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. 2025 Apr 16;2025(4):CD016144. doi: 10.1002/14651858.CD016144

Blood pressure lowering efficacy of dual glucose‐dependent insulinotropic polypeptide/glucagon‐like peptide‐1 (GIP/GLP‐1) receptor agonists compared to glucagon‐like peptide‐1 (GLP‐1) receptor agonists

Guillaume Grenet 1,2,3,✉, Arthur Gougeon 2, Douglas M Salzwedel 1, Ciprian D Jauca 1, James M Wright 1
Editor: Cochrane Central Editorial Service
PMCID: PMC12001313  PMID: 40237182

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To compare the blood pressure effects of dual glucose‐dependent insulinotropic polypeptide/glucagon‐like peptide‐1 (GIP/GLP‐1) receptor agonists with the blood pressure effects of glucagon‐like peptide‐1 (GLP‐1) receptor agonists.

Background

Description of the condition

Blood pressure is the pressure of circulating blood on the walls of arterial blood vessels [1]. Systolic (maximum during one heartbeat) and diastolic (minimum in between two heartbeats) blood pressures are usually measured in millimeters of mercury (mmHg). When the resting blood pressure is chronically elevated, it is called hypertension and leads to an increased risk of stroke, myocardial infarction and heart failure [1]. When blood pressure is too low, it can lead to fainting, falls and injuries [1].

In some cases, an increased or a decreased blood pressure can be observed as a side or complementary effect of substances that were not initially designed for these impacts [2, 3]. Therefore, it is important to confirm such effects when suggested for other drugs.

Description of the intervention and how it might work

Dual glucose‐dependent insulinotropic polypeptide (formerly known as gastric inhibitory peptide)/glucagon‐like peptide‐1 (GIP/GLP‐1) receptor agonists and glucagon‐like peptide‐1 (GLP‐1) receptor agonists have been developed for type 2 diabetes management and have become new weight‐management drugs. Both share a mechanism of action through the GLP‐1 receptor and are referred to as part of the "incretin‐based therapies" [4] or the "GLP‐1 medicines" [5]. The dual GIP/GLP‐1 receptor agonists also provide a complementary action on the GIP pathway, and have been reported to be superior to GLP‐1 receptor agonists in the correction of metabolic disorder from insulin sensitivity [6] to glycemic control [7].

Both are expected to improve blood pressure as "additional benefits" [8]. Indeed, both have been associated with effects on blood pressure [9]. Even if weight loss is associated with lower systolic blood pressure [8], it has been suggested that the drug's induced weight loss only partly explains the blood pressure lowering effect [10, 11]. Direct mediation via GLP‐1 receptor activation on blood vessels and kidneys, including improvement of endothelial function, vasodilation and natriuresis, has been suggested as a potential mechanism, but it remains unclear how these drugs impact blood pressure regulation [12].

Dual GIP/GLP‐1 receptor agonists decrease systolic and diastolic blood pressure in people with type 2 diabetes [10, 13], and in people with a body mass index of 27 kg/m2 or greater without type 2 diabetes [14]. GLP‐1 receptor agonists might decrease systolic blood pressure in people with type 2 diabetes [15, 16], and in people without type 2 diabetes [17, 18], but might increase diastolic blood pressure in people with type 2 diabetes [19, 20]. It is unclear why GLP‐1 receptor agonists would have a differential effect on systolic blood pressure versus diastolic blood pressure. Effects on extracellular volume homeostasis and arterial stiffness have been suggested to explain a better effect of GLP‐1 receptor agonists on systolic blood pressure [21]. Head‐to‐head trials of dual GIP/GLP‐1 receptor agonists and GLP‐1 receptor agonists in people with type 2 diabetes reported changes in systolic and diastolic blood pressure within each arm (compared to their respective baseline) but without formal between‐arm comparisons [6, 22]. In type 2 diabetes, one meta‐analysis reported a reduction in systolic blood pressure when pooling all GLP‐1 receptor agonists and dual GIP/GLP‐1 receptor agonists compared to insulin (mean difference [MD] −3.7 mmHg, 95% confidence interval [CI] −4.3 to −3.1), that was most prominent in the comparison of tirzepatide versus basal insulin treatment (MD −5.6 mmHg, −6.4 to −4.8); and suggested a subgroup difference between dual GIP/GLP‐1 receptor agonists and long‐acting GLP‐1 receptor agonists when compared to basal insulin (the heterogeneity of the incretin effect compared to insulin was substantial with an I2 statistic of 72%), but without formal indirect comparison [23]. They reported similar findings for the effect on diastolic blood pressure (however, with no significant differences for the pooled GLP‐1 receptor agonists treatments).

