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 antidiabetic 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.

    • "Conversely, those subjects who reached the glycaemic target were not added other drugs but exclusively observed for another year (T3) (Table 3). That choice arose from the well-known properties of GLP-1 agonists of reducing weight, blood pressure and TC in obese patients with and without diabetes (Visboll et al., 2012;Robinson et al., 2013) which would be expected to have a beneficial effect both on metabolic targets (Canadian Diabetes Association Clinical Practice Guidelines Expert Committee , Cheng AY, 2013; International Diabetes Federation Guideline Development Group, 2014;Handelsman et al., 2015;Inzucchi et al., 2015) and on the vascular system (and hence on ED) (Seftel et al., 2004;Lewis et al., 2010;Glina et al., 2013). Indeed, from a pathophysiologic point of view, we speculated that the L co-administration could have potentiated the positive effect of T supplementation on metabolic Table 5Clinical characteristics and metabolic and hormonal parameters of the poor responders among patients belonging to the prepubertal onset hypogonadal group (G2N; n = 10) at T1, after 1 year of Met and TU therapy (T2) and after the addition of L (1.2 lg/day) for further 12 months (T3) G2 N (n = 10) T1 T2 p1 (p) T 3 p 2( p)Statistically significant p values are in bold. "
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    ABSTRACT: The aim of this retrospective observational study was to evaluate whether adding liraglutide to lifestyle changes, metformin (Met) and testosterone replacement therapy (TRT), by means of improving weight and glycaemic control, could boost erectile function in type 2 diabetic obese men with overt hypogonadism and erectile dysfunction (ED) in a 'real-life setting'. Forty-three obese, diabetic and hypogonadal men (aged 45-59 years) were evaluated because of complaining about the recent onset of ED. They were subdivided into two groups according to whether hypogonadism occurred after puberty (G1; n = 30: 25 with dysfunctional hypogonadism and 5 with acquired hypogonadotropic hypogonadism) or before puberty (G2; n = 13: 10 with Klinefelter's syndrome and 3 with idiopathic hypogonadotropic hypogonadism). Both G1 and G2 patients were given a combination of testosterone (T) [testosterone undecanoate (TU) 1000 mg/every 12 weeks] and Met (2000-3000 mg/day) for 1 year. In the poor responders (N) to this therapy in terms of glycaemic target (G1N: n = 16; G2N: n = 10), liraglutide (L) (1.2 μg/day) was added for a second year, while the good responders (Y) to T + Met (G1Y: 14/30 and G2Y: 3/13) continued this two drugs regimen therapy for another year. All patients were asked to fill in the International Index of Erectile Function (IIEF 15) questionnaire before starting TU plus Met (T1) and after 12 months (T2) and 24 months (T3) of treatment. Patients underwent a clinical examination and a determination of serum sex hormone binding globulin (SHBG), total testosterone (T) and glycosylated haemoglobin (HbA1c) at T1, T2 and T3. At T2, each patient obtained an improvement of ED (p < 0.01) and of the metabolic parameters without reaching, however, the glycaemic goals [HbA1c = >7.5% (>58 mmol/mol)], while T turned out to be within the range of young men. L added to TU and Met regimen in G1N and G2N allowed these patients to reach not only the glycaemic target [HbA1c = <7.5% (<58 nmol/mol)] and a significant reduction in body weight (p < 0.01), but also a further increase in SHBG (p < 0.05) and T (p < 0.01) plasma levels as well as a significant increment of IIEF score (T3). Conversely, at T3 G1Y and G2Y, who received the combined therapy with TRT and Met for the second year, showed a partial failure of that treatment given that there was no improvement of the IIEF score and they showed a significant rise in serum HbA1c (p < 0.05) and weight (p < 0.04) compared with the assessments at T2. These results suggest that TRT could improve clinical and metabolic parameters in obese, type 2 diabetic men with ED and overt hypogonadism (independently of when T deficit occurred). Furthermore, in case of insufficient metabolic control the addition of L to TRT and Met regimen allows to achieve serum T levels in the range of healthy men, as well as to reach glycaemic target and to lower weight, leading to a considerable improvement of ED.
    No preview · Article · Oct 2015 · Andrology
    • "Downloaded from GH Scholz and H Fleischmann 105 of the metabolic vascular syndrome, with a small but significant enhancement of heart rate [Robinson et al. 2013; Monami et al. 2014a; Katout et al. 2014]. All GLP-1 RA meta-analyses regarding CVD actually have considerable limits because most finished and analyzed RCTs were not specifically designed to answer CVD questions . "
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    ABSTRACT: The combination of basal insulin and glucagon-like protein 1 receptor agonists (GLP-1 RAs) is a new intriguing therapeutic option for patients with type 2 diabetes. In our daily practice we abbreviate this therapeutic concept with the term BIT (basal insulin combined incretin mimetic therapy) in a certain analogy to BOT (basal insulin supported oral therapy). In most cases BIT is indeed an extension of BOT, if fasting, prandial or postprandial blood glucose values have not reached the target range. In our paper we discuss special features of combinations of short- or prandial-acting and long- or continuous-acting GLP-1 RAs like exenatide, lixisenatide and liraglutide with basal insulin in relation to different glycemic targets. Overall it seems appropriate to use a short-acting GLP-1 RA if, after the near normalization of fasting blood glucose with BOT, the prandial or postprandial values are elevated. A long-acting GLP-1 RA might well be given, if fasting blood glucose values are the problem. Based on pathophysiological findings, recent clinical studies and our experience with BIT and BOT as well as BOTplus we developed chart-supported algorithms for decision making, including features and conditions of patients. The development of these practical tools was guided by the need for a more individualized antidiabetic therapy and the availability of the new BIT principle.
    No preview · Article · Oct 2014 · Therapeutic advances in endocrinology and metabolism
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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.
    Full-text · Article · Jun 2014 · European Journal of Internal Medicine
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