Home Browse Combining Glucagon-Like Peptide-1 Receptor agonists and Sodium-Glucose...
ALL Metrics
-
Views
-
Downloads
Get PDF
Get XML
Cite
Export
Track
▬
✚
Study Protocol

Combining Glucagon-Like Peptide-1 Receptor agonists and Sodium-Glucose Cotransporter-2 Inhibitors in the management of Type 2 Diabetes Mellitus: A protocol for a scoping review

[version 1; peer review: 1 approved with reservations]
Carlos E. Builes-Montaño
https://orcid.org/0000-0002-2418-6159
1,2, Andres F. Suarez-Rodriguez3, Johanna Carreño3
Carlos E. Builes-Montaño
https://orcid.org/0000-0002-2418-6159
1,2, Andres F. Suarez-Rodriguez3, Johanna Carreño3
PUBLISHED 13 Feb 2025
Author details Author details
OPEN PEER REVIEW
REVIEWER STATUS

Abstract

Introduction

Diabetes treatment has evolved from solely focusing on glucose control to a more patient-centered approach that includes medications designed to reduce specific risks in addition to managing blood glucose control.

Methods and analysis

We propose a scoping review to explore the available clinical research on the combined use of GLP-1RAs and SGLT2is. This review will adhere to the guidelines outlined in the Joanna Briggs Institute Reviewer’s Manual and the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews).

Keywords

Diabetes mellitus; Glucagon-like peptide-1 receptor agonists; Sodium-glucose cotransporter-2 inhibitors.

Corresponding author: Carlos E. Builes-Montaño
Competing interests: The authors declare the following conflicts of interest. Carlos E. Builes-Montaño has received consulting or speaker fees from Sanofi, Novo Nordisk, Novartis, and Boehringer Ingelheim. Andres F. Suarez-Rodriguez and Johanna Carreño are Novo Nordisk employees.
Grant information: Festina Lente provided medical writing in English and editorial assistance, funded by Novo Nordisk Colombia. Novo Nordisk Colombia will finance the journal's publication fees directly.
Copyright:  © 2025 Builes-Montaño CE et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Builes-Montaño CE, Suarez-Rodriguez AF and Carreño J. Combining Glucagon-Like Peptide-1 Receptor agonists and Sodium-Glucose Cotransporter-2 Inhibitors in the management of Type 2 Diabetes Mellitus: A protocol for a scoping review [version 1; peer review: 1 approved with reservations]. F1000Research 2025, 14:202 (https://doi.org/10.12688/f1000research.159628.1) First published: 13 Feb 2025, 14:202 (https://doi.org/10.12688/f1000research.159628.1) Latest published: 13 Feb 2025, 14:202 (https://doi.org/10.12688/f1000research.159628.1)

Article summary

Strengths and limitations of this study

This scoping review will be the first to comprehensively examine the available literature on combined therapy with GLP-1RAs and SGLT2is.

By including all the available literature, this review will provide a comprehensive summary of the effects of combined therapy and trace the progression of research on the combined use of GLP-1RAs and SGLT2is.

This scoping review will focus exclusively pn clinically meaningful outcomes; surrogate and intermediate outcomes will not be considered.

Introduction

Diabetes mellitus (DM) is one of the leading non-communicable diseases and a significant risk factor for other non-communicable conditions such as cardiovascular and chronic kidney diseases. These conditions account for a high proportion of deaths and disability around the world,1 and DM incidence is expected to rise, especially in low and middle-income countries.2

The approach to DM treatment has evolved from a strict glucose control aimed at reducing the risk of micro- and macrovascular complications3–5 to a more patient-centered strategy. This new paradigm emphasizes reducing the risk of conditions such as cardiovascular disease, heart failure, and kidney disease through medications with a disease-modifying effect, independent of glucose control.3,4

Most recent advancements in DM treatment stem from the clinical evidence on two classes of medication: glucagon-like peptide-1 receptor agonists (GLP-1RAs)5–8 and sodium-glucose cotransporter-2 inhibitors (SGLT2is). Individually, these medications meet the glucose reduction and cardiovascular safety requirements for DM and they modify the risk of cardiovascular events, heart failure hospitalizations, and progression of kidney disease. They also are related to modest weight loss and a low risk of hypoglycemia.9–12

While guidelines recommend combining DM treatments as simultaneous or add-on therapies13,14—a natural progression in T2D management—most clinical trials are structured to evaluate a single interventions, including those on GLP-1Ras and SGLT2is. Real-world clinical practice often differs significantly from the controlled environment of clinical trials. Following guidelines recommendations, combined therapy with GLP-1RAs and SGLT2is is expected to become one of the most commonly prescribed treatments for DM. Recently, meta-analyses of clinical trials have synthesized the combined effects of these two drug classes. However, observational studies and post hoc analyses on combination therapy and its impact on key outcomes are likely to offer a more extensive body of evidence. This prompted us to design a scoping review to map the clinical research landscape surrounding combined GLP-1Ras and SGLT2is therapy, focusing on its effects on metabolic, cardiovascular, and renal outcomes.