Why it is important to do this review

The approval of GLP‐1 and dual GIP/GLP‐1 receptor agonists for weight management in addition to their use in type 2 diabetes in 2023 [24], raises the question of which class is the best choice in these conditions. This question will potentially concern vast numbers of people, from 800 million with diabetes [25] to more than one billion with obesity [26]. This question might also extend to their use for metabolic dysfunction‐associated steatotic liver disease, cardiovascular disease prevention and a large variety of other hypothetic benefits [27].

One Cochrane review assessing GLP‐1 receptor agonists for type 2 diabetes reported liraglutide 1.8 mg daily, a GLP‐1 receptor agonist, reduced systolic blood pressure by about 2 mmHg compared with placebo; however, it was published in 2011 and this result was limited to about 1000 participants from three trials [28]. A more recent update of another Cochrane review assessing the long‐term effects of weight‐reducing drugs in people with hypertension did not identify any relevant studies investigating liraglutide in people with hypertension [29]. One Cochrane protocol assessing GLP‐1 receptor agonists for overweight or obese adults includes blood pressure as a secondary outcome, but is limited to GLP‐1 receptor agonists [30].

Choosing between a dual GIP/GLP‐1 or a GLP‐1 receptor agonist for diabetes, weight management or other conditions is an important issue. As arterial hypertension remains "one of the world's leading risk factors for death and disability" [31], better understanding of the blood pressure effect of dual GIP/GLP‐1 receptor agonists versus GLP‐1 receptor agonists will help in choosing the most appropriate treatment.

Objectives

To compare the blood pressure effects of dual glucose‐dependent insulinotropic polypeptide/glucagon‐like peptide‐1 (GIP/GLP‐1) receptor agonists with the blood pressure effects of glucagon‐like peptide‐1 (GLP‐1) receptor agonists.

Methods

The review will be conducted following the Methodological Expectations for Cochrane Intervention Reviews [32] and reported following PRISMA guidelines [33].

Criteria for considering studies for this review

Types of studies

We will include only randomized controlled trials (i.e. with a random allocation of the interventions). This will ensure that we have more confidence in the findings compared to non‐randomized studies, and our outcomes of interest are expected to be well captured in randomized trials. Hence, we will exclude non‐randomized studies (including 'quasi‐randomized' as defined in the Cochrane Handbook for Systematic Reviews of Interventions [34]).

We will exclude cluster‐randomized studies because they do not allow assessment of the intervention effect at the individual level. We will include cross‐over studies, but will use only data from the first period to avoid a carry‐over effect. There will be no restrictions on the year of publication, report status or language.

Types of participants

We will include participants of any age, sex and ethnicity, with and without hypertension. Following a previous approach [3], all participants treated with the interventions of interest will be included without restriction by type of disease.

We will include healthy participants. We will use the definition of the US National Institutes of Health (NIH) to characterize 'healthy' participants as people with "no known significant health problems who participate in research to test a new drug" [35]. Including healthy participants will allow us to assess the specific impact of the intervention on blood pressure without the potential impact of the underlying indication of the intervention.

We will include studies with subsets of eligible participants only if data for that subset are reported separately. If not, we will contact the study authors to request those data.

Types of interventions

Experimental intervention

We will include any dose of any dual GIP/GLP‐1 receptor agonist with any administration form, including tirzepatide, VK2735, SCO‐094 and CT‐388.

Control intervention

We will include any dose and any administration form of any peptide GLP‐1 receptor agonist, including albiglutide, dulaglutide, efpeglenatide, exenatide, ITCA 650, liraglutide, lixisenatide, semaglutide and taspoglutide.

Excluded interventions (experimental or control)

We will exclude other gut hormone agonists such as: GLP‐1 receptor agonists – GIP antagonists (AMG 133 [maridebart cafraglutide]), dual GLP‐1/glucagon receptor agonists (cotadutide, survodutide, mazdutide), dual GLP‐1/amylin receptor agonists (cagrisema) and triple GLP‐1/GIP/glucagon receptor agonists (retatrutide). We will exclude non‐peptide GLP‐1 receptor partial agonists (orforglipron).

