Skip to main content

Advertisement

SpringerLink
Log in

Microvascular effects of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized controlled trials

  • Original Article
  • Published:
Acta Diabetologica Aims and scope Submit manuscript

An Erratum to this article was published on 19 September 2017

This article has been updated

Abstract

Aims

Results with GLP1-receptor agonists (GLP-1RA) on microvascular complications of diabetes are contrasting. In trials designed for cardiovascular outcomes, both liraglutide and semaglutide were associated with a relevant reduction in the incidence and progression of nephropathy. On the other hand, in the same trials, semaglutide was associated with an increased progression of retinopathy, and a similar trend was observed for liraglutide. This meta-analysis is aimed at assessing the effects of GLP-1RA on retinopathy and nephropathy.

Methods

A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials with a duration >11 weeks, enrolling patients with type 2 diabetes, and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug.

Results

Of the 113 trials fulfilling the inclusion criteria, 78 and 62 did not report information on retinopathy and nephropathy, respectively. Treatment with GLP1-RA was not associated with a significant increase in the incidence of retinopathy (MH-OR [95% CI] 0.92 [0.74–1.16]. p = 0.49). In subgroup analyses, GLP1-RA were associated with a lower risk of retinopathy in comparison with sulfonylureas. Cases of macular edema were reported only in nine trials with no sign of increased risk. GLP1-RA reduced the incidence of nephropathy with respect to comparators (MH-OR [95% CI] 0.74 [0.60–0.92]. p = 0.005). This difference was significant versus placebo, but not versus any class of active comparators.

Conclusions

GLP1-RA appear to reduce the incidence and/or progression of nephropathy and to have no specific effect on retinopathy—with the notable exception of semaglutide, which could have a negative impact on the retina.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Change history

  • 19 September 2017

    In the manuscript, the events of nephropathy and retinopathy recorded for the LEADER trial (Marso et al. 2016) were erroneously imputed; the numbers reported in Table 1 for that trial refer to serious adverse events, and not to total events, as stated in Methods. The correct figures are 268 and 416 cases of nephropathy, and 106 and 92 cases of retinopathy in liraglutide and control arms, respectively. As a consequence, the overall risk (MH-OR [95% CI]) of nephropathy and retinopathy with GLP-1RA (vs all comparators) is 0.77 [0.67–0.88], p < 0.001, and 0.99 [0.80–1.21], p = 0.90, respectively. The analyses reported in Figs. 1 and 2 were also corrected and reported below, together with supplementary figures 3 and 5. Please note that liraglutide is associated with a significant reduction in the incidence of nephropathy, whereas for retinopathy the difference from placebo is no longer statistically significant.

References

  1. Monami M, Dicembrini I, Marchionni N, Rotella CM, Mannucci E (2012) Effects of glucagon-like peptide-1 receptor agonists on body weight: a meta-analysis. Exp Diabetes Res [Epub-ahead of print]

  2. Monami M, Marchionni N, Mannucci E (2009) Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials. Eur J Endocrinol 160:909–917

    Article  CAS  PubMed  Google Scholar 

  3. Pfeffer MA, Claggett B, Diaz R et al (2015) Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 373:2247–2257

    Article  CAS  PubMed  Google Scholar 

  4. Marso SP, Daniels GH, Brown-Frandsen K et al (2016) Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 375:311–322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Marso SP, Bain SC, Consoli A et al (2016) Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 375:1834–1844

    Article  CAS  PubMed  Google Scholar 

  6. http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015020245. Last accessed on 3rd Nov 2016

  7. http://www.fda.gov. Last accessed on 3rd Nov 2016

  8. http://www.ema.europa.eu/ema/. Last accessed on 3rd Nov 2016

  9. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101

    Article  CAS  PubMed  Google Scholar 

  10. Egger M, Davey SG, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple. Graphical test. BMJ 315:629–634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151:264–269

    Article  PubMed  Google Scholar 

  12. Zinman B, Wanner C, Lachin JM et al (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373:2117–2128

    Article  CAS  PubMed  Google Scholar 

  13. ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J et al (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358:2560–2572

    Article  Google Scholar 

  14. UK Prospective Diabetes Study (UKPDS) (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33. Lancet 352(9131):837–853

    Article  Google Scholar 

  15. Fu Z, Kuang HY, Hao M, Gao XY, Liu Y, Shao N (2012) Protection of exenatide for retinal ganglion cells with different glucose concentrations. Peptides 37:25–31

    Article  PubMed  Google Scholar 

  16. Dorecka M, Siemianowicz K, Francuz T et al (2013) Exendin-4 and GLP-1 decreases induced expression of ICAM-1, VCAM-1 and RAGE in human retinal pigment epithelial cells. Pharmacol Rep 65(4):884–890