Methods

Scoping review

This is a scoping literature review on the body of research on the combined use of GLP-1Ras and SGLT2is in people with T2DM.

The scoping review methodology was chosen to map the range of evidence on this topic, summarize research findings, and identify gaps for further research.13 This review will follow the approach for scoping reviews as outlined in the Joanna Briggs Institute Reviewer’s Manual14 and will adhere to the PRISMA-ScR guidelines.15

The research question

What is the scope of published evidence on the effects of using GLP-1Ras and SGLT2is in individuals with T2DM?

The research sub-questions are:

  • 1. Does the combined use of GLP-1Ras and SGLT2is differ from their separate use in terms of metabolic control, weight change, major cardiovascular events, hospitalizations for heart failure, major renal events, and adverse events?

  • 2. Are there clinical characteristics that influence the response to combined therapy with GLP-1Ras and SGLT2is?

  • 3. Are there differences in the effects based on the specific types of GLP-1Ras and SGLT2is used in combination?

Inclusion criteria

To be included in the review, studies must meet the following criteria:

Report on the combined use of GLP-1Ras and SGLT2is in individuals with T2DM.

Include all types of research reports such as case reports and case series.

Exclude narrative reviews.

Search methods for identification of studies.

Electronic searches

The following databases will be searched from inception to the specified date.

MEDLINE (Pubmed) until September 2024.

Embase until September 2024.

Studies in any language, country, and date will be included. Finally, we will screen reference lists from relevant published studies. The details of the search strategy are provided in Supplementary Table 1.

Data collection and charting

Study selection

To determine which studies should be included, two authors (CEBM and AFSR) will independently review the titles and abstracts of all records retrieved from the search. All articles deemed potentially relevant will be read in full. In case of any disagreements, a third author (JC) will intervene to resolve and provide justification them in a group meeting.

The selection process will follow the recommendations of the PRISMA-ScR checklist,15 and a PRISMA flowchart illustrating the study selection will be provided according to the PRISMA statement.16

Data charting

Relevant information from each included study will be recorded in a data charting form with the following fields: author(s), year of publication, country of origin, if the combination was an add-on, study population, and sample size, study design, intervention or exposition type and details of these, comparator, outcomes and elements of these, and key findings that relate to the scoping review questions.

Presentation of the results

A narrative report will summarise the extracted data within the following conceptual categories: metabolic outcomes, cardiovascular outcomes, renal outcomes, and adverse events. The determination of these conceptual categories will be an iterative process, with potential adjustments after the review if necessary.

Discussion

This review synthesizes the evidence on the metabolic, cardiovascular, and renal outcomes of combined GLP-1Ras and SGLT2is therapy in individuals with DM. Evidence suggests potential benefits from this combined therapy in managing cardiovascular disease,17,18 kidney disease,19 synergistic pathways to enhance glucose control,20 and promoting weight loss.21 Understanding whether these potential benefits translate into clinically meaningful changes for people with DM is essential, which is why this scoping review focuses on clinically significant outcomes. for people with DM. This is why we have centered this scoping review on clinically significant outcomes. Additionally, we plan to investigate whether any differences exist when the combination therapy is used simultaneously or as an add-on approach, as this distinction could guide future research.

Ethics and dissemination

We intend to publish the results in a specialized peer-reviewed journal and present them at local, national, and international conferences. The paper will also serve as the basis for a position statement in our country.

Author contributions

CEBM conceived and designed the review, led the development of the search strategy, and offered guidance for protocol design. All authors critically reviewed and contributed to the final version of the manuscript.

Patient and public involvement

Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Ethics and dissemination

We intend to publish the results in a specialized peer-reviewed journal and present them at local, national, and international conferences. They will also be used as educational material in meetings. Ethical approval and consent were not required.

Data availability

Underlying data

No data are associated with this article.

Extended data

The underlying data has been deposited in The Open Science Framework (OSF) Combining Glucagon-Like Peptide-1 Receptor agonists and Sodium-Glucose Cotransporter-2 Inhibitors in the management of Type 2 Diabetes Mellitus: A protocol for a scoping review. https:doi.org/10.17605/OSF.IO/RX84A.22

The project contains the following underlying data:

  • • PRISMA-P.docx and Supplementary material.docx. (Supplementary table 1 and supplementary table 2).