Outcome measures

We will include studies that meet the above inclusion criteria regardless of whether they report the following outcomes.

Critical outcomes

  • Resting systolic and diastolic arterial blood pressure (mmHg) measured at short‐term (between 3 and 12 weeks), medium‐term (between 3 and 12 months) and long‐term (beyond 12 months)

We selected these pragmatic time frames for the following reasons: short‐term is expected to be related to any direct blood pressure effect of the drug itself [12]; medium‐term is expected to reflect the indirect effect via weight loss [11]; and long‐term is expected to show if the blood pressure effects are sustained or transient, as suggested in a previous trial [36].

The preferred measure of the outcome will be resting (and sitting) clinic measurement. We will use home blood pressure measurement if no clinic measurement is available. The preferred measurement of the outcome will be using an oscillometric technique. We will use an auscultatory technique if no oscillometric measurement is available.

In line with a previous Cochrane protocol [37], if more than one blood pressure measurement is reported during one treatment period, we will use the weighted mean of the blood pressure measurements to optimize use of the available data for the corresponding treatment period. The preferred measure of blood pressure change will be the change from baseline versus control (i.e. the difference, between experimental and control intervention, in change from baseline). If the change is not reported, we will use the end of treatment blood pressure value of the experimental versus the control intervention to calculate the pooled difference.

It should be noted that this review will be limited to the assessment of the blood pressure effect. Blood pressure is often used as a surrogate for cardiovascular prevention, but a benefit on blood pressure only suggests a potential clinical benefit that remains to be demonstrated. Previous Cochrane reviews addressed the issue of blood pressure targets, for example in adults with hypertension [38].

Important outcomes

  • Heart rate (beats per minute, resting), weight (kilograms) and body mass index (weight in kilograms divided by height in meters squared): changes at the same time periods as blood pressure measurements and defined as for the blood pressure outcomes (preferably difference in change from baseline, if not available, then difference in end of treatment value).

  • Withdrawal due to adverse effects and serious adverse events: over the duration of the study. It should be noted that we classified these safety outcomes under secondary outcomes because the review's primary concern is the blood pressure effect. However, adverse events of any type are crucial, especially for drugs that are relatively new and with proven intolerance.

Search methods for identification of studies

Electronic searches

The Cochrane Hypertension Information Specialist will search the following databases for randomized controlled trials without language, publication year or publication status restrictions.

  • Cochrane Hypertension Specialised Register via the Cochrane Register of Studies

  • Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies

  • Ovid MEDLINE(R) ALL

  • Ovid Embase

  • US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (https://www.clinicaltrials.gov)

We will retrieve results from the World Health Organization International Clinical Trials Registry Platform (https://trialsearch.who.int) as part of the search of CENTRAL.

The Information Specialist will model the subject strategies for databases on the search strategy designed for MEDLINE. Where appropriate, they will combine the subject strategy adaptations of the sensitivity and precision maximizing search strategy designed by Cochrane for identifying randomized controlled trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions [32]). We present the MEDLINE search strategy in Supplementary material 1.

Searching other resources

The Information Specialist will search the Hypertension Specialised Register segment to retrieve published systematic reviews related to this review title, so that we can scan their reference lists to identify additional relevant trials.

We will check the reference lists of included studies and any relevant systematic reviews identified for further references to relevant trials.

We will check the included studies for retractions and errata via the Retraction Watch Database and report the search dates in the review (retractiondatabase.org).

We will search Epistemonikos for related systematic reviews (https://www.epistemonikos.org).

We may contact the original authors or funders of included studies for clarification and further data if trial reports are unclear.

Data collection and analysis

No review authors are involved in studies potentially eligible for inclusion.

Selection of studies

Two review authors (AG and GG) will independently conduct the study selection process. First, we will screen titles and abstracts of citations against the inclusion and exclusion criteria. We will retrieve and assess full‐text articles of potentially relevant trials for inclusion. Assessing for inclusion criteria will be standardized by looking sequentially at each parameter of the PIC(O) (study design criteria, participant criteria, intervention criteria, comparator criteria), as far as needed to reach a conclusion regarding the study's eligibility. A third review author (JMW) will resolve discrepancies. We will report the results using a flow chart. If needed, we will contact trial authors to request any missing information that would help determine study eligibility.

