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GLP-1 and Anxiety: Clinical Insights (public)

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September 11, 2025

Clinical studies evaluating the effects of GLP-1 on anxiety

Clinical studies of GLP-1 agents measured anxiety only as secondary outcomes using indirect methods rather than dedicated anxiety scales, with results showing modest changes that do not support a clear direct effect on anxiety.

Abstract

GLP-1 agent studies in patients with type 2 diabetes, overweight/obesity, or cardiovascular disease provide only indirect insights into anxiety outcomes. None of the five trials employed dedicated, validated anxiety scales. Instead, anxiety was measured as a subdomain of general quality‐of‐life instruments (including SF-36v2, DTR-QoL, EQ-5D/EQ-5D-5L, and TRIM-D) or recorded as infrequent neuropsychiatric adverse events.

• In one trial, DTR-QoL anxiety scores increased by 12.9 (SD 20.8) with an insulin degludec/liraglutide combination versus 0.4 (SD 17.2) with insulin degludec alone.
• Another trial reported an EQ-5D Visual Analog Scale improvement of +2.83 with albiglutide compared to +1.36 with placebo (p < 0.001).
• Where systematically documented, anxiety or anxiety disorder adverse events occurred in 0.1–0.8% of participants.

The studies consistently measured anxiety only as a secondary or adverse outcome, and the modest changes and low event rates do not support a clear, direct effect of GLP-1 agents on anxiety.

Methods

We analyzed 5 sources from an initial pool of 18, using 7 screening criteria. Each paper was reviewed for 6 key aspects that mattered most to the research question. More on methods

Papers identified with Elicit search

n = 18

Papers screened using: Human Participants, GLP-1 Intervention, Anxiety Outcomes, Study Design, GLP-1 Effect Attribution, Publication Type, Intervention Focus

n = 18

Papers screened out

n = 13

Papers included for extraction

n = 5

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Paper search

Using your research question “Clinical studies evaluating the effects of GLP-1 on anxiety”, we searched across all trials from the ClinicalTrials.gov corpus. We retrieved the 18 trials most relevant to the query.

Screening

We screened in sources based on their abstracts that met these criteria:

• Human Participants: Does this study involve human participants of any age?
• GLP-1 Intervention: Does this study involve administration of GLP-1 receptor agonists (e.g., exenatide, liraglutide, semaglutide, dulaglutide) or native GLP-1?
• Anxiety Outcomes: Does this study measure anxiety as a primary or secondary outcome using validated instruments OR report anxiety-related adverse events with quantifiable data?
• Study Design: Is this study a randomized controlled trial, cohort study, case-control study, cross-sectional study, case series with 3 or more participants, systematic review, or meta-analysis?
• GLP-1 Effect Attribution: Can the effects of GLP-1 on anxiety be isolated or clearly attributed to the GLP-1 intervention (rather than confounded by other simultaneous interventions)?
• Publication Type: Is this a peer-reviewed original research study with sufficient methodological detail (not a conference abstract, editorial, commentary, or opinion piece without original data)?
• Intervention Focus: Does this study focus on GLP-1 agonists or native GLP-1 (rather than focusing solely on GLP-1 antagonists or inhibitors)?

We considered all screening questions together and made a holistic judgement about whether to screen in each paper.

Data extraction

We asked a large language model to extract each data column below from each paper. We gave the model the extraction instructions shown below for each column.

• Study Design Type:

Identify the specific type of study design from the full text. Look in the methods section for precise description. Possible types include:

• Randomized controlled trial
• Observational study
• Crossover study
• Parallel group study

If multiple design elements are present, list all. If unclear, note “design not clearly specified”. Prioritize the most specific design description available.

• Intervention Details Related to GLP-1:

Extract specific details about GLP-1 related intervention:

• Specific GLP-1 medication used (e.g., semaglutide, liraglutide)
• Dosage
• Route of administration
• Frequency of administration
• Duration of intervention

Be precise about numerical values. If ranges are provided, record the full range. If multiple intervention arms exist, extract details for each arm separately.

• Participant Demographics:

Extract key demographic information:

• Total sample size
• Age range or mean age
• Gender distribution
• Specific medical conditions or inclusion/exclusion criteria
• Geographic location of study

If percentages or means are provided, record them. If ranges are given, note the full range. If subgroup analyses exist, note those details.

• Anxiety Measurement Methods:

Identify and extract:

• Specific anxiety measurement tools used (e.g., HAM-A, STAI)
• Timing of anxiety assessments
• Primary vs secondary outcome status
• Specific anxiety-related metrics measured

Record exact names of measurement tools. If multiple tools were used, list all. If scoring methods are described, include those details.

• Anxiety-Related Outcomes:

Extract quantitative anxiety outcomes:

• Mean anxiety scores
• Standard deviations
• Statistical significance of anxiety-related findings
• Effect sizes if reported

Prioritize primary outcome data. If multiple time points exist, extract data from each. Note any statistical adjustments or confounding factors considered.

• Study Limitations and Potential Biases:

Extract information about:

• Funding sources
• Potential conflicts of interest
• Limitations acknowledged by authors
• Dropout rates
• Blinding procedures

If multiple limitations are mentioned, list comprehensively. Look specifically in discussion/limitations sections of the full text.

