Effect of liraglutide on blood pressure: a meta-analysis of liraglutide randomized controlled trials

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Abstract

Background

Several clinical trials have studied the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycometabolism and cardiovascular risk factors since they were identified. Because of their cardiovascular benefits and efficacy in lowering glucose, GLP-1RAs are becoming increasingly important in clinical therapy for patients with or without pathoglycaemia. The aim of this study was to assess the effect of the GLP-1RA liraglutide on blood pressure based on randomised controlled trials (RCTs).

Methods

We searched PubMed for RCTs published from 2009 to 2018 comparing the effect of liraglutide on blood pressure with that of placebo in individuals with or without pathoglycaemia. RCTs in humans that included data describing blood pressure changes from baseline to the end of the trial were selected for inclusion in the meta-analysis.

Results

A total of 18 RCTs that enrolled 7616 individuals in the liraglutide group and 6046 individuals in the control group were included in this meta-analysis. Compared with placebo, liraglutide reduced systolic blood pressure (SBP) by 3.18 mmHg (95% CI -4.32, − 2.05), P < 0.00001, but had no significant effect on diastolic blood pressure (DBP). Subgroup analysis showed that the degree of reduction in SBP was associated with the dose of liraglutide but that significance disappeared when the intervention lasted over 1 year. Liraglutide 3.0 mg/d significantly reduced DBP by 1.46 mmHg (95% CI -2.61, 0.32), P = 0.01, but liraglutide 1.8 mg/d slightly increased DBP by 0.47 mmHg (95% CI 0.11, 0.83), P = 0.01, compared with placebo.

Conclusions

This meta-analysis demonstrated that liraglutide significantly reduced SBP in individuals with or without pathoglycaemia compared with placebo, but the difference was no longer significant when the intervention lasted over 1 year. Moreover, the effect of liraglutide on blood pressure is associated with the dose. This finding may provide additional evidence for cardiovascular protection.

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

Michael Nauck, Anders Frid, Kjeld Hermansen … (2009)

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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Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways.

Kiwon Ban, M Hossein Noyan-Ashraf, Judith Hoefer … (2008)

The glucagon-like peptide 1 receptor (GLP-1R) is believed to mediate glucoregulatory and cardiovascular effects of the incretin hormone GLP-1(7-36) (GLP-1), which is rapidly degraded by dipeptidyl peptidase-4 (DPP-4) to GLP-1(9-36), a truncated metabolite generally thought to be inactive. Novel drugs for the treatment of diabetes include analogues of GLP-1 and inhibitors of DPP-4; however, the cardiovascular effects of distinct GLP-1 peptides have received limited attention. Here, we show that endothelium and cardiac and vascular myocytes express a functional GLP-1R as GLP-1 administration increased glucose uptake, cAMP and cGMP release, left ventricular developed pressure, and coronary flow in isolated mouse hearts. GLP-1 also increased functional recovery and cardiomyocyte viability after ischemia-reperfusion injury of isolated hearts and dilated preconstricted arteries from wild-type mice. Unexpectedly, many of these actions of GLP-1 were preserved in Glp1r(-/-) mice. Furthermore, GLP-1(9-36) administration during reperfusion reduced ischemic damage after ischemia-reperfusion and increased cGMP release, vasodilatation, and coronary flow in wild-type and Glp1r(-/-) mice, with modest effects on glucose uptake. Studies using a DPP-4-resistant GLP-1R agonist and inhibitors of DPP-4 and nitric oxide synthase showed that the effects of GLP-1(7-36) were partly mediated by GLP-1(9-36) through a nitric oxide synthase-requiring mechanism that is independent of the known GLP-1R. These data describe cardioprotective actions of GLP-1(7-36) mediated through the known GLP-1R and novel cardiac and vascular actions of GLP-1(7-36) and its metabolite GLP-1(9-36) independent of the known GLP-1R. Our data suggest that the extent to which GLP-1 is metabolized to GLP-1(9-36) may have functional implications in the cardiovascular system.

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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

D. Russell‐Jones, A Vaag, O. Schmitz … (2009)

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

Contributors

Xu Zhao:

ORCID: http://orcid.org/0000-0003-2954-6245

soso11019@126.com

Kun Huang:

ORCID: http://orcid.org/0000-0002-3347-0688

khuang@bjmu.edu.cn

Meijie Zheng: moon850617@163.com

Junting Duan:

ORCID: http://orcid.org/0000-0001-5884-7579

+86-18810526954 , duanjunting123@sina.com

Journal

Journal ID (nlm-ta): BMC Endocr Disord

Journal ID (iso-abbrev): BMC Endocr Disord

Title: BMC Endocrine Disorders

Publisher: BioMed Central (London )

ISSN (Electronic): 1472-6823

Publication date (Electronic): 7 January 2019

Publication date PMC-release: 7 January 2019

Publication date Collection: 2019

Volume: 19

Electronic Location Identifier: 4

Affiliations

[1 ]ISNI 0000 0001 2256 9319, GRID grid.11135.37, Civil Aviation General Hospital, Peking University, ; Beijing, China

[2 ]GRID grid.459327.e, Endocrinology Department, , Civil Aviation General Hospital, ; Chaoyang Road, Beijing, China

Author information

Xu Zhao http://orcid.org/0000-0003-2954-6245

Kun Huang http://orcid.org/0000-0002-3347-0688

Junting Duan http://orcid.org/0000-0001-5884-7579

Article

Publisher ID: 332

DOI: 10.1186/s12902-018-0332-5

PMC ID: 6323665

PubMed ID: 30616638

SO-VID: 4059c826-d3c6-44eb-9690-139ae2a5522a

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 9 August 2018

Date accepted : 27 December 2018

Custom metadata

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: blood pressure,cardiovascular risk factor,dbp,glp-1ras,liraglutide,sbp

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: blood pressure, cardiovascular risk factor, dbp, glp-1ras, liraglutide, sbp

Effect of liraglutide on blood pressure: a meta-analysis of liraglutide randomized controlled trials

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Journal of the ASEAN Federation of Endocrine Societies

Most cited references 54

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

Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways.

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

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