Data extraction and management

Two review authors (GG and AG) will independently extract data using a standardized template. We will discuss any disagreements to reach consensus, and if necessary, a third review author (JMW) will resolve any disagreements. We will extract data from available reports of included trials. In the case of discrepancies in data from reports of the same trial, we will prioritize as follows: regulatory data; published data; registry data; preprint data and non‐academic reports.

For continuous outcomes, such as blood pressure, we will use the available data as defined in the Outcome measures section. For binary outcomes, we will use the reported (adjusted) hazard ratio (HR). If the HR is not reported, we will use the risk ratio (RR) or incident rate ratio if the RR is not available.

We will transfer data into Review Manager [39]. We will pilot‐test a data collection form using a random sample of five studies before commencing the full data extraction. We will extract the following data.

  • Study description, including identification of the trial, study design, eligibility criteria (including indication of the intervention), setting, intervention, number of people (randomized and lost to follow‐up), demographics of the included population, time of follow‐up, subgroup category.

  • Data for risk of bias assessment and of funding for the trial and other notable conflicts of interest of the trial authors.

  • Data for the outcome assessment including baseline, short‐term, medium‐term and long‐term values for continuous outcomes and including number of people exposed and number of people with events (or number of events if not available) for binary outcomes.

  • Information needed to assess the certainty of the evidence following the GRADE approach.

Risk of bias assessment in included studies

We will assess the risk of bias in each trial using a modified version of Cochrane's RoB 1 tool for assessing risk of bias as outlined in the Cochrane Handbook for Systematic Reviews of Interventions [40]. We will assess the following domains: sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data and within‐study selective outcome reporting. Two review authors (GG and AG) will independently assess the risk of bias for each study based on these domains with ratings of 'low', 'high' and 'unclear' risk of bias. We will resolve discrepancies by discussion and consensus, and, if needed, by consulting a third review author (JMW). All our outcomes might be potentially influenced by knowledge of intervention received, and, therefore, do not need to be assessed differently for any of the domains.

We will report trial sponsorship, role of sponsor and intervention related to the sponsor (experimental or control) separately from the risk of bias assessment. We will conduct sensitivity analyses to assess the robustness of findings when restricting the synthesis to trials at overall low risk of bias and non‐industry sponsored trials. Indeed, the potential industry bias remains important to consider because of its impact on the results [41]. The overall risk of bias will be defined as the least favorable assessment across the domains of bias.

Measures of treatment effect

We will use mean differences (MDs) and corresponding 95% confidence intervals (CIs) to compare the effects of different treatments on the continuous outcomes. We will extract and use change from baseline values, or end‐of‐treatment values if the former are not available. We will ensure that all scales are measuring their effect in the same direction, and we will convert any that run counter to others. We do not expect that it will be necessary to use standardized mean differences (SMDs) and their 95% CIs. Randomization allows integrating differences in mean changes and differences in end‐of‐treatment values as previously done [37]. If data are not reported in a randomized controlled trial in a format that we can enter directly into a meta‐analysis, we will convert them to the required format using the method described in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions [42]. We will assess withdrawals due to adverse events and serious adverse events using relative estimates of the treatment effect; absolute estimates of the treatment effect will be provided by applying the relative risk to the risk in the control group.

Unit of analysis issues

For cross‐over studies, we will include data from only the first period. We will exclude cluster‐randomized trials. Following Cochrane guidance, we will combine arms assessing different doses of the same drug [43].

Dealing with missing data

We will contact study authors to request missing data. We will use available data to estimate missing summary data following standard calculations if needed [44]. For continuous outcomes, such as blood pressure measurements, if neither the change from baseline nor the end‐of‐treatment values are available, we will consider data as missing. We will look for patterns suggesting data are not missing at random, but will limit the analysis to the available data (including transformed data following standard calculations). We will not use one of the time measurements as a replacement value for another time measurement and will not impute missing data. For withdrawal due to adverse effects and serious adverse events, if studies do not report the number of people with at least one event, we will use the number of events instead. If they do not report the number of people exposed, then we will use the number of people randomized instead.

Reporting bias assessment

We will assess the risk of reporting bias for each outcome with at least 10 point estimates available. First, we will report both contour‐enhanced funnel plots [45] and the P value of the Egger's test [46], the latest being more sensitive than the Begg's test [47]. Then, in case of suspected publication bias based on the visual inspection of the funnel plot or the Egger's test (or both), we will provide pooled estimates adjusted for publication bias using the trim‐and‐fill method [48].