Results

Characteristics of Included Studies

Study Identifier

GLP-1 Agent(s)

Population

Primary Outcomes

Duration

NCT03015220

Semaglutide (oral, 3/7/14 mg daily), Dulaglutide (0.75 mg weekly)

Japanese adults with type 2 diabetes (n=458), mean age 58, 74.5% male, all Asian

Glycemic control, safety

52 weeks\

NCT02911948

Insulin degludec/liraglutide (fixed-ratio), Insulin degludec

Japanese adults with type 2 diabetes inadequately controlled on insulin (n=210), mean age 56, 63.3% male, all Asian

Glycemic control, safety

26 weeks\

NCT01644500

Dulaglutide (0.75, 1.5 mg weekly), Glimepiride

Asian adults with type 2 diabetes (n=737), mean age 52.8, 55.4% male, all Asian

Glycemic control, safety

26 weeks\

NCT03574597

Semaglutide (dose not specified, weekly)

Adults with overweight/obesity and prior cardiovascular disease (n=17,604), mean age 61.6, 72.3% male, 84% White

Major adverse cardiovascular events

2.5–5 years\

NCT02465515

Albiglutide (30–50 mg weekly)

Adults with type 2 diabetes and established cardiovascular disease (n=9,463), mean age 64.1, 69.4% male, 85% White

Major adverse cardiovascular events

Median 1.65 years\

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Key characteristics across studies:

• GLP-1 agents studied:
  • Semaglutide (oral and injectable) in 2 studies
  • Dulaglutide (injectable) in 2 studies
  • Liraglutide (as part of a fixed-ratio with insulin) in 1 study
  • Albiglutide in 1 study
  • One study directly compared two GLP-1 agents (oral semaglutide vs. dulaglutide)
  • One study evaluated a fixed-ratio GLP-1/insulin combination
  • In two studies, the comparator was not a GLP-1 agent (glimepiride, insulin degludec)
• Population:
  • Four studies included adults with type 2 diabetes (three exclusively, one with established cardiovascular disease)
  • One study included adults with overweight/obesity and prior cardiovascular disease
  • Three studies were conducted exclusively in Japanese or Asian populations
  • Two studies were global, with the majority of participants being White (84–85%)
  • Three studies had sample sizes under 1,000; two studies had sample sizes over 1,000
• Primary outcomes:
  • Glycemic control and safety in three studies
  • Major adverse cardiovascular events in two studies
• Duration:
  • Two studies: less than 1 year (26 weeks)
  • One study: 1 year (52 weeks)
  • One study: between 1 and 2 years (median 1.65 years)
  • One study: greater than 2 years (2.5–5 years)

Effects

Direct Anxiety Outcomes

No study used a dedicated, validated anxiety scale (such as the Hamilton Anxiety Rating Scale, State-Trait Anxiety Inventory, or Generalized Anxiety Disorder-7) as a primary or secondary outcome. Anxiety-related outcomes were assessed only indirectly, via subdomains of general quality of life instruments or as adverse events.

Study

Anxiety Measurement Tool(s)

Timing

Primary/Secondary Outcome

Quantitative Results

Statistical Significance/Effect Size

NCT03015220

Short Form-36 version 2 (SF-36v2, mental health), Diabetes Therapy-Related Quality of Life (DTR-QoL, anxiety/dissatisfaction)

Weeks 26, 52

Secondary

SF-36v2 mental health: changes from baseline ranged from -1.64 to +0.27; DTR-QoL anxiety: changes from +0.98 to +12.24

No mention found\

NCT02911948

DTR-QoL (anxiety/dissatisfaction), EuroQol 5-Dimension 5-Level (EQ-5D-5L, anxiety/depression)

Weeks 0, 26

Secondary

DTR-QoL anxiety: +12.9 (SD 20.8) with degludec/liraglutide vs. +0.4 (SD 17.2) with degludec; EQ-5D-5L index: +0.02 (SD 0.08) vs. -0.01 (SD 0.11)

No mention found\

NCT01644500

EQ-5D (anxiety/depression)

Week 26

Secondary

Most participants reported “no problems” (208–214 per group); “some problems” in 7–17 per group; “extreme problems” in none

No mention found\

NCT03574597

EQ-5D-5L (anxiety/depression)

Weeks 0, 104

Secondary

No mention found quantitatively; only as adverse events

No mention found\

NCT02465515

EQ-5D (anxiety/depression), Treatment-Related Impact Measure for Diabetes (TRIM-D, psychological health)

Baseline, months 8, 16

Secondary

EQ-5D Visual Analog Scale (VAS): +2.83 (albiglutide) vs. +1.36 (placebo) at 8 months; TRIM-D psychological health: +6.92 (albiglutide) vs. +4.53 (placebo) at 8 months

EQ-5D VAS: p<0.001 at 8 months; TRIM-D: p<0.001 at 8 months\

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Patterns in anxiety measurement and reporting:

