, University of Warwick, Coventry, UK.
BMJ Open (Impact Factor: 2.27). 01/2013; BMJ Open 2013;3:e001986.. DOI: 10.1136/bmjopen-2012-001986


Objectives: To synthesise current evidence for the effects of exenatide and liraglutide on heart rate, blood pressure and body weight.

Design: Meta-analysis of available data from randomised controlled trials comparing Glucagon-like peptide-1 (GLP-1) analogues with placebo, active anti-diabetic drug therapy or lifestyle intervention.

Participants: Patients with type 2 diabetes.

Outcome measures: Weighted mean differences between trial arms for changes in heart rate, blood pressure and body weight, after a minimum of 12-week follow-up.

Results: 32 trials were included. Overall, GLP-1 agonists increased the heart rate by 1.86 beats/min (bpm) (95% CI 0.85 to 2.87) versus placebo and 1.90 bpm (1.30 to 2.50) versus active control. This effect was more evident for liraglutide and exenatide long-acting release than for exenatide twice daily. GLP-1 agonists decreased systolic blood pressure by -1.79 mm Hg (-2.94 to -0.64) and -2.39 mm Hg (-3.35 to -1.42) compared to placebo and active control, respectively. Reduction in diastolic blood pressure failed to reach statistical significance (-0.54 mm Hg (-1.15 to 0.07) vs placebo and -0.50 mm Hg (-1.24 to 0.24) vs active control). Body weight decreased by -3.31 kg (-4.05 to -2.57)
compared to active control, but by only -1.22 kg (-1.51 to -0.93) compared to placebo.

Conclusions: GLP-1 analogues are associated with a small increase in heart rate and modest reductions in body weight and blood pressure. Mechanisms underlying the rise in heart rate require further investigation.

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    • "The average weight loss amounted to 1.6 kg in the exenatide-treated groups. Additionally, significant reductions in systolic blood pressure compared to placebo (difference of 2.8 mmHg) have been reported after 6 months of treatment with exenatide [36] while no significant increases in heart rate have been reported [37]. The main side effects of exenatide are mild to moderate nausea, diarrhoea and vomiting. "
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    ABSTRACT: Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone, secreted in response to ingestion of nutrients, and has important effects on several of the pathophysiological features of type 2 diabetes (T2D). The effects include potentiation of insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and suppression of appetite. In circulation, GLP-1 has a half-life of approximately 2 min due to rapid degradation by the enzyme dipeptidyl peptidase 4 (DPP-4). Because of this short half-life GLP-1 receptor (GLP-1R) agonists, resistant to degradation by DPP-4 have been developed. At the moment four different compounds are available for the treatment of T2D and many more are in clinical development. These compounds, although all based on the effects of native GLP-1, differ with regards to structure, pharmacokinetics and size, which ultimately leads to different clinical effects. This review gives an overview of the clinical data on GLP-1R agonists that have been compared in head-to-head studies and focuses on relevant differences between the compounds. Highlighting these similarities and differences could be beneficial for physicians in choosing the best treatment strategy for their patients.
    European Journal of Internal Medicine 06/2014; 25(5). DOI:10.1016/j.ejim.2014.03.005 · 2.89 Impact Factor
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    • "The CAFE study established that central aortic pressure is a strong predictor of clinical outcomes [42]. There is also in vivo evidence that exenatide reduces both systolic and diastolic blood pressure [43]. Moreover, GLP-1 receptor agonists are associated with outstanding improvements of other CV risk factors such as body weight and lipid profiles, while they have only a small effect on heart rate and QTc. "
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    ABSTRACT: It has been reported that GLP-1 agonist exenatide (exendin-4) decreases blood pressure. The dose-dependent vasodilator effect of exendin-4 has previously been demonstrated, although the precise mechanism is not thoroughly described. Here we have aimed to provide in vitro evidence for the hypothesis that exenatide may decrease central (aortic) blood pressure involving three gasotransmitters, namely nitric oxide (NO) carbon monoxide (CO), and hydrogen sulphide (H2S). We determined the vasoactive effect of exenatide on isolated thoracic aortic rings of adult rats. Two millimetre-long vessel segments were placed in a wire myograph and preincubated with inhibitors of the enzymes producing the three gasotransmitters, with inhibitors of reactive oxygen species formation, prostaglandin synthesis, inhibitors of protein kinases, potassium channels or with an inhibitor of the Na+/Ca2+-exchanger. Exenatide caused dose-dependent relaxation of rat thoracic aorta, which was evoked via the GLP-1 receptor and was mediated mainly by H2S but also by NO and CO. Prostaglandins and superoxide free radical also play a part in the relaxation. Inhibition of soluble guanylyl cyclase significantly diminished vasorelaxation. We found that ATP-sensitive-, voltage-gated- and calcium-activated large-conductance potassium channels are also involved in the vasodilation, but that seemingly the inhibition of the KCNQ-type voltage-gated potassium channels resulted in the most remarkable decrease in the rate of vasorelaxation. Inhibition of the Na+/Ca2+-exchanger abolished most of the vasodilation. Exenatide induces vasodilation in rat thoracic aorta with the contribution of all three gasotransmitters. We provide in vitro evidence for the potential ability of exenatide to lower central (aortic) blood pressure, which could have relevant clinical importance.
    Cardiovascular Diabetology 04/2014; 13(1):69. DOI:10.1186/1475-2840-13-69 · 4.02 Impact Factor
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    • "Heart rate increase is predictive of adverse cardiac morbidity and mortality and is therefore undesirable [78]. A meta-analysis found a small heart rate increase of 1.86 beats per minute with GLP-1 receptor agonists exenatide and liraglutide compared with placebo [79]. In a 26 week randomized controlled trial of liraglutide vs. sitagliptin, a dose dependent increase in heart rate from baseline (2.32 and 3.94 beats per minute for the 1.2 mg and 1.8 mg doses, respectively) was observed for liraglutide but not sitagliptin [80]. "
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    ABSTRACT: Coronary heart disease and type-2 diabetes are both major global health burdens associated with an increased risk of myocardial infarction (MI). Following MI, ischaemia-reperfusion injury (IRI) remains a significant contributor to myocardial injury at the cellular level. Research has focussed on identifying a strategy or intervention to minimise IRI to optimise reperfusion therapy, with the aim of delivering a superior clinical outcome. The incretin hormone glucagon-like peptide-1, already an established basis for the treatment of type-2 diabetes, also has the potential to protect against IRI. We explain the physiology and cellular processes involved in IRI, and the intracellular pathways activated by GLP-1, which could intercept IRI and deliver cardioprotection. The review also examines the current preclinical and clinical evidence for GLP-1 in cardioprotection and future directions for research as we look for an effective adjunctive treatment to minimise IRI.
    Cardiovascular Diabetology 01/2014; 13(1):12. DOI:10.1186/1475-2840-13-12 · 4.02 Impact Factor
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