Synthesis methods

We will use the inverse‐variance weighting method to provide a pooled estimate of the effect (point estimate with 95% CI) for each outcome. As we expect a low number of dual GIP/GLP‐1 receptor agonists (probably only one at this stage), and in order to not overemphasize small trials, we will use a fixed‐effect model to pool the estimates. We will use Review Manager for analysis [39]. All P values will be considered as 'significant' at the 5% threshold without multiple testing correction. If meta‐analysis is not possible, we will report the available point estimates of the treatment effect and, if possible, their range and distribution. The synthesis will be limited to univariate analysis without covariate adjustment. We do not expect enough data for more complex analysis. However, we will explore the potential impact of some covariates in subgroup analysis (see Investigation of heterogeneity and subgroup analysis).

Investigation of heterogeneity and subgroup analysis

We will assess methodological heterogeneity by describing the proportion of each time point of the critical outcome (how many trials report the short‐term, medium‐term and long‐term critical outcome). We will assess clinical heterogeneity by describing the proportions of each indication of the intervention (how many trials investigating the intervention in diabetes, in obesity, etc.). We expect enough similarity in studies to conduct meta‐analysis, but we will report an assessment of the heterogeneity using the I2 statistic. We plan the following subgroup analyses to assess potential heterogeneity related to:

  • participants (subgroups: healthy versus non‐healthy, as defined in Types of participants);

  • drugs (subgroups: each included drug comparisons, i.e. each dual GIP/GLP‐1 receptor agonist versus each peptide GLP‐1 receptor agonist, doses and administration form pooled for each drug; rather than drug classes comparisons).

Indeed, the blood pressure effect of the GLP‐1 receptor agonist class might vary depending on the GLP‐1 receptor agonist used. For example, an increased diastolic blood pressure has been reported with liraglutide [20], but not with others such as dulaglutide [49]. All P values will be considered as 'significant' at the 5% threshold without multiple testing correction, even for the subgroup interaction tests.

Equity‐related assessment

It has been well documented that lower socioeconomic position is associated with higher adult body mass index and increased obesity risk [50]. Better understanding the effect of weight management drugs might help to address such health inequity issues. Gender differences in the regulation of blood pressure have also been reported [51]. We will report the description of the socioeconomic status and the gender of the participants in the included trials.

Sensitivity analysis

We will assess the robustness of the pooled estimates using sensitivity analysis as follows.

  • Restricted to trials at overall low risk of bias

  • Outcome measure subgroups

    • Home versus in the clinic blood pressure measurement

    • Differences of mean change versus differences of end‐of‐treatment values

  • Using a random‐effects model

Certainty of the evidence assessment

We will follow the GRADE approach [52] for assessing the certainty of the evidence using the GRADEpro GDT software [53] and according to the guidelines provided in the CochraneHandbook for Systematic Reviews of Interventions [54]. We will use the five GRADE considerations (overall risk of bias, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of the body of evidence for blood pressure, withdrawal due to adverse effects and serious adverse events as follows.

  • Prioritized comparison: dual GIP/GLP‐1 receptor agonists class versus GLP‐1 receptor agonists class

  • Blood pressure outcomes hierarchized as follows: short‐term systolic blood pressure, short‐term diastolic blood pressure, medium‐term systolic blood pressure, medium‐term diastolic blood pressure

  • Safety outcomes: withdrawals due to adverse effects and serious adverse events

The GRADE system uses the following criteria for assigning a grade for the certainty of evidence.

  • High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.

  • Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.

  • Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.

  • Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Two review authors (GG and AG) will independently judge the certainty of evidence. We will resolve any disagreements by discussion or by consulting a third review author (JMW). We will include justified, documented, and incorporated judgments into the reporting of results for each outcome using footnotes to aid the reader's understanding. We will present the findings of the review in a summary of findings table.

Consumer involvement

This review will be focused on blood pressure, an outcome that is commonly used as a target in worldwide clinical practice, and patients and the public are familiar with. We will prepare a clearly written plain language summary, so that patients can understand why it should matter to them that we have written this review. We will involve patients and the public in assessing the readability of the plain language summary.

Supporting Information

Supplementary materials are available with the online version of this article: 10.1002/14651858.CD016144.