• Measurement tools used:
  • Diabetes Therapy-Related Quality of Life (DTR-QoL): 2 studies
  • EuroQol 5-Dimension (EQ-5D): 2 studies
  • EuroQol 5-Dimension 5-Level (EQ-5D-5L): 2 studies
  • Short Form-36 version 2 (SF-36v2): 1 study
  • Treatment-Related Impact Measure for Diabetes (TRIM-D): 1 study
  • Some studies used more than one tool
• Quantitative anxiety results:
  • Quantitative results were found for 4 studies
    • DTR-QoL anxiety scores: 2 studies
    • EQ-5D or EQ-5D-5L anxiety/depression: 2 studies
    • SF-36v2 mental health and TRIM-D psychological health: each in 1 study
    • One study (NCT01644500) reported proportions of participants with “no problems” or “some problems” on EQ-5D, rather than mean changes
  • No mention found of quantitative anxiety results for 1 study
• Statistical significance or effect size:
  • Statistical significance (p-values) for anxiety-related outcomes was found in 1 study (NCT02465515, p<0.001 for both EQ-5D VAS and TRIM-D)
  • No mention found of statistical significance or effect size reporting for the other 4 studies

Summary of direct anxiety outcomes:

• No study used a dedicated, validated anxiety scale.
• Anxiety was assessed only as a subdomain of general quality of life instruments or as an adverse event.
• Where measured, changes in anxiety-related domains were small and not robustly tested for statistical significance, except in one study.
• The most commonly used tools for anxiety-related domains were DTR-QoL and EQ-5D/EQ-5D-5L (each in 2 studies).

Neuropsychiatric Adverse Events

Study

GLP-1 Agent

Reported Neuropsychiatric Events

Frequency

NCT03015220

Semaglutide, Dulaglutide

No mention found of systematic reporting; no anxiety-specific adverse events noted

No mention found\

NCT02911948

Insulin degludec/liraglutide

No mention found of systematic reporting; no anxiety-specific adverse events noted

No mention found\

NCT01644500

Dulaglutide

Anxiety: 2 (0.8%) in 1.5 mg group, 1 (0.4%) in 0.75 mg group, 2 (0.8%) in glimepiride group; Anxiety disorder: 1 (0.4%) in 1.5 mg group

Rare\

NCT03574597

Semaglutide

Anxiety: 6 (0.1%) semaglutide, 3 (0.0%) placebo; Anxiety disorder: 1 (0.0%) semaglutide, 0 placebo; Mixed anxiety/depressive disorder: 0 semaglutide, 2 (0.0%) placebo

Very rare\

NCT02465515

Albiglutide

No mention found of systematic reporting; no anxiety-specific adverse events noted

No mention found\

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Key findings on neuropsychiatric adverse events:

• Systematic reporting:
  • Systematic reporting of anxiety-specific neuropsychiatric events was found in 2 out of 5 studies
  • The other 3 studies did not systematically report these events and did not note any anxiety-specific adverse events
• Frequency of events:
  • In the 2 studies with systematic reporting, anxiety or anxiety disorder events were rare or very rare:
    • One study reported anxiety events as rare (0.4–0.8% incidence)
    • One study reported anxiety events as very rare (≤0.1% incidence)
  • No mention found of frequency information for the other 3 studies
• Summary:
  • Among studies that systematically reported anxiety-specific neuropsychiatric events, these events were rare or very rare
  • The majority of studies did not systematically report on these events, limiting interpretability

Indirect Effects Potentially Relevant to Anxiety

Several studies reported small improvements in general psychological health or mental health domains of quality of life instruments with GLP-1 agents compared to placebo or active comparators.

Examples from included studies:

• In NCT02911948, the DTR-QoL anxiety domain improved more with degludec/liraglutide than with degludec alone, though without statistical testing.
• In NCT02465515, the TRIM-D psychological health domain improved more with albiglutide than with placebo, with statistical significance at 8 months.
• These effects were modest and not specific to anxiety.

Interpretation of indirect effects:

• Improvements in psychological health domains may reflect overall health benefits or improved diabetes control, rather than a direct anxiolytic effect of GLP-1 agents.
• The lack of dedicated anxiety measurement and the small magnitude of changes limit interpretability of these findings.

Summary

• Absence of direct evidence:
  • The available studies did not use dedicated, validated anxiety measures as primary or secondary outcomes.
  • Anxiety-related outcomes were assessed only as subdomains of general quality of life instruments or as rare adverse events.
• Magnitude and significance of effects:
  • Where measured, changes in anxiety-related domains were small.
  • Statistical significance was only reported in one study, and only for general psychological health domains, not for anxiety specifically.
• Adverse events:
  • Neuropsychiatric adverse events, including anxiety, were rare or very rare in studies that systematically reported them.
  • Most studies did not systematically report on anxiety-specific adverse events.
• Limitations of the evidence base:
  • The evidence is limited by the lack of dedicated anxiety assessment and the indirect nature of available data.
  • The findings do not provide clear evidence for or against an effect of GLP-1 agents on anxiety.

References

Lead Sponsor: Novo Nordisk A/S, Sponsor: None\ (2024).NCT03574597: Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity. NIH

Lead Sponsor: Novo Nordisk A/S, Sponsor: None\ (2021).NCT03015220: Safety and Efficacy of Oral Semaglutide Versus Dulaglutide Both in Combination With One OAD (Oral Antidiabetic Drug) in Japanese Subjects With Type 2 Diabetes. NIH

Lead Sponsor: Novo Nordisk A/S, Sponsor: None\ (2021).NCT02911948: A Double-blinded Trial Comparing the Efficacy and Safety of Insulin Degludec/Liraglutide and Insulin Degludec Both in Combination With Metformin in Japanese Subjects With Type 2 Diabetes Mellitus Inadequately Controlled With Basal or Pre-mix/Combination Insulin Therapy and Oral Anti-diabetic Drugs. NIH