Data are available under the terms of the Creative Commons Attribution 4.0 International license CC0 1.0 Universal.

Acknowledgments

Festina Lente provided medical writing in English and editorial assistance. The Authors are responsible for the content and conclusions expressed in this manuscript.

References

  • 1.  Hajat C, Stein E: The global burden of multiple chronic conditions: A narrative review. Prev. Med. Rep. 2018; 12: 284–293. PubMed Abstract | Publisher Full Text | Free Full Text
  • 2.  Sun H, Saeedi P, Karuranga S, et al.: IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res. Clin. Pract. 2022; 183: 109119. PubMed Abstract | Publisher Full Text | Free Full Text
  • 3.  ElSayed NA, Aleppo G, Aroda VR, et al.: 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2023. Diabetes Care. 2023; 46(Suppl 1): S140–S157. PubMed Abstract | Publisher Full Text | Free Full Text
  • 4.  Kelsey MD, Nelson AJ, Green JB, et al.: Guidelines for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes: JACC Guideline Comparison. J. Am. Coll. Cardiol. 2022; 79(18): 1849–1857. Publisher Full Text
  • 5.  Jendle J, Grunberger G, Blevins T, et al.: Efficacy and safety of dulaglutide in the treatment of type 2 diabetes: a comprehensive review of the dulaglutide clinical data focusing on the AWARD phase 3 clinical trial program. Diabetes Metab. Res. Rev. 2016; 32(8): 776–790. PubMed Abstract | Publisher Full Text
  • 6.  Aroda VR, Ahmann A, Cariou B, et al.: Comparative efficacy, safety, and cardiovascular outcomes with once-weekly subcutaneous semaglutide in the treatment of type 2 diabetes: Insights from the SUSTAIN 1-7 trials. Diabetes Metab. 2019; 45(5): 409–418. PubMed Abstract | Publisher Full Text
  • 7.  Rodbard HW, Dougherty T, Taddei-Allen P: Efficacy of oral semaglutide: overview of the PIONEER clinical trial program and implications for managed care. Am. J. Manag. Care. 2020; 26(16 Suppl): S335–S343. PubMed Abstract | Publisher Full Text
  • 8.  McGill JB: Insights from the Liraglutide Clinical Development Program--the Liraglutide Effect and Action in Diabetes (LEAD) studies. Postgrad. Med. 2009; 121(3): 16–25. PubMed Abstract | Publisher Full Text
  • 9.  Sattar N, Lee MMY, Kristensen SL, et al.: Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 2021; 9(10): 653–662. PubMed Abstract | Publisher Full Text
  • 10.  Kani R, Watanabe A, Miyamoto Y, et al.: Comparison of Effectiveness Among Different Sodium-Glucose Cotransoporter-2 Inhibitors According to Underlying Conditions: A Network Meta-Analysis of Randomized Controlled Trials. J. Am. Heart Assoc. 2024; 13(3): e031805. PubMed Abstract | Publisher Full Text | Free Full Text
  • 11.  Patel SM, Kang YM, Im K, et al.: Sodium-Glucose Cotransporter-2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis. Circulation. 2024; 149(23): 1789–1801. PubMed Abstract | Publisher Full Text | Free Full Text
  • 12.  Yao H, Zhang A, Li D, et al.: Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis. BMJ (Clinical Research ed). 2024; 384: e076410. Publisher Full Text
  • 13.  Arksey H, O’Malley L: Scoping studies: towards a methodological framework. Int. J. Soc. Res. Methodol. 2005; 8(1): 19–32. Publisher Full Text
  • 14.  Peters MD, Godfrey CM, Khalil H, et al.: Guidance for conducting systematic scoping reviews. Int. J. Evid. Based Healthc. 2015; 13(3): 141–146. Publisher Full Text
  • 15.  Tricco AC, Lillie E, Zarin W, et al.: PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann. Intern. Med. 2018; 169(7): 467–473. PubMed Abstract | Publisher Full Text
  • 16.  Liberati A, Altman DG, Tetzlaff J, et al.: The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ (Clinical Research ed). 2009; 339: b2700. PubMed Abstract | Publisher Full Text | Free Full Text
  • 17.  Katogiannis K, Thymis J, Kousathana F, et al.: Effects of Liraglutide, Empagliflozin and Their Combination on Left Atrial Strain and Arterial Function. Medicina (Kaunas). 2024; 60(3). Publisher Full Text
  • 18.  Vernstrøm L, Gullaksen S, Sørensen SS, et al.: Separate and combined effects of empagliflozin and semaglutide on vascular function: A 32-week randomized trial. Diabetes Obes. Metab. 2024; 26(5): 1624–1635. PubMed Abstract | Publisher Full Text
  • 19.  Gullaksen S, Vernstrøm L, Sørensen SS, et al.: The effects of semaglutide, empagliflozin and their combination on the kidney sodium signal from magnetic resonance imaging: A prespecified, secondary analysis from a randomized, clinical trial. J. Diabetes Complicat. 2024; 38(2): 108673. PubMed Abstract | Publisher Full Text
  • 20.  Cersosimo E, Alatrach M, Solis-Herrera C, et al.: Emergence of a New Glucoregulatory Mechanism for Glycemic Control With Dapagliflozin/Exenatide Therapy in Type 2 Diabetes. J. Clin. Endocrinol. Metab. 2023; 109(1): 161–170. PubMed Abstract | Publisher Full Text
  • 21.  van Ruiten CC , Veltman DJ, Nieuwdorp M, et al.: Brain Activation in Response to Low-Calorie Food Pictures: An Explorative Analysis of a Randomized Trial With Dapagliflozin and Exenatide. Front. Endocrinol (Lausanne). 2022; 13: 863592. PubMed Abstract | Publisher Full Text | Free Full Text
  • 22.  Builes-Montaño CE, Suarez-Rodriguez AF, Carreño J: Combine glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) in people with type 2 diabetes mellitus (T2DM): A protocol for a scoping review.Publisher Full Text

