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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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NCT03574597: Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity

Lead Sponsor: Novo Nordisk A/S, Sponsor: None

NIH·

2024·

Citations unknown

ClinicalTrials

Study Design Type

This study is a randomized controlled trial with a parallel group design. The study is specifically described as interventional with randomized allocation using a parallel intervention model, where treatment assignment is decided by chance. The design includes both randomized controlled trial and parallel group study elements.

Intervention Details Related to GLP-1

GLP-1 Medication Details:

Specific GLP-1 medication: Semaglutide

Route of Administration: Subcutaneous injection into a skin fold, in the stomach, thigh or upper arm using a pen device

Frequency of Administration: Once a week at the same day of the week (to the extent possible)

Duration of Intervention: Approximately 2.5 to 5 years

Dosage: Not mentioned (specific dosage amount not provided in the document)

Study Arms: Two intervention arms - semaglutide treatment arm and placebo (semaglutide) control arm with identical administration methods

Participant Demographics

Total Sample Size: - 17,604 participants (actual enrollment)

Age Demographics: - Mean age: 61.6 years (standard deviation 8.9) - Minimum eligibility age: 45 years

Gender Distribution: - Female: 4,872 participants (27.7%) - Male: 12,732 participants (72.3%)

Race/Ethnicity Distribution: - White: 14,791 participants (84.0%) - Asian: 1,447 participants (8.2%) - Black or African American: 671 participants (3.8%) - Other racial categories: 695 participants (3.9%) - Hispanic or Latino ethnicity: 1,822 participants (10.4%) - Not Hispanic or Latino: 15,611 participants (88.7%)

Key Inclusion Criteria: - BMI ≥27 kg/m² - Established cardiovascular disease (prior myocardial infarction, prior stroke, or symptomatic peripheral arterial disease with specific criteria)

Key Exclusion Criteria: - History of type 1 or type 2 diabetes (history of gestational diabetes allowed) - Recent cardiovascular events within 60 days - HbA1c ≥6.5%

Geographic Distribution: - 43 countries with 833 study locations - Largest representation: United States (205 sites), Russia (49), Japan (49), India (34), Germany (31), Canada (28), Romania (26), South Africa (25), Italy (24), Poland (22), Turkey (21), France (17), and others

Anxiety Measurement Methods

Not mentioned (no dedicated anxiety measurement tools were used in this cardiovascular outcomes trial).

The only anxiety-related assessments were:

Indirect Assessment: - EQ-5D-5L questionnaire anxiety/depression dimension with 5 levels (not at all, mild, moderate, severe, extreme) assessed at week 0 and week 104 as part of health-related quality of life measurement (secondary outcome)

Adverse Event Reporting: - Anxiety reported as serious adverse events: 6 cases (0.1%) semaglutide vs 3 cases (0.0%) placebo - Mixed anxiety and depressive disorder: 0 cases semaglutide vs 2 cases (0.0%) placebo

This was a cardiovascular outcomes trial focused on cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke as the primary outcome, with no systematic anxiety measurement using standardized tools like HAM-A, STAI, or GAD-7.

Anxiety-Related Outcomes

Not mentioned (no quantitative anxiety scores, statistical tests, or effect sizes reported). The trial only reported anxiety-related outcomes as serious adverse events, showing anxiety in 6 participants (0.1%) with semaglutide vs 3 participants (0.0%) with placebo, anxiety disorder in 1 participant (0.0%) with semaglutide vs 0 participants with placebo, and mixed anxiety and depressive disorder in 0 participants with semaglutide vs 2 participants (0.0%) with placebo. No mean anxiety scores, standard deviations, statistical significance testing, or effect sizes were provided for anxiety outcomes, as these were not formal study endpoints but rather adverse event classifications.