Lead Sponsor: GlaxoSmithKline, Collaborator: Duke Clinical Research Institute, Sponsor: None\ (2019).NCT02465515: Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Subjects With Type 2 Diabetes Mellitus. NIH

Lead Sponsor: Eli Lilly and Company, Sponsor: None\ (2019).NCT01644500: A Study Comparing the Effects and Safety of Dulaglutide With Glimepiride in Type 2 Diabetes Mellitus. NIH

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NCT01644500: A Study Comparing the Effects and Safety of Dulaglutide With Glimepiride in Type 2 Diabetes Mellitus

Lead Sponsor: Eli Lilly and Company, Sponsor: None

NIH·

2019·

Citations unknown

ClinicalTrials

Study Design Type

Study Design Types:

- Randomized controlled trial - Parallel group study

This study is specifically described as an interventional study with randomized allocation and a parallel intervention model, with triple masking of participants, care providers, and investigators. The randomized allocation and interventional nature classify this as a randomized controlled trial, while the parallel intervention model indicates it uses a parallel group design rather than a crossover design.

Intervention Details Related to GLP-1

Specific GLP-1 medication: Dulaglutide

Dosage: Two intervention arms with different dosages: - 0.75 mg Dulaglutide - 1.5 mg Dulaglutide

Route of administration: Subcutaneous (SC)

Frequency of administration: Once-weekly

Duration of intervention: 26 weeks (study ran from July 2012 to August 2014)

Participant Demographics

Total Sample Size: - 737 participants (ACTUAL)

Age Distribution: - Age: Minimum: 18 Years - Mean age overall: 52.81 (10.317) - By treatment group: 1.5 mg Dulaglutide 52.69 (10.754), 0.75 mg Dulaglutide 53.79 (10.093), Glimepiride 51.97 (10.052)

Gender Distribution: - Female: 329 total (44.6%) - Male: 391 total (55.4%) - Eligibility criterion: Sex: ALL

Race/Ethnicity: - Asian: 720 total (100% of participants)

Geographic Distribution: - Study locations: China (21), South Korea (3), Taiwan (6) - By enrollment numbers: China: 556 participants, South Korea: 78 participants, Taiwan: 86 participants

Medical Conditions/Inclusion Criteria: - Primary condition: Type 2 diabetes mellitus - HbA1c requirements: ≥7.0% to ≤10.5% for OAM-naïve participants or ≥6.5% to ≤10.0% for participants taking OAM monotherapy - BMI requirements: ≥19.0 to ≤35.0 kilograms per square meter (kg/m^2)

Key Exclusion Criteria: - Have type 1 diabetes mellitus - Have cardiac disorder defined as unstable angina, myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary intervention, heart failure, arrhythmia, transient ischemic attack, or stroke

Anxiety Measurement Methods

Specific anxiety measurement tool used:

- European Quality of Life Questionnaire-5 Dimensions (EQ-5D) which assesses 5 dimensions associated with quality of life (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression)

Scoring method: - Each dimension has 3 possible levels of response: no problem, some problem, and extreme problem with additional categories for ambiguous and missing responses

Timing of anxiety assessments: - Time Frame: Week 26 (assessment conducted at 26 weeks)

Primary vs secondary outcome status: - Anxiety measurement was part of the Secondary Outcomes (specifically listed as one of 20 secondary outcomes)

Specific anxiety-related metrics measured: - Anxiety/Depression - no problems: 208 participants (1.5mg dulaglutide), 214 participants (0.75mg dulaglutide), 213 participants (glimepiride) - Anxiety/Depression - some problems: 13 participants (1.5mg dulaglutide), 7 participants (0.75mg dulaglutide), 17 participants (glimepiride) - Anxiety/Depression - extreme problems: 0 participants in all groups

Additional anxiety-related observations: - Anxiety was reported as an adverse event: 2 participants (1.5mg dulaglutide), 1 participant (0.75mg dulaglutide), 2 participants (glimepiride) - Anxiety disorder was reported as an adverse event: 1 participant (1.5mg dulaglutide), 0 participants in other groups

No other specific anxiety measurement scales (such as HAM-A or STAI) were identified in this study.

Anxiety-Related Outcomes

The study collected anxiety-related outcomes through two measures: the EQ-5D quality of life questionnaire and adverse event reporting.

EQ-5D Anxiety/Depression Dimension at 26 weeks: - No problems: 208 participants (1.5 mg dulaglutide), 214 participants (0.75 mg dulaglutide), 213 participants (glimepiride) - Some problems: 13 participants (1.5 mg dulaglutide), 7 participants (0.75 mg dulaglutide), 17 participants (glimepiride) - Extreme problems: 0 participants in all groups

Anxiety-Related Adverse Events: - Anxiety: 2 participants (0.8%) in 1.5 mg dulaglutide group, 1 participant (0.4%) in 0.75 mg dulaglutide group, 2 participants (0.8%) in glimepiride group - Anxiety disorder: 1 participant (0.4%) in 1.5 mg dulaglutide group only

The data was collected at week 26 using the EQ-5D questionnaire which assesses anxiety/depression as one of five quality of life dimensions. The EQ-5D uses a 3-level response scale (no problem, some problem, extreme problem) rather than continuous anxiety scores. No mean anxiety scores, standard deviations, statistical significance tests, or effect sizes were reported for anxiety outcomes. The study did not include formal statistical comparisons for anxiety-related measures between treatment groups.

