Glycemic Velocity and Early Retinal Microvascular Change With GLP-1RA Versus SGLT2i Initiation in Type 2 Diabetes (GLIDE) (GLIDE)

July 22, 2026 updated by: Wit Tharanon, Thammasart University Hospital

Glycemic Velocity as a Modifiable Determinant of Early Retinal Microvascular and Choroidal Change During Initiation of GLP-1 Receptor Agonist Versus SGLT2 Inhibitor Therapy in Type 2 Diabetes: A Prospective Multimodal Retinal Imaging Cohort Study (the GLIDE Study)

The GLIDE study looks at how the small blood vessels of the eye respond during the first months of a new diabetes medicine. Two widely used classes of glucose-lowering drugs, GLP-1 receptor agonists and SGLT2 inhibitors, are compared in adults with type 2 diabetes who have no diabetic retinopathy or only early (mild) diabetic retinopathy.

When blood sugar (HbA1c) falls quickly after starting treatment, the retina can undergo a brief, temporary worsening before it stabilizes and benefits over the long term. This study asks whether it is the speed of that blood-sugar reduction, which we call "glycemic velocity," rather than the specific drug, that drives early changes in retinal and choroidal blood flow.

Participants are patients whose own physician has decided, independently of the study, to start one of these two drugs for the first time. The study does not choose, provide, or change any medicine; it adds only eye imaging, blood tests, and observation. Each participant is followed with specialized, non-invasive eye scans, optical coherence tomography angiography (OCT-A) and structural/choroidal OCT, together with HbA1c and other measurements, at the start of treatment and again over the following months.

The main measurement is the change, from the start of treatment to month 3, in the density of the tiny deep-layer capillaries at the center of the retina, measured on OCT-A. The study will test whether faster HbA1c reduction is linked to greater early change in these vessels and, using statistical mediation analysis, will estimate how much of any difference between the two drug groups is explained by glycemic velocity versus a direct drug effect.

If glycemic velocity, a factor physicians can influence by adjusting how quickly treatment is intensified, turns out to drive early retinal change, the findings could guide safer treatment strategies and help identify patients who need closer eye monitoring when starting these medicines.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Background and rationale:

GLP-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) are central therapies for type 2 diabetes, and their ocular safety remains unresolved. The cardiovascular outcome trial SUSTAIN-6 reported more adjudicated diabetic-retinopathy complications with semaglutide than placebo, concentrated among patients with pre-existing retinopathy and concurrent insulin use, whereas large real-world datasets have not reproduced a consistent signal. Mechanistic and meta-analytic work increasingly attributes the trial signal not to the molecule itself but to the magnitude and rapidity of the accompanying fall in glycated hemoglobin (HbA1c), the long-recognized phenomenon of transient "early worsening" of retinopathy after rapid glycemic correction, first characterized in the Oslo study and subsequently in the DCCT.

Central hypothesis and definition of the exposure:

The study formalizes the driver of early worsening as a continuous, patient-level exposure termed glycemic velocity: the rate at which HbA1c falls after treatment initiation, computed as (HbA1c at baseline - HbA1c at Month 3) divided by elapsed time and expressed in percentage points per month. It is analyzed per +1 SD, with a clinically anchored secondary scale of +0.5 percentage points per month and a pre-specified test for non-linearity or a threshold effect. Baseline HbA1c and the absolute magnitude of HbA1c reduction are retained as separate covariates so that the effect of rate is distinguished from that of magnitude and of starting level. The complementary mechanistic hypothesis is that a transient disturbance of retinal and choroidal perfusion (relative hypoxia) is the shared intermediate underlying GLP-1RA-associated ocular signals, and that its magnitude tracks with glycemic velocity.