Study Limitations and Potential Biases

Funding Sources: - Novo Nordisk A/S served as the study sponsor

Potential Conflicts of Interest: - Principal investigator was not a sponsor employee, however the study was sponsored and conducted by Novo Nordisk A/S, the manufacturer of semaglutide - Clinical Transparency department from Novo Nordisk A/S served as study director - All study contact information directed to Novo Nordisk A/S

Blinding Procedures: - Quadruple masking was employed (participant, care provider, investigator, outcomes assessor), representing robust blinding methodology

Dropout Rates: - Overall completion rates were high with low dropout rates - 259 participants (2.9%) in semaglutide group and 284 participants (3.2%) in placebo group did not complete the study - 67 semaglutide participants and 96 placebo participants withdrew by subject choice - 192 semaglutide participants and 188 placebo participants were lost to follow-up

Acknowledged Limitations: - Adverse events were not collected systematically, with additional details referenced in protocol section 9.2 - This represents a potential limitation in comprehensive safety assessment

Note: This analysis is based on clinical trial registry information rather than a published manuscript, so typical author-acknowledged limitations from discussion sections are not available in this document format.

Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (NCT03574597)

Summary

• Status: COMPLETED
• Study Type: INTERVENTIONAL
• Phase: PHASE3
• Allocation: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Purpose: TREATMENT
• Masking: QUADRUPLE (PARTICIPANT, CARE_PROVIDER, INVESTIGATOR, OUTCOMES_ASSESSOR)
• Enrollment: 17604 participants (ACTUAL)
• Start Date: 2018-10-24
• Primary Completion Date: 2023-06-21
• Completion Date: 2023-06-29
• First Posted: 2018-07-02
• Results First Posted: 2024-08-30
• Last Update Posted: 2024-08-30
• Sponsor: Novo Nordisk A/S

The researchers are doing the study to see if semaglutide may reduce the risk of having cardiovascular events in patients with overweight or obesity and with prior cardiovascular disease. The participant will either get semaglutide (active medicine) or placebo (“dummy” medicine). Which treatment the participants get is decided by chance. The participant’s chance of getting semaglutide or placebo is the same. The participant will get the study medicine in a pen. The participants will need to use the pen to inject the study medicine in a skinfold once a week. The study will last for about 2.5 to 5 years. Participants will have up to 25 clinic visits with the study doctor.

Conditions & Interventions

Conditions (2)

• Overweight
• Obesity

Interventions (2)

Eligibility

• Age: Minimum: 45 Years
• Sex: ALL
• Accepts Healthy Volunteers: No

Eligibility Criteria

Inclusion Criteria:

• Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial
• Male or female, age greater than or equal to 45 years at the time of signing informed consent
• Body mass index (BMI) greater than or equal to 27 kg/m^2
• Have established cardiovascular (CV) disease as evidenced by at least one of the following: prior myocardial infarction; prior stroke (ischemic or haemorrhagic stroke); or symptomatic peripheral arterial disease (PAD), as evidenced by intermittent claudication with ankle-brachial index (ABI) less than 0.85 (at rest), or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease

Exclusion Criteria:

Cardiovascular-related:

• Any of the following: myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within the past 60 days prior to the day of screening
• Planned coronary, carotid or peripheral artery revascularisation known on the day of screening
• Presently classified as being in New York Heart Association (NYHA) Class IV heart failure

Glycaemia-related:

• HbA1c greater than or equal to 48 mmol/mol (6.5 %) as measured by the central laboratory at screening
• History of type 1 or type 2 diabetes (history of gestational diabetes is allowed)
• Treatment with glucose-lowering agents within 90 days before screening
• Treatment with any glucagon-like-peptide-1 receptor agonist (GLP-1 RA) within 90 days before screening

General safety:

• History or presence of chronic pancreatitis
• Presence of acute pancreatitis within the past 180 days prior to the day of screening
• Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma
• End stage renal disease or chronic or intermittent haemodialysis or peritoneal dialysis
• Presence or history of malignant neoplasms within the past 5 years prior to the day of screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed
• Severe psychiatric disorder which in the investigator’s opinion could compromise compliance with the protocol
• Known or suspected hypersensitivity to trial products or related products
• Previous participation in this trial. Participation is defined as randomisation
• Receipt of any investigational medicinal product within 30 days before screening
• Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using a highly effective contraceptive method
• Any disorder, unwillingness or inability, which in the investigator’s opinion, might jeopardise the participant’s safety or compliance with the protocol