Study Limitations and Potential Biases

Funding Sources: - Sponsored by Eli Lilly and Company, which manufactures dulaglutide, one of the study drugs

Potential Conflicts of Interest: - Study director employed by Eli Lilly and Company - Point of contact is Chief Medical Officer at Eli Lilly and Company - Pharmaceutical company sponsorship of study investigating their own product

Dropout Rates: - Overall completion rates: 222/244 (91.0%) for 1.5mg dulaglutide, 224/248 (90.3%) for 0.75mg dulaglutide, 230/245 (93.9%) for glimepiride - Reasons for withdrawal included: adverse events (6, 1, 2 participants respectively), subject withdrawal (11, 12, 12 participants respectively), and lost to follow-up (3, 8, 0 participants respectively)

Blinding Procedures: - Triple masking employed (participant, care provider, investigator), which helps minimize assessment bias

Study Limitations: Not mentioned - the document appears to be a clinical trial registry entry rather than a published manuscript, so no author-acknowledged limitations or discussion section is provided. The primary limitation evident from the available information is the potential for bias due to industry sponsorship, where the manufacturer of the investigational drug funded and conducted the study.

A Study Comparing the Effects and Safety of Dulaglutide With Glimepiride in Type 2 Diabetes Mellitus (NCT01644500)

Summary

• Status: COMPLETED
• Study Type: INTERVENTIONAL
• Phase: PHASE3
• Allocation: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Purpose: TREATMENT
• Masking: TRIPLE (PARTICIPANT, CARE_PROVIDER, INVESTIGATOR)
• Enrollment: 737 participants (ACTUAL)
• Start Date: 2012-07
• Primary Completion Date: 2014-08
• Completion Date: 2014-08
• First Posted: 2012-07-19
• Results First Posted: 2015-12-17
• Last Update Posted: 2019-09-18
• Sponsor: Eli Lilly and Company

The purpose of this study is to examine if once-weekly dulaglutide is efficient and safe compared to glimepiride in participants with type 2 diabetes mellitus who have inadequate glycemic control with oral antihyperglycemic medication (OAM) or are OAM-naïve.

Conditions & Interventions

Conditions (1)

• Type 2 Diabetes Mellitus

Interventions (4)

Eligibility

• Age: Minimum: 18 Years
• Sex: ALL
• Accepts Healthy Volunteers: No

Eligibility Criteria

Inclusion Criteria:

• Type 2 diabetes mellitus
• OAM-naïve or have been taking OAM monotherapy for at least 3 months
• Glycosylated Hemoglobin (HbA1c) value of ≥7.0% to ≤10.5% for OAM-naïve participants or ≥6.5% to ≤10.0% for participants taking OAM monotherapy
• Adult men or adult non-pregnant, non-breastfeeding women
• Stable weight (±5%) ≥3 months prior to screening
• Body mass index (BMI) of ≥19.0 to ≤35.0 kilograms per square meter (kg/m^2)

Exclusion Criteria:

• Have type 1 diabetes mellitus
• Have previously been treated with a glucagon-like peptide-1 (GLP-1) receptor agonist, GLP-1 analog, or any other incretin mimetic during the 3 months before screening
• Are currently taking dipeptidylpeptidase-IV (DPP-IV) inhibitor and thiazolidinediones (TZD) during the 3 months before screening
• Have gastric emptying abnormality
• Have cardiac disorder defined as unstable angina, myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary intervention, heart failure, arrhythmia, transient ischemic attack, or stroke
• Have poorly controlled hypertension (systolic blood pressure above 160 millimeters of mercury [mmHg] or diastolic blood pressure above 95 mmHg)
• Have impaired liver function
• Have impaired kidney function
• Have history of chronic pancreatitis or acute pancreatitis
• Have a serum calcitonin ≥20 picogram/milliliter (pg/mL)
• Have a personal or family history of medullary C-cell hyperplasia, focal hyperplasia, carcinoma or multiple endocrine neoplasia type 2 (MEN 2)

Locations (30)

Study Officials

• Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST) (STUDY_DIRECTOR) - Eli Lilly and Company

Countries: China (21), South Korea (3), Taiwan (6)

Oversight & Regulatory

Data Monitoring Committee: Yes

Results

Participant Flow

Study Groups: 3

• FG000: 1.5 mg Dulaglutide
• FG001: 0.75 mg Dulaglutide
• FG002: Glimepiride

Overall Study

Withdrawals

Adverse Event

• 1.5 mg Dulaglutide: 6

• 0.75 mg Dulaglutide: 1

• Glimepiride: 2 Death

• 1.5 mg Dulaglutide: 0

• 0.75 mg Dulaglutide: 1

• Glimepiride: 0 Lost to Follow-up

• 1.5 mg Dulaglutide: 3

• 0.75 mg Dulaglutide: 8

• Glimepiride: 0 Protocol Violation

• 1.5 mg Dulaglutide: 1

• 0.75 mg Dulaglutide: 1

• Glimepiride: 0 Withdrawal by Subject

• 1.5 mg Dulaglutide: 11

• 0.75 mg Dulaglutide: 12

• Glimepiride: 12 Physician Decision

• 1.5 mg Dulaglutide: 1

• 0.75 mg Dulaglutide: 1

• Glimepiride: 1

Baseline Characteristics

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Region of Enrollment

Taiwan

Outcome Measures

Primary Outcomes (1)

Change From Baseline in HbA1c at 26 Weeks

HbA1c is a form of hemoglobin that is measured primarily to identify the average plasma glucose concentration over prolonged periods of time. Least Squares (LS) means were calculated using mixed model repeated measures (MMRM) analysis adjusting for treatment, country, pre-study therapy stratum, visit, and treatment-by-visit as fixed effects; baseline HbA1c as covariate; and participant as a random effect.