Supplementary materials are published alongside the article and contain additional data and information that support or enhance the article. Supplementary materials may not be subject to the same editorial scrutiny as the content of the article and Cochrane has not copyedited, typeset or proofread these materials. The material in these sections has been supplied by the author(s) for publication under a Licence for Publication and the author(s) are solely responsible for the material. Cochrane accordingly gives no representations or warranties of any kind in relation to, and accepts no liability for any reliance on or use of, such material.

Supplementary material 1 Search strategies

CD016144-SUP-01-searchStrategy.html (29.1KB, html)

New

Additional information

Acknowledgements

Cochrane Hypertension supported the authors in the development of this protocol. DMS, CDJ and JMW are members of Cochrane Hypertension (Information Specialist, Managing Editor and Co‐ordinating Editor, respectively), but were not involved in the editorial process or decision‐making for this review. GG is affiliated with the Cochrane Hypertension Working Group of the Therapeutics Initiative but is not involved in the editorial process of Cochrane Hypertension.

Editorial and peer‐reviewer contributions

The following people conducted the editorial process for this article.

  • Sign‐off Editor (final editorial decision): Juan Erviti, Navarre Health Service, Pamplona, Spain

  • Managing Editor (selected peer reviewers, provided editorial guidance to authors, edited the article): Sue Marcus, Cochrane Editorial Service

  • Editorial Assistant (conducted editorial policy checks, collated peer‐reviewer comments and supported editorial team): Jacob Hester, Cochrane Central Editorial Service

  • Copy Editor (copy editing and production): Anne Lawson, Cochrane Central Production Service

  • Peer‐reviewers (provided comments and recommended an editorial decision): Hammam Omar Ibrahim – Egypt/Ministry of Health (consumer review); Clare Miles, Evidence Production and Methods Directorate (methods review); Ina Monsef, Cochrane Evidence Synthesis Unit (ESU) Germany, Institute of Public Health, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany (search review). Two additional peer reviewers provided clinical/consumer peer review but chose not to be publicly acknowledged.

Contributions of authors

GG formulated the idea and wrote the first draft of the protocol.

AG, CDJ, DMS and JMW contributed to the write‐up and reviewed the manuscript.

DMS devised the search strategy.

Declarations of interest

GG has received a grant from the French association for balneotherapy research "Association Française pour la Recherche Thermale" (AFRETh, http://www.afreth.org/) that is not related to this review.

AG is a PhD candidate funded by RCTs (https://www.rcts.fr/en, an international full‐service clinical research organization) under the "dispositif des Conventions industrielles de formation par la recherche (Cifre)" French policy and his PhD funding is not related to this review.

DMS: no relevant interests; Information Specialist of Cochrane Hypertension but was not involved in any part of the editorial process of this review.

CDJ: no relevant interests; Managing Editor of Cochrane Hypertension but was not involved in any part of the editorial process of this review.

JMW: no relevant interests; Co‐ordinating Editor of Cochrane Hypertension but was not involved in any part of the editorial process of this review.

We will follow the Cochrane's Conflict of Interest documentation (COI policy: https://training.cochrane.org/online-learning/coi-policy/coi-policy-cochrane-library), "Anyone engaged in writing a Cochrane review, who has had direct involvement in the conduct, analysis, and publication of a study that could be included in the review, cannot make study eligibility decisions about, extract data from, carry out the risk of bias assessment for, or perform GRADE assessments of that study." None of the authors of this protocol has been involved in any studies expected to be included.

Sources of support

Internal sources

  • Faculty of Medicine, University of British Columbia, Canada

    Salary and infrastructure support. The Faculty of Medicine, University of British Columbia had no involvement in the development of the protocol. The views and opinions expressed herein are those of the review authors and do not necessarily reflect those of the Faculty of Medicine, University of British Columbia.

External sources

  • British Columbia Ministry of Health, Canada

    Infrastructure grant to our parent organization, the Therapeutics Initiative. The British Columbia Ministry of Health had no involvement in the development of the protocol. The views and opinions expressed herein are those of the review authors and do not necessarily reflect those of the British Columbia Ministry of Health.

Registration and protocol

This is the protocol that is submitted for publication.

Data, code and other materials

Data sharing not applicable to this article as it is a protocol, so no datasets were generated or analyzed.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary material 1 Search strategies

CD016144-SUP-01-searchStrategy.html (29.1KB, html)

Data Availability Statement

Data sharing not applicable to this article as it is a protocol, so no datasets were generated or analyzed.

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