Rationale for the design:

Drug choice is made by the treating physician on clinical grounds; the study assigns, provides, and alters no therapy, adding only observation, imaging, and data collection. A new-user, active-comparator structure is used because enrolling only treatment-naive initiators removes prevalent-user and immortal-time biases, while an active comparator rather than non-users minimizes confounding by indication and the healthy-user effect. SGLT2i was selected as the comparator because it shares the glucose-lowering indication and a broadly comparable position in contemporary treatment algorithms, yet is not classically implicated in early retinopathy worsening, providing the contrast needed to separate a drug-specific retinal effect from the drug-independent consequence of rapid glycemic correction. Because glycemic velocity is a continuous measured variable present in both groups, the primary hypothesis remains testable irrespective of how patients were allocated to drug class. Enrollment into each group is capped to preserve balance for the between-group comparison. Both eyes are imaged, with the eye-visit as the unit of observation and statistical accounting for inter-eye correlation.

Visit schedule and data acquisition:

Patients are identified at the point of treatment initiation and referred the same day, or within the permitted baseline window, for screening and baseline imaging. Assessments occur at Baseline (V0), Month 1 (V1, plus or minus 2 weeks), and Month 3 (V2, plus or minus 2 weeks), with a pre-planned companion analysis of longer-term trajectory over an extended follow-up described in the protocol. All imaging is performed on a single OCT-angiography/OCT platform by trained operators using a fixed acquisition protocol, and only scans meeting a pre-specified signal-strength and artifact threshold are analyzed. Quantitative metrics are produced by validated device software, with choroidal indices derived by standardized image binarization. Two independent graders, masked to drug class, glycemic data, and visit sequence, perform ETDRS grading and quality control, with senior adjudication of discrepancies; inter- and intra-grader reliability is quantified on a randomly selected double-graded subset using intraclass correlation coefficients and weighted kappa, against a pre-specified target. Data are captured in REDCap with role-based access rights and a full audit trail, and the metabolic and imaging datasets are reconciled only at the analysis stage.

Sample-size justification:

Enrolment is governed by the between-group contrast in the primary outcome: detecting a difference of 2.0 percentage points (SD 3.5; Cohen's d approximately 0.57) at a two-sided alpha of 0.05 with 80% power requires approximately 49 participants per group. This exceeds the requirement for the primary association (approximately 62 participants for a partial correlation of r = 0.35, by Fisher's z-transformation) and therefore governs, and is inflated by approximately 20% for anticipated attrition and ungradable imaging. Repeated measures and the use of both eyes further increase effective precision. A non-inferential feasibility review after 40 participants complete Month 3 assesses imaging gradability, recruitment rate, and the plausibility of the assumed effect sizes; no efficacy stopping rule applies.

Statistical analysis:

The primary analysis fits a linear mixed-effects model of the primary outcome over time, with the glycemic velocity by time interaction as the principal test, adjusted for drug class and for pre-specified confounders (age, sex, diabetes duration, baseline retinopathy severity, baseline HbA1c, magnitude of HbA1c reduction, blood pressure, eGFR, axial length, and OCT-angiography signal strength), and with random intercepts for participant and for eye nested within participant. The model uses all available eye-visit observations under a missing-at-random assumption. A causal mediation analysis in the counterfactual framework decomposes the total effect of drug class on the primary outcome into a natural indirect effect transmitted through glycemic velocity and a natural direct, unmediated effect; exposure-mediator interaction is permitted, and inference uses bootstrap confidence intervals with E-value sensitivity analysis for unmeasured mediator-outcome confounding. Baseline balance between groups is summarized using standardized mean differences rather than significance tests, and propensity-score methods (overlap weighting or matching) serve as a confounding-control sensitivity analysis. Pre-specified effect modification by baseline retinopathy severity and by insulin co-therapy is tested through interaction terms and interpreted as hypothesis-generating. Analyses follow a statistical analysis plan finalized and signed before database lock, are conducted in R or Stata, and are reported in accordance with STROBE and, for the mediation component, AGReMA.