Time Frame: Baseline, 26 Weeks | Units: percentage of HbA1c | Type: LEAST_SQUARES_MEAN

Statistical Analyses

• Method: Mixed Models Analysis | P-value: <0.001
• Method: Mixed Models Analysis | P-value: <0.001

Secondary Outcomes (20)

Percentage of Participants Attaining HbA1c of <7% or ≤6.5% at 26 Weeks

Percentages of participants who achieved HbA1c levels of <7% or ≤6.5% were analyzed using a logistic regression model, controlling for treatment, pre-treatment, baseline HbA1c and country.

Time Frame: 26 Weeks | Units: percentage of participants | Type: NUMBER

Statistical Analyses

• Method: Fisher Exact | P-value: <0.001
• Method: Fisher Exact | P-value: <0.001
• Method: Fisher Exact | P-value: <0.001
• Method: Fisher Exact | P-value: 0.192

Change From Baseline in Fasting Blood Glucose (FBG) at 26 Weeks

FBG is a test to determine how much glucose (sugar) is in a blood sample after an overnight fast. FBG was measured by a central laboratory. LS means were calculated using MMRM analysis adjusting for treatment, country, pre-study therapy stratum, visit, and treatment-by-visit as fixed effects; baseline FBG as covariate; and participant as a random effect.

Time Frame: Baseline, 26 Weeks | Units: millimoles per liter (mmol/L) | Type: LEAST_SQUARES_MEAN

Statistical Analyses

• Method: Mixed Models Analysis | P-value: <0.001
• Method: Mixed Models Analysis | P-value: 0.022

Change From Baseline in 7-point Self-monitored Blood Glucose (SMBG) Profiles at 26 Weeks

Change from baseline in mean daily blood glucose (BG) values were measured with a 7-point SMBG profile. Participants recorded their 7-point SMBG profiles on 2 separate, non-consecutive days during the 2-week period immediately before randomization, Week 8, Week 16, and Week 26 (or the Early Discontinuation Visit). The 7-point SMBG profile consisted of pre-prandial BG measures before the morning (fasting), midday, and evening meals; BG measures 2 hours after the start (post-prandial) of the morning, midday, and evening meals; and BG measures at bedtime. Mean at 26 weeks was assessed in all treatment groups. LS means were calculated using MMRM analysis adjusting for treatment, country, pre-study therapy stratum, visit, and treatment-by-visit as fixed effects; baseline body weight as covariate; and participant as a random effect.

Time Frame: Baseline, 26 Weeks | Units: mmol/L | Type: LEAST_SQUARES_MEAN

Statistical Analyses

• Method: Mixed Models Analysis | P-value: <0.001
• Method: Mixed Models Analysis | P-value: 0.304
• Method: Mixed Models Analysis | P-value: <0.001
• Method: Mixed Models Analysis | P-value: 0.015
• Method: Mixed Models Analysis | P-value: <0.001
• Method: Mixed Models Analysis | P-value: 0.740
• Method: Mixed Models Analysis | P-value: <0.001
• Method: Mixed Models Analysis | P-value: <0.001
• Method: Mixed Models Analysis | P-value: <0.001
• Method: Mixed Models Analysis | P-value: 0.638
• Method: Mixed Models Analysis | P-value: <0.001
• Method: Mixed Models Analysis | P-value: 0.030
• Method: Mixed Models Analysis | P-value: <0.001
• Method: Mixed Models Analysis | P-value: <0.001

Rate of Hypoglycemic Episodes

Hypoglycemic episodes are defined as events that are associated with reported signs and symptoms of hypoglycemia and/or documented BG concentrations of ≤70 milligrams per deciliter (mg/dL) (≤3.9 mmol/L). A severe hypoglycemic episode was defined as any hypoglycemic event for which the participant required the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs between bedtime and waking. Log mean rates of total hypoglycemia (per 30 days per participant) are presented and were calculated from negative binomial regression model. The model included country/region, prior medication group, treatment, visit, and treatment-by-visit interaction. The logarithm of days between visits was adjusted as an offset to account for possible unequal duration between visits and between participants.

Time Frame: Baseline through 26 Weeks | Units: episodes/participant/30 days | Type: MEAN

Statistical Analyses

• Method: Negative binomial regression model | P-value: <0.001
• Method: Negative binomial regression model | P-value: <0.001
• Method: Negative binomial regression model | P-value: 0.008
• Method: Negative binomial regression model | P-value: 0.006

Number of Participants With Self-Reported Hypoglycemic Episodes

The overall number of participants with self-reported hypoglycemic episodes is presented.