    Article  CAS  PubMed  Google Scholar 

  17. Hernández C, Bogdanov P, Corraliza L et al (2016) Topical administration of GLP-1 receptor agonists prevents retinal neurodegeneration in experimental diabetes. Diabetes 65:172–187

    PubMed  Google Scholar 

  18. Fan Y, Liu K, Wang Q, Ruan Y, Ye W, Zhang Y (2014) Exendin-4 alleviates retinal vascular leakage by protecting the blood-retinal barrier and reducing retinal vascular permeability in diabetic Goto-Kakizaki rats. Exp Eye Res 127:104–116. doi:10.1016/j.exer.2014.05.004

    Article  CAS  PubMed  Google Scholar 

  19. Shurter A, Genter P, Ouyang D, Ipp E (2013) Euglycemic progression: worsening of diabetic retinopathy in poorly controlled type 2 diabetes in minorities. Diabetes Res Clin Pract 100:362–367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions, and Complications Research Group, Lachin JM, Genuth S, Cleary P, Davis MD, Nathan DM (2000) Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 342:381–389

    Article  Google Scholar 

  21. Nauck MA, Petrie JR, Sesti G et al (2016) A phase 2, randomized, dose-finding study of the novel once-weekly human GLP-1 analog, semaglutide, compared with placebo and open-label liraglutide in patients with type 2 diabetes. Diabetes Care 39:231–241

    Article  CAS  PubMed  Google Scholar 

  22. ACCORD Study Group, Cushman WC, Evans GW, Byington RP et al (2010) Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 362:1575–1585

    Article  Google Scholar 

  23. ACCORD Study Group, ACCORD Eye Study Group, Chew EY, Ambrosius WT, Davis MD et al (2010) Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 363:233–244

    Article  Google Scholar 

Download references

Acknowledgements

This research was performed independently of any funding, as part of the institutional activity of the investigators.

Author information

Authors and Affiliations

  1. Diabetology, Azienda Ospedaliero Universitaria Careggi, University of Florence, Via delle Oblate 4, 50141, Florence, Italy

    Ilaria Dicembrini, Besmir Nreu, Edoardo Mannucci & Matteo Monami

  2. Diabetology Unit, Ospedale San Donato Arezzo, Arezzo, Italy

    Alessia Scatena

  3. Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy

    Francesco Andreozzi & Giorgio Sesti

Authors
  1. Ilaria Dicembrini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Besmir Nreu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alessia Scatena
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francesco Andreozzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Giorgio Sesti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Edoardo Mannucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Matteo Monami
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Matteo Monami was involved in each of the following points: (1) design, (2) data collection, (3) analysis, (4) writing manuscript. Besmir Nreu, Alessia Scatena, and Ilaria Dicembrini were involved in each of the following points: (1) data collection, (2) manuscript revision. Giorgio Sesti was involved in each of the following points: (1) design, (2) reviewing manuscript. Edoardo Mannucci was involved in each of the following points: (1) design, (2) data collection, (3) analysis, (4) writing manuscript. All the authors approved the final version of this manuscript.

Corresponding author

Correspondence to Matteo Monami.

Ethics declarations

Conflict of interest

Matteo Monami has received speaking fees from Bristol Myers Squibb, Eli-Lilly, Merck, Novonordisk, Merck, and Takeda, and research grants from Bristol Myers Squibb. Ilaria Dicembrini, Nreu Besmir, Alessia Scatena, and Francesco Andreozzi have no conflicts of interest. Giorgio Sesti has received consultancy fees from Servier, Intarcia, Novo Nordisk, Janssen, Boehringer Ingelheim, Eli Lilly, Astra Zeneca, MSD Italy, Sanofi, Pfizer, and Abbott, and speaking fees from Novo Nordisk, MSD Italy, Boehringer Ingelheim, Eli Lilly, Janssen, Astra Zeneca, Theras Lifetech and Takeda. Edoardo Mannucci has received consultancy fees from Merck and Novartis, speaking fees from Astra Zeneca, Bristol Myers Squibb, Merck, and Novartis, and research grants from Merck, Novartis, and Takeda.

Human and animal rights

Informed consent was not necessary because of no experimentation with human subjects/animals was performed.

Informed consent

For this type of study formal consent is not required.

Additional information

Managed by Massimo Porta.

An erratum to this article is available at https://doi.org/10.1007/s00592-017-1049-z.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 823 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dicembrini, I., Nreu, B., Scatena, A. et al. Microvascular effects of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized controlled trials. Acta Diabetol 54, 933–941 (2017). https://doi.org/10.1007/s00592-017-1031-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00592-017-1031-9

Keywords

Search

Navigation