Study Type

Observational

Enrollment (Estimated)

126

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Wit Tharanon, Doctor of medicine
  • Phone Number: +66944989500
  • Email: wthara@tu.ac.th

Study Contact Backup

  • Name: Kanokporn Sanpawithayakul, MD, MSc, PhD
  • Phone Number: +66 86 772 4409
  • Email: kanokpor2@tu.ac.th

Study Locations

  • Thailand
    • Khlong Luang
      • Pathum Thani, Khlong Luang, Thailand, 12120
        • Faculty of Medicine, Thammasat University
        • Contact:
          • Wit Tharanon, Doctor of medicine
          • Phone Number: +66944989500
          • Email: wthara@tu.ac.th
        • Principal Investigator:
          • Kanokporn Sanpawithayakul, MD, MSc, PhD
        • Sub-Investigator:
          • Wit Tharanon, MD.
        • Sub-Investigator:
          • Kittichai Akrapipatkul, Assoc.Prof.
        • Sub-Investigator:
          • Nattapon Wongcumchang, Assoc.Prof.
        • Sub-Investigator:
          • Pacharaporn Dedpirattanamongkhon, MD.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Adults with type 2 diabetes attending the diabetes/endocrinology clinics of Thammasat University Hospital who are initiating, for the first time, a GLP-1 receptor agonist or an SGLT2 inhibitor on their treating physician's decision, and who have no diabetic retinopathy or only mild non-proliferative diabetic retinopathy at baseline.

Description

Inclusion Criteria:

  • Adults aged 18 years or older with a documented diagnosis of type 2 diabetes mellitus.
  • Clinical decision, made by the treating physician independently of the study, to initiate a first-ever GLP-1 receptor agonist or a first-ever SGLT2 inhibitor.
  • Baseline retinal status ranging from no diabetic retinopathy to mild non-proliferative diabetic retinopathy (NPDR) in the study eye(s), confirmed by fundus photography / ETDRS grading.
  • Baseline HbA1c within a range permitting a measurable subsequent change (e.g., 7.0% or higher), obtained within 30 days before or after the scheduled ophthalmic assessment.
  • Media sufficiently clear and fixation adequate to obtain gradable OCT-A and OCT images.
  • Able and willing to provide written informed consent and to attend scheduled follow-up visits.

Exclusion Criteria:

  • Moderate-to-severe NPDR, proliferative diabetic retinopathy, or center-involving diabetic macular edema at baseline.
  • Prior or concurrent treatment for diabetic retinopathy or maculopathy: pan-retinal or focal/grid laser photocoagulation, intravitreal anti-VEGF or corticosteroid therapy, or vitreoretinal surgery.
  • Any prior exposure to a GLP-1 receptor agonist or SGLT2 inhibitor (to preserve the new-user design).
  • Type 1 diabetes, latent autoimmune diabetes of adults, or secondary diabetes.
  • Other retinal or choroidal disease that would confound microvascular/choroidal measurement: age-related macular degeneration, retinal vein or artery occlusion, uveitis, high myopia (spherical equivalent more negative than -6.0 D or axial length greater than 26.0 mm), or significant media opacity precluding imaging.
  • Coexisting glaucoma or optic neuropathy that independently alters retinal vascular or neural metrics.
  • Recent (within 3 months) intraocular surgery in the study eye, including cataract surgery.
  • Uncontrolled systemic hypertension or a known systemic condition (e.g., significant anemia, severe renal impairment with eGFR < 30 mL/min/1.73 m², or active malignancy) that independently affects retinal perfusion or oximetry, at investigator discretion.
  • Pregnancy, or planned simultaneous initiation of insulin such that the index glucose-lowering exposure cannot be attributed (concurrent stable insulin is permitted and recorded as a pre-specified effect modifier).
  • Inability to provide informed consent or to comply with the imaging and follow-up schedule.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
GLP-1 receptor agonist initiators
Adults with type 2 diabetes and no-to-mild NPDR who are starting a first-ever GLP-1 receptor agonist, prescribed by the treating physician independently of the study. Followed with the standardized multimodal retinal-imaging and metabolic battery. Primary exposure of interest, glycemic velocity, is measured within this cohort.
Drug: GLP-1 Receptor Agonists
First-ever GLP-1 receptor agonist initiated as routine clinical care; class and rate of titration are recorded but not controlled by the study. Mapped to Cohort 1.
SGLT2 inhibitor initiators
Adults with type 2 diabetes and no-to-mild NPDR who are starting a first-ever SGLT2 inhibitor, prescribed by the treating physician independently of the study. Active comparator that shares the glucose-lowering indication but is not classically associated with early retinopathy worsening. Followed with the identical battery.
Drug: SGLT2 inhibitor
First-ever SGLT2 inhibitor initiated as routine clinical care; recorded but not controlled by the study. Mapped to Cohort 2.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in parafoveal deep-capillary-plexus (DCP) vessel density on OCT angiography
Time Frame: Baseline to Month 3
Vessel density (%) of the deep capillary plexus in the parafoveal ring on OCT angiography (fixed macular scan, validated quantification, pre-specified image-quality threshold, masked grading); primary metric is the change from baseline to Month 3.
Baseline to Month 3

