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

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          Abstract

          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.

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          Most cited references51

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          Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, in Type 2 Diabetes

          OBJECTIVE—The efficacy and safety of adding liraglutide (a glucagon-like peptide-1 receptor agonist) to metformin were compared with addition of placebo or glimepiride to metformin in subjects previously treated with oral antidiabetes (OAD) therapy. RESEARCH DESIGN AND METHODS—In this 26-week, double-blind, double-dummy, placebo- and active-controlled, parallel-group trial, 1,091 subjects were randomly assigned (2:2:2:1:2) to once-daily liraglutide (either 0.6, 1.2, or 1.8 mg/day injected subcutaneously), to placebo, or to glimepiride (4 mg once daily). All treatments were in combination therapy with metformin (1g twice daily). Enrolled subjects (aged 25–79 years) had type 2 diabetes, A1C of 7–11% (previous OAD monotherapy for ≥3 months) or 7–10% (previous OAD combination therapy for ≥3 months), and BMI ≤40 kg/m2. RESULTS—A1C values were significantly reduced in all liraglutide groups versus the placebo group (P < 0.0001) with mean decreases of 1.0% for 1.8 mg liraglutide, 1.2 mg liraglutide, and glimepiride and 0.7% for 0.6 mg liraglutide and an increase of 0.1% for placebo. Body weight decreased in all liraglutide groups (1.8–2.8 kg) compared with an increase in the glimepiride group (1.0 kg; P < 0.0001). The incidence of minor hypoglycemia with liraglutide (∼3%) was comparable to that with placebo but less than that with glimepiride (17%; P < 0.001). Nausea was reported by 11–19% of the liraglutide-treated subjects versus 3–4% in the placebo and glimepiride groups. The incidence of nausea declined over time. CONCLUSIONS—In subjects with type 2 diabetes, once-daily liraglutide induced similar glycemic control, reduced body weight, and lowered the occurrence of hypoglycemia compared with glimepiride, when both had background therapy of metformin.
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            Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial.

            New treatments for type 2 diabetes mellitus are needed to retain insulin-glucose coupling and lower the risk of weight gain and hypoglycaemia. We aimed to investigate the safety and efficacy of liraglutide as monotherapy for this disorder. In a double-blind, double-dummy, active-control, parallel-group study, 746 patients with early type 2 diabetes were randomly assigned to once daily liraglutide (1.2 mg [n=251] or 1.8 mg [n=247]) or glimepiride 8 mg (n=248) for 52 weeks. The primary outcome was change in proportion of glycosylated haemoglobin (HbA(1c)). Analysis was done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NTC00294723. At 52 weeks, HbA(1c) decreased by 0.51% (SD 1.20%) with glimepiride, compared with 0.84% (1.23%) with liraglutide 1.2 mg (difference -0.33%; 95% CI -0.53 to -0.13, p=0.0014) and 1.14% (1.24%) with liraglutide 1.8 mg (-0.62; -0.83 to -0.42, p<0.0001). Five patients in the liraglutide 1.2 mg, and one in 1.8 mg groups discontinued treatment because of vomiting, whereas none in the glimepiride group did so. Liraglutide is safe and effective as initial pharmacological therapy for type 2 diabetes mellitus and leads to greater reductions in HbA(1c), weight, hypoglycaemia, and blood pressure than does glimepiride.
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              Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial

              Aims/hypothesis The aim of the study was to compare the efficacy and safety of liraglutide in type 2 diabetes mellitus vs placebo and insulin glargine (A21Gly,B31Arg,B32Arg human insulin), all in combination with metformin and glimepiride. Methods This randomised (using a telephone or web-based randomisation system), parallel-group, controlled 26 week trial of 581 patients with type 2 diabetes mellitus on prior monotherapy (HbA1c 7.5–10%) and combination therapy (7.0–10%) was conducted in 107 centres in 17 countries. The primary endpoint was HbA1c. Patients were randomised (2:1:2) to liraglutide 1.8 mg once daily (n = 232), liraglutide placebo (n = 115) and open-label insulin glargine (n = 234), all in combination with metformin (1 g twice daily) and glimepiride (4 mg once daily). Investigators, participants and study monitors were blinded to the treatment status of the liraglutide and placebo groups at all times. Results The number of patients analysed as intention to treat were: liraglutide n = 230, placebo n = 114, insulin glargine n = 232. Liraglutide reduced HbA1c significantly vs glargine (1.33% vs 1.09%; −0.24% difference, 95% CI 0.08, 0.39; p = 0.0015) and placebo (−1.09% difference, 95% CI 0.90, 1.28; p < 0.0001). There was greater weight loss with liraglutide vs placebo (treatment difference –1.39 kg, 95% CI 2.10, 0.69; p = 0.0001), and vs glargine (treatment difference −3.43 kg, 95% CI 4.00, 2.86; p < 0.0001). Liraglutide reduced systolic BP (−4.0 mmHg) vs glargine (+0.5 mmHg; −4.5 mmHg difference, 95% CI 6.8, −2.2; p = 0.0001) but not vs placebo (p = 0.0791). Rates of hypoglycaemic episodes (major, minor and symptoms only, respectively) were 0.06, 1.2 and 1.0 events/patient/year, respectively, in the liraglutide group (vs 0, 1.3, 1.8 and 0, 1.0, 0.5 with glargine and placebo, respectively). A slightly higher number of adverse events (including nausea at 14%) were reported with liraglutide, but only 9.8% of participants in the group receiving liraglutide developed anti-liraglutide antibodies. Conclusions/interpretation Liraglutide added to metformin and sulfonylurea produced significant improvement in glycaemic control and bodyweight compared with placebo and insulin glargine. The difference vs insulin glargine in HbA1c was within the predefined non-inferiority margin. Trial registration: ClinicalTrials.gov NCT00331851 Funding: The study was funded by Novo Nordisk A/S. Electronic supplementary material The online version of this article (doi:10.1007/s00125-009-1472-y) contains a list of members of the LEAD-5 Study Group, which is available to authorised users.
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                Author and article information

                Journal
                BMJ Open
                BMJ Open
                bmjopen
                bmjopen
                BMJ Open
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2044-6055
                2013
                24 January 2013
                : 3
                : 1
                : e001986
                Affiliations
                [1 ]Warwick Medical School, University of Warwick , Coventry, UK
                [2 ]Department of Primary Care Health Sciences, University of Oxford , Oxford, UK
                Author notes
                [Correspondence to ] Dr Tim A Holt; tim.holt@ 123456phc.ox.ac.uk
                Article
                bmjopen-2012-001986
                10.1136/bmjopen-2012-001986
                3563145
                23355666
                95bbd19f-d4da-4101-861d-061bbea75c14
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

                History
                : 28 August 2012
                : 15 November 2012
                : 3 December 2012
                Categories
                Diabetes and Endocrinology
                Research
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                Medicine
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                Medicine
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