Time Frame: Baseline through 26 Weeks | Units: participants | Type: NUMBER

Statistical Analyses

• Method: Fisher Exact | P-value: <0.001
• Method: Fisher Exact | P-value: <0.001

Change From Baseline in Homeostasis Model Assessment 2 Steady-state Beta (β) - Cell Function (HOMA2-%B) at 26 Weeks

Change from baseline in HOMA2-%B was assessed by using the homeostasis model assessment (HOMA) to quantify β-cell function. HOMA2-%B is a computer model that uses FBG, insulin, and C-peptide concentrations to estimate steady state β-cell function (%B) as a percentage of a normal reference population (normal young adults). The normal reference population was set at 100%. LS means were calculated using an analysis of covariance (ANCOVA) model with country, baseline, pre-treatment, and treatment as fixed effects.

Time Frame: Baseline, up to 26 Weeks | Units: percentage of HOMA2-%B | Type: LEAST_SQUARES_MEAN

Statistical Analyses

• Method: ANCOVA | P-value: <0.001
• Method: ANCOVA | P-value: 0.012
• Method: ANCOVA | P-value: <0.001
• Method: ANCOVA | P-value: <0.001

Change From Baseline in Homeostasis Model Assessment 2 Insulin Sensitivity - Cell Function (HOMA2-%S) at 26 Weeks

Change from baseline in HOMA2-%S was assessed by using the HOMA to quantify insulin sensitivity. HOMA2-%S is a computer model that uses fasting plasma insulin and glucose concentrations to estimate steady state insulin sensitivity (%S) as a percentage of a normal reference population (normal young adults). The normal reference population was set at 100%. LS means were calculated using an ANCOVA model with country, baseline, pre-treatment, and treatment as fixed effects.

Time Frame: Baseline, up to 26 Weeks | Units: percentage of HOMA2-%S | Type: LEAST_SQUARES_MEAN

Statistical Analyses

• Method: ANCOVA | P-value: 0.913
• Method: ANCOVA | P-value: 0.318
• Method: ANCOVA | P-value: 0.576
• Method: ANCOVA | P-value: 0.007

Change From Baseline in Pancreatic Enzymes at 26 Weeks

Amylase (total and pancreas-derived) and lipase concentrations were measured.

Time Frame: Baseline, 26 Weeks | Units: units per liter (u/L) | Type: MEAN

Change From Baseline in Serum Calcitonin at 26 Weeks

Time Frame: Baseline, 26 Weeks | Units: picomoles per liter (pmol/L) | Type: MEAN

Change From Baseline in Sitting Blood Pressure at 26 Weeks

Sitting systolic blood pressure (SBP) and sitting diastolic blood pressure (DBP) were measured. LS means were calculated using MMRM analysis adjusting for treatment, country, pre-study therapy stratum, visit, and treatment-by-visit as fixed effects; baseline blood pressure as covariate; and participant as a random effect.

Time Frame: Baseline, 26 Weeks | Units: millimeters of mercury (mmHg) | Type: LEAST_SQUARES_MEAN

Statistical Analyses

• Method: Mixed Models Analysis | P-value: 0.180
• Method: Mixed Models Analysis | P-value: 0.245
• Method: Mixed Models Analysis | P-value: 0.717
• Method: Mixed Models Analysis | P-value: 0.619

Change From Baseline in Sitting Pulse Rate at 26 Weeks

LS means were calculated using MMRM analysis adjusting for treatment, country, pre-study therapy stratum, visit, and treatment-by-visit as fixed effects; baseline pulse rate as covariate; and participant as a random effect.

Time Frame: Baseline, 26 Weeks | Units: beats per minute (bpm) | Type: LEAST_SQUARES_MEAN

Statistical Analyses

• Method: Mixed Models Analysis | P-value: <0.001
• Method: Mixed Models Analysis | P-value: 0.035

Change From Baseline in Electrocardiogram (ECG) Parameters, Fridericia Corrected QT (QTcF) Interval and P-R Wave (PR) Interval at 26 Weeks

The QT interval is a measure of the time between the start of the Q wave and the end of the T wave and was calculated from electrocardiogram (ECG) data using Fridericia’s formula: QTcF = QT/RR^0.33. Corrected QT (QTc) is the QT interval corrected for heart rate and R-R wave (RR), which is the interval between two R waves. PR is the interval between the P wave and the ventricular depolarization wave (QRS) complex.

Time Frame: Baseline, 26 Weeks | Units: milliseconds (msec) | Type: MEAN

Change From Baseline in Heart Rate From ECG at 26 Weeks

Time Frame: Baseline, 26 Weeks | Units: bpm | Type: MEAN

Change From Baseline in Body Weight at 26 Weeks

LS means were calculated using MMRM analysis adjusting for treatment, country, pre-study therapy stratum, visit, and treatment-by-visit as fixed effects; baseline body weight as covariate; and participant as a random effect.

Time Frame: Baseline, 26 Weeks | Units: kilogram (kg) | Type: LEAST_SQUARES_MEAN

Statistical Analyses

• Method: Mixed Models Analysis | P-value: <0.001
• Method: Mixed Models Analysis | P-value: <0.001

Change From Baseline in Body Mass Index (BMI) at 26 Weeks

BMI is an estimate of body fat based on body weight divided by height squared. LS means were calculated using MMRM analysis adjusting for treatment, country, pre-study therapy stratum, visit, and treatment-by-visit as fixed effects; baseline body weight as covariate; and participant as a random effect.