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Superficial capillary plexus (SCP) vessel density and perfusion density
Time Frame: Baseline to Month 3
SCP vessel density and perfusion density (%) in standardized macular sectors on OCT angiography.
Baseline to Month 3
Foveal avascular zone (FAZ) area
Time Frame: Baseline to Month 3
FAZ area (mm²) by automated or masked manual delineation on OCT angiography.
Baseline to Month 3
Subfoveal choroidal thickness
Time Frame: Baseline to Month 3
Vertical distance from the outer RPE to the chorioscleral interface at the fovea (µm) on EDI-OCT.
Baseline to Month 3
Choroidal vascularity index (CVI)
Time Frame: Baseline to Month 3
Ratio of luminal to total choroidal area (%) by standardized image binarization on EDI-OCT; indexes the choroidal / hypoxia arm of the mechanism.
Baseline to Month 3
Central subfield thickness
Time Frame: Baseline to Month 3
Mean retinal thickness of the central 1-mm ETDRS subfield (µm) on SD-OCT; surrogate for incipient macular edema.
Baseline to Month 3
Best-corrected visual acuity (BCVA)
Time Frame: Baseline to Month 3
logMAR acuity by ETDRS protocol refraction; functional correlate.
Baseline to Month 3
Proportion of drug-class effect mediated by glycemic velocity
Time Frame: Baseline to Month 3
From causal mediation analysis: the proportion of any between-group (GLP-1RA vs SGLT2i) difference in early DCP vessel-density change that is transmitted through glycemic velocity (natural indirect effect) versus a direct, unmediated drug-class effect.
Baseline to Month 3
Diabetic-retinopathy severity step-change (ETDRS)
Time Frame: Baseline to Month 3
Change in ETDRS diabetic-retinopathy level by masked grading of fundus photographs; ≥ 1-step and ≥ 2-step worsening or improvement.
Baseline to Month 3

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Thammasart University Hospital

Collaborators

Thammasat University
Thammasat University Hospital

Investigators

  • Principal Investigator: Kanokporn Sanpawithayakul, MD, MSc, PhD, Department of Clinical Epidemiology, Faculty of Medicine, Thammasat University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

September 1, 2026

Primary Completion (Estimated)

June 1, 2027

Study Completion (Estimated)

September 1, 2027

Study Registration Dates

First Submitted

July 19, 2026

First Submitted That Met QC Criteria

July 19, 2026

First Posted (Actual)

July 23, 2026

Study Record Updates

Last Update Posted (Actual)

July 24, 2026

Last Update Submitted That Met QC Criteria

July 22, 2026

Last Verified

July 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MTU-EC-CE-0-208/69

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

The current protocol does not include an individual-participant-data sharing plan. De-identified data are held under Thailand's Personal Data Protection Act (PDPA); this statement can be updated if a target journal or funder later requires an IPD-sharing commitment.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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