Locations (833)

Study Officials

• Clinical Transparency (dept.2834) (STUDY_DIRECTOR) - Novo Nordisk A/S

Countries: Algeria (5), Argentina (10), Australia (13), Austria (7), Belgium (7), Brazil (15), Bulgaria (16), Canada (28), Colombia (7), Croatia (7), Czechia (12), Denmark (6), Finland (7), France (17), Germany (31), Greece (14), Hungary (6), India (34), Ireland (6), Israel (12), Italy (24), Japan (49), Latvia (8), Malaysia (13), Mexico (9), Netherlands (10), Norway (9), Poland (22), Portugal (6), Puerto Rico (1), Romania (26), Russia (49), Serbia (6), South Africa (25), Spain (11), Sweden (6), Taiwan (5), Thailand (9), Turkey (Türkiye) (21), Ukraine (17), United Kingdom (42), United States (205)

Oversight & Regulatory

Data Monitoring Committee: Yes

FDA Regulation

• FDA Regulated Drug: Yes
• FDA Regulated Device: No

Results

Participant Flow

Study Groups: 2

• FG000: Semaglutide
• FG001: Placebo

Overall Study

Withdrawals

Withdrawal by Subject

• Semaglutide: 67

• Placebo: 96 Lost to Follow-up

• Semaglutide: 192

• Placebo: 188

Baseline Characteristics

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race/Ethnicity, Customized

Outcome Measures

Primary Outcomes (1)

Participants From Time of Randomization to First Occurrence of a Composite Outcome Measure Consisting of: Cardiovascular (CV) Death, Non-fatal Myocardial Infarction (MI), or Non-fatal Stroke

Number of participants with first occurrence of composite outcome measure consisted of CV death (undetermined cause of death presumed CV death), non-fatal MI, or non-fatal stroke are presented. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: From randomisation (week 0) up to 240 weeks | Units: Participants | Type: COUNT_OF_PARTICIPANTS

Statistical Analyses

• Method: Regression, Cox | P-value: < 0.0001

Secondary Outcomes (28)

Participants From Time of Randomisation to CV Death

Number of participants with CV death are presented. The outcome measure was evalulated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: From randomisation (week 0) up to 240 weeks | Units: Participants | Type: COUNT_OF_PARTICIPANTS

Participants From Time of Randomisation to First Occurrence of a Composite Heart Failure (HF) Outcome Measure Consisting of: HF Hospitalisation, Urgent HF Visit or CV Death

Number of participants with first occurrence of a composite HF outcome measure consisted of HF hospitalisation, urgent HF visit or CV death are presented. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: From randomisation (week 0) up to 240 weeks | Units: Participants | Type: COUNT_OF_PARTICIPANTS

Participants From Time of Randomisation to All-cause Death

Number of participants with all-cause death are presented. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: From randomisation (week 0) up to 240 weeks | Units: Participants | Type: COUNT_OF_PARTICIPANTS

Participants From Time of Randomisation to First Occurrence of an Expanded Composite CV Outcome Measure Consisting of: CV Death, Non-fatal MI, Non-fatal Stroke, Coronary Revascularisation or Unstable Angina Pectoris (UAP) Requiring Hospitalisation

Number of participants with first occurrence of an expanded composite CV outcome measure consisted of CV death, non-fatal MI, non-fatal stroke, coronary revascularisation or UAP requiring hospitalisation are presented. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: From randomisation (week 0) up to 240 weeks | Units: Participants | Type: COUNT_OF_PARTICIPANTS

Participants From Time of Randomisation to First Occurrence of a Composite Outcome Measure Consisting of: All-cause Death, Non-fatal MI, or Non-fatal Stroke

Number of participants with first occurrence of a composite outcome measure consisted of all-cause death, non-fatal MI, or non-fatal stroke are presented. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: From randomisation (week 0) up to 240 weeks | Units: Participants | Type: COUNT_OF_PARTICIPANTS