Comments on this article Comments (0)

Version 1
VERSION 1 PUBLISHED 13 Feb 2025
Comment
Author details Author details
Competing interests
Grant information
Article Versions (1)
Copyright
Download
 
Export To
metrics
Views Downloads
F1000Research - -
PubMed Central
Data from PMC are received and updated monthly.
 - -
Citations
SEE MORE DETAILS
CITE
how to cite this article
Builes-Montaño CE, Suarez-Rodriguez AF and Carreño J. Combining Glucagon-Like Peptide-1 Receptor agonists and Sodium-Glucose Cotransporter-2 Inhibitors in the management of Type 2 Diabetes Mellitus: A protocol for a scoping review [version 1; peer review: 1 approved with reservations]. F1000Research 2025, 14:202 (https://doi.org/10.12688/f1000research.159628.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
track
receive updates on this article
Track an article to receive email alerts on any updates to this article.

Open Peer Review

Current Reviewer Status: ?
Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 1
VERSION 1
PUBLISHED 13 Feb 2025
Views
1
Cite
Reviewer Report 09 Apr 2025
Paschalis Karakasis, Aristotle University of Thessaloniki, Thessaloniki, Greece 
Approved with Reservations
VIEWS 1
https://doi.org/10.5256/f1000research.175387.r375414
The authors present protocol for a scoping review that aims to synthesize the current evidence on the combined use of GLP-1 receptor agonists (GLP-1RAs) and SGLT-2 inhibitors (SGLT-2is) in the treatment of type 2 diabetes mellitus (T2DM).

... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Karakasis P. Reviewer Report For: Combining Glucagon-Like Peptide-1 Receptor agonists and Sodium-Glucose Cotransporter-2 Inhibitors in the management of Type 2 Diabetes Mellitus: A protocol for a scoping review [version 1; peer review: 1 approved with reservations]. F1000Research 2025, 14:202 (https://doi.org/10.5256/f1000research.175387.r375414)
The direct URL for this report is:
https://f1000research.com/articles/14-202/v1#referee-response-375414
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Report a concern

Comments on this article Comments (0)

Version 1
VERSION 1 PUBLISHED 13 Feb 2025
Comment

Open Peer Review

Reviewer Status

Alongside their report, reviewers assign a status to the article:

Approved
The paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations
A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved
Fundamental flaws in the paper seriously undermine the findings and conclusions

Reviewer Reports

Invited Reviewers
1
Version 1
13 Feb 25 		read
  1. Paschalis Karakasis, Aristotle University of Thessaloniki, Thessaloniki, Greece

Comments on this article

All Comments(0)

Add a comment
Sign up for content alerts

Browse by related subjects

    keyboard_arrow_left Back to all reports
    Alongside their report, reviewers assign a status to the article:
    Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
    Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
    Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
    Sign In
    If you've forgotten your password, please enter your email address below and we'll send you instructions on how to reset your password.

    The email address should be the one you originally registered with F1000.
    Email address not valid, please try again

    You registered with F1000 via Google, so we cannot reset your password.

    To sign in, please click here.

    If you still need help with your Google account password, please click here.

    You registered with F1000 via Facebook, so we cannot reset your password.

    To sign in, please click here.

    If you still need help with your Facebook account password, please click here.

    Code not correct, please try again
    Email us for further assistance.
    Server error, please try again.