Time Frame: Baseline, 26 Weeks | Units: kilograms per meter squared (kg/m^2) | Type: LEAST_SQUARES_MEAN

Statistical Analyses

• Method: Mixed Models Analysis | P-value: <0.001
• Method: Mixed Models Analysis | P-value: <0.001

Percentage of Participants Developing Antibodies to Dulaglutide

Dulaglutide anti-drug antibodies (ADA) were assessed at baseline and 26 weeks. A participant was considered to have treatment-emergent dulaglutide ADA if the participant had at least 1 titer that was treatment-emergent relative to baseline, defined as a 4-fold or greater increase in titer from baseline measurement.

Time Frame: Baseline through 26 Weeks | Units: percentage of participants | Type: NUMBER

Number of Participants With Adjudicated Cardiovascular Events

Deaths and nonfatal cardiovascular adverse events (AEs) were adjudicated by a committee of physicians with cardiology expertise external to the Sponsor. The nonfatal cardiovascular AEs that were adjudicated included myocardial infarction; hospitalization for unstable angina; hospitalization for heart failure; coronary interventions (such as coronary artery bypass graft or percutaneous coronary intervention); and cerebrovascular events, including cerebrovascular accident (stroke) and transient ischemic attack. A summary of serious and other non-serious AEs regardless of causality, is located in the Reported Adverse Events module.

Time Frame: Baseline through 26 Weeks | Units: number of participants | Type: NUMBER

Number of Participants With Adjudicated Pancreatitis

The number of adjudicated (by an independent committee of expert physicians) pancreatic events is summarized at 26 weeks. A summary of serious and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.

Time Frame: Baseline through 26 Weeks | Units: participants | Type: NUMBER

European Quality of Life Questionnaire-5 Dimensions (EQ-5D) Health State Score Responses at 26 Weeks

The EQ-5D questionnaire is a widely used, generic questionnaire that assesses 5 dimensions associated with quality of life (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension has 3 possible levels of response: no problem, some problem, and extreme problem. Additional categories of response include ambiguous and missing. The number of participants per each of the 5 response categories is summarized for each of the 5 dimensions.

Time Frame: Week 26 | Units: participants | Type: NUMBER

Visual Analog Scale (VAS) Score at 26 Weeks

The EQ-5D questionnaire is a widely used, generic questionnaire that assesses health-related quality of life and consists of a 100-milliliter (mm) visual analog scale (VAS) on which the participant rated their perceived health state on that day from 0-mm (worst imaginable health state) to 100-mm (best imaginable health state).

Time Frame: Week 26 | Units: units on a scale | Type: MEAN

Adverse Events

Reporting Threshold: 0

All randomized participants who received at least one dose of study drug.

Event Summary

Serious Adverse Events (23)

Other Adverse Events (234)

Additional Information

PI is Sponsor Employee: No

Point of Contact

• Title: Chief Medical Officer
• Organization: Eli Lilly and Company
• Phone: 800-545-5979

IPD Sharing Statement

IPD Sharing: YES

Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.

Information Types

• STUDY_PROTOCOL
• SAP
• CSR Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.

Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.

URL: https://vivli.org/

Documents & Links

References (5)

• [1] Kuang J, Zhu J, Liu S, Li Q. Efficacy and Safety of Once-Weekly Dulaglutide in Elderly Chinese Patients with Type 2 Diabetes: A Post Hoc Analysis of AWARD-CHN Studies. Diabetes Ther. 2020 Oct;11(10):2329-2339. doi: 10.1007/s13300-020-00910-1. Epub 2020 Aug 28. (PMID: 32857293) [DERIVED]
• [2] Guo L, Zhang B, Hou J, Zhou Z. Evaluation of Characteristics of Gastrointestinal Adverse Events with Once-Weekly Dulaglutide Treatment in Chinese Patients with Type 2 Diabetes: A Post Hoc Pooled Analysis of Two Randomized Trials. Diabetes Ther. 2020 Aug;11(8):1821-1833. doi: 10.1007/s13300-020-00869-z. Epub 2020 Jul 4. (PMID: 32621083) [DERIVED]
• [3] Yu M, Yuan GY, Zhang B, Wu HY, Lv XF. Efficacy and Safety of Dulaglutide by Baseline HbA1c in Chinese Patients with Type 2 Diabetes: A Post Hoc Analysis. Diabetes Ther. 2020 May;11(5):1147-1159. doi: 10.1007/s13300-020-00804-2. Epub 2020 Apr 10. (PMID: 32277401) [DERIVED]
• [4] Li YM, Zhang LH, Li XJ, Zhang B, Hou JN, Tong NW. Efficacy and Safety of Dulaglutide Monotherapy Compared to Glimepiride in Oral Antihyperglycemic Medication-Naive Chinese patients with Type 2 Diabetes: A Post Hoc Analysis of AWARD-CHN1. Diabetes Ther. 2020 May;11(5):1077-1090. doi: 10.1007/s13300-020-00799-w. Epub 2020 Mar 26. (PMID: 32219675) [DERIVED]
• [5] Li H, Xu X, Wang J, Kong X, Chen M, Jing T, Zhang Z, Yin G, Liu X, Hu Y, Ye L, Su X, Ma J. A Randomized Study to Compare the Effects of Once-Weekly Dulaglutide Injection and Once-Daily Glimepiride on Glucose Fluctuation of Type 2 Diabetes Mellitus Patients: A 26-Week Follow-Up. J Diabetes Res. 2019 Apr 30;2019:6423987. doi: 10.1155/2019/6423987. eCollection 2019. (PMID: 31183384) [DERIVED]

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