Participants From Time of Randomisation to First Occurrence of Non-fatal MI

Number of participants with first occurrence of non-fatal MI are presented. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: From randomisation (week 0) up to 240 weeks | Units: Participants | Type: COUNT_OF_PARTICIPANTS

Participants From Time of Randomisation to First Occurrence of Non-fatal Stroke

Number of participants with first occurrence of non-fatal stroke are presented. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: From randomisation (week 0) up to 240 weeks | Units: Participants | Type: COUNT_OF_PARTICIPANTS

Participants From Time of Randomisation to First Occurrence of Coronary Revascularisation

Number of participants with first occurrence of coronary revascularisation are presented. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: From randomisation (week 0) up to 240 weeks | Units: Participants | Type: COUNT_OF_PARTICIPANTS

Participants From Time of Randomisation to First Occurrence of UAP Requiring Hospitalisation

Number of participants with first occurrence of UAP requiring hospitalisation are presented. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: From randomisation (week 0) up to 240 weeks | Units: Participants | Type: COUNT_OF_PARTICIPANTS

Participants From Time of Randomisation to First Occurrence of HF Requiring Hospitalisation or Urgent HF Visit

Number of participants with first occurrence of HF requiring hospitalisation or urgent HF visit are presented. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: From randomisation (week 0) up to 240 weeks | Units: Participants | Type: COUNT_OF_PARTICIPANTS

Participants From Time of Randomisation to First Occurrence of Glycosylated Haemoglobin (HbA1c) Greater Than Equals to (≥) 48 Millimole Per Mole (mmol/Mol) (6.5 Percentage [%])

Number of participants with first occurrence of HbA1c ≥ 48 mmol/mol (6.5%) are presented. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: From randomisation (week 0) up to 240 weeks | Units: Participants | Type: COUNT_OF_PARTICIPANTS

Participants From Time of Randomisation to First Occurrence of a 5-component Composite Nephropathy Outcome Measure

Number of participants with first occurrence of a 5-component composite nephropathy outcome measure consisted of onset of persistent macroalbuminuria (UACR > 300 milligram per gram [mg/g]), persistent 50% reduction in estimated glomerular filtration rate (eGFR) compared with baseline (randomisation), onset of persistent eGFR < 15 ml/min/1.73m^2, initiation of chronic renal replacement therapy (dialysis or transplantation) or renal death. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: From randomisation (week 0) up to 240 weeks | Units: Participants | Type: COUNT_OF_PARTICIPANTS

Participants From Time of Randomisation to HbA1c ≥ 39 mmol/Mol (5.7%) (for Participants With a Screening HbA1c <39 mmol/Mol [5.7%])

Number of participants with HbA1c ≥ 39 mmol/mol (5.7%) are presented. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: From randomisation (week 0) up to 240 weeks | Units: Participants | Type: COUNT_OF_PARTICIPANTS

Participants With HbA1c < 39 mmol/Mol (5.7%) (for Participants With a Screening HbA1c ≥ 39 mmol/Mol [5.7%])

Number of participants with HbA1c < 39 mmol/mol (5.7%) are presented. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: At week 52, week 104 | Units: Participants | Type: COUNT_OF_PARTICIPANTS

Change in Systolic Blood Pressure (SBP)

Change in SBP from randomisation (week 0) to week 104 is presented. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: Week 0, week 104 | Units: Millimetre of mercury (mmHg) | Type: MEAN

Change in Diastolic Blood Pressure (DBP)

Change in DBP from randomisation (week 0) to week 104 is presented. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: Week 0, week 104 | Units: mmHg | Type: MEAN

Change in Pulse

Change in pulse from randomisation (week 0) to week 104 is presented. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: Week 0, week 104 | Units: beats per mintue (bpm) | Type: MEAN

Change in High Sensitivity C-Reactive Protein (hsCRP) - Ratio to Baseline

Change in hsCRP (milligram per liter [mg/L]) from randomisation (week 0) to week 104 presented as ratio to baseline (week 0). The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: Week 0, week 104 | Units: ratio of hsCRP | Type: GEOMETRIC_MEAN

Change in Total Cholesterol - Ratio to Baseline

Change in total cholesterol (milligram per deciliter [mg/dL]) from randomisation (week 0) to week 104 is presented as ratio to baseline (week 0). The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: Week 0, week 104 | Units: ratio of total cholesterol | Type: GEOMETRIC_MEAN

Change in High Density Lipoprotein (HDL) Cholesterol - Ratio to Baseline

Change in HDL (mg/dL) from randomisation (week 0) to week 104 is presented as ratio to baseline (week 0). The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: Week 0, week 104 | Units: ratio of HDL | Type: GEOMETRIC_MEAN

Change in Low Density Lipoprotein (LDL) Cholesterol - Ratio to Baseline

Change in LDL (mg/dL) from randomisation (week 0) to week 104 is presented as ratio to baseline (week 0). The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: Week 0, week 104 | Units: ratio of LDL | Type: GEOMETRIC_MEAN

Change in Triglycerides - Ratio to Baseline

Change in triglycerides (mg/dL) from randomisation (week 0) to week 104 is presented as ratio to baseline (week 0). The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: Week 0, week 104 | Units: ratio of triglycerides | Type: GEOMETRIC_MEAN

Change in Body Weight

Percentage change in body weight from randomisation (week 0) to week 104 is presented. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: Week 0, week 104 | Units: percentage change in body weight | Type: MEAN

Change in Waist Circumference

Change is waist circumference from randomisation (week 0) to week 104 is presented. The outcome measure was evaluated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: Week 0, week 104 | Units: centimeter (cm) | Type: MEAN

Change From Randomisation (Week 0) in Participant Reported Outcome (PRO): EuroQol Five Dimensions Five Level Questionnaire (EQ-5D-5L) Index Score to Week 104

EQ-5D-5L is a PRO tool used to estimate impact on participant’s health-related quality of life and provides a description of their problems by dimensions (descriptive system). EQ-5D has 5 dimensions: mobility, self-care, usual activities, pain, anxiety/depression, and each dimension has 5 levels: not at all, mild, moderate, severe, extreme. Participant marks most appropriate statement in each dimension, resulting in 1-digit number and digits from 5 dimensions can be combined in 5-digit number describing participant’s health state. Index score records an average health status according to dimensions using an algorithm, ranges 0-1 with higher score indicates better health status. Outcome measure was evaluated based on data from in-trial observation period (defined as date of randomisation to one of the dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant [who were lost to follow-up], date of death).

Time Frame: Week 0, week 104 | Units: score on a scale | Type: MEAN

Change From Randomisation (Week 0) in PRO: EuroQol Five Dimensions Visual Analogue Scale (EQ-5D-VAS) to Week 104

Time Frame: Week 0, week 104 | Units: score on a scale | Type: MEAN

Change in HbA1c - Percentage

Change in HbA1c (percentage) from randomisation (week 0) to week 104 is presented. The outcome measure was evaulated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: Week 0, week 104 | Units: Percentage of HbA1c | Type: MEAN

Change in HbA1c - mmol/Mol

Change in HbA1c (mmol/mol) from randomisation (week 0) to week 104 is presented. The outcome measure was evaulated based on data from in-trial observation period. In-trial observation period defined as the period from date of randomisation to one of the following dates, whichever comes first: date of follow-up visit, date when participant withdrew consent, date of last contact with participant for participants who were lost to follow-up (participant did not complete the trial and did not withdraw consent), date of death.

Time Frame: Week 0, week 104 | Units: mmol/mol | Type: MEAN

Adverse Events

Reporting Threshold: 5

Time Frame: From randomisation (week 0) up to 240 weeks

AEs are reported based on data from in-trial observation period. Not all the AEs were collected systematically and more details on the approach followed for collecting the AEs is mentioned in the section 9.2 of protocol. AEs were not separately collected for each dose level. Hence, AEs are presented in randomized arm (semaglutide vs placebo).

Event Summary

Serious Adverse Events (1761)