GLP-1/GCG Dual Agonist in Type 2 Diabetes With Cognitive Dysfunction (LIGHT-COG Study)

Nanjing University

Status and phase: Not yet enrolling; Phase 4

Conditions: Mild Cognitive Impairment; Dementia, Mild; Type 2 Diabetes

Treatments: Drug: Placebo; Drug: Mazdutide

Study type: Interventional

Funder types: Other

Identifiers

NCT07083154

2025-0502-01

Details and patient eligibility

About

The LIGHT-COG study is a 76-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. A total of 432 type 2 diabetes patients with early dementia are randomized 1:1 to either the active treatment group (receiving subcutaneous injections of mazdutide weekly, with stepwise dose escalation to a maintenance dose per protocol) or the placebo group (receiving matched placebo injections). The primary objective is to evaluate the potential disease-modifying effects of mazdutide on cognitive dysfunction in type 2 diabetes.

Full description

The LIGHT-COG study is a 76-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial investigating the potential disease-modifying effects of the GLP-1/GCG dual receptor agonist mazdutide on cognitive dysfunction in 432 patients with type 2 diabetes (T2D) and early dementia. Participants will be randomized 1:1 to receive either weekly subcutaneous injections of mazdutide (starting at 2.0 mg, with stepwise dose escalation to a target maintenance dose of 4.0 mg and optional adaptive increase to 6.0 mg if necessary and tolerated) or matched placebo, in addition to their existing glucose-lowering therapy. The primary objective is to assess cognitive improvement, with key secondary endpoints including brain structure and function alterations, metabolic improvement, neurodegenerative biomarkers, and safety outcomes.

Participants will undergo comprehensive cognitive and metabolic assessments at baseline, followed by safety visits at Week 4 and every 8 weeks thereafter for monitoring of adverse events, adherence, and metabolic parameters. Comprehensive evaluations at Weeks 28, 52, and 76 will include cognitive assessments, advanced neuroimaging, and metabolic profiling. Rescue therapy with basal insulin (glargine) will be initiated for glycemic decompensation (fasting glucose ≥11.1 mmol/L on two consecutive visits or HbA1c ≥9%), with discontinuation for persistent intolerance or inadequate glycemic control despite rescue therapy.

Enrollment: 432 estimated patients

Sex: All

Ages: 50 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Type 2 diabetes mellitus (T2DM).

2. Aged 50-75 years (inclusive), male or female.

3. Early symptomatic dementia (Mild cognitive impairment or mild dementia), defined as:

   1. MMSE score >20 and <27,
   2. CDR global score 0.5-1.0 (inclusive), with a CDR memory subscore ≥0.5,
   3. Subjective memory complaints for ≥6 months.

4. Stable glycemic control regimen for ≥3 months prior to screening, meeting one of the following:

   1. Lifestyle/dietary intervention alone (no glucose-lowering drugs),
   2. Oral antidiabetic drugs (OADs), with or without once-daily basal insulin.

5. HbA1c 7.0-9.0% (inclusive) at screening.

6. BMI ≥20 kg/m², with stable weight (fluctuation <5%) for ≥3 months.

7. Stable cognitive impairment treatment (including no treatment) for ≥3 months prior to screening.

8. Ability to comply with systematic cognitive and functional assessments.

9. Fully understands the trial protocol, voluntarily signs the informed consent form (ICF), and agrees to adhere to all study requirements and restrictions.

Exclusion criteria

1. Evidence of neurodegenerative disorders, including:

   1. Frontotemporal dementia (FTD) and its variants
   2. Parkinson's disease (PD), dementia with Lewy bodies (DLB)
   3. Progressive supranuclear palsy (PSP), corticobasal degeneration (CBD)
   4. Multiple system atrophy (MSA), multiple sclerosis (MS), Huntington's disease (HD)

2. Clinically relevant or unstable psychiatric disorders.

3. Clinically significant structural CNS abnormalities on MRI/CT, such as:

   1. Large-vessel cerebrovascular disease (>10 mm cortical infarcts)
   2. Prior major hemorrhage (>1 cm³) or >4 microbleeds (≤10 mm)
   3. Vascular malformations, cerebral amyloid angiopathy, intracranial aneurysms/tumors
   4. Hydrocephalus or significant small vessel disease (Fazekas score ≥2 for deep white matter hyperintensities [WMH] or periventricular WMH score=3; or ≥1 lacunar infarct)

4. Acute hyperglycemic/hypoglycemic events within 1 year, including: Diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), and Hypoglycemic coma

5. Use of GLP-1R agonists, GLP-1R/GIPR dual agonists, or GLP-1R/GCGR dual agonists within 3 months prior to screening.

6. Regular use (>2 doses/week) of:

   1. Moderate/high anticholinergics, antiparkinsonian/antiepileptic drugs
   2. Antipsychotics, benzodiazepines/sedatives, opioid analgesics
   3. Stimulants, medical cannabis, or cannabidiol (CBD)
   4. Alcohol abuse (defined as >21 units/week for men or >14 units/week for women; 1 unit = 360 mL beer, 150 mL wine, or 45 mL spirits).

7. Personal or first-degree family history of type 1 diabetes (T1DM).

8. Medical history of:

   1. Medullary thyroid carcinoma (MTC), pancreatitis
   2. Multiple endocrine neoplasia type 2 (MEN2)
   3. Gallbladder/biliary disease, severe gastrointestinal disorders, or bowel resection
   4. Active malignancy

9. Uncontrolled or potentially unstable diabetic retinopathy/maculopathy.

10. Severe organ dysfunction, including:

    1. ALT/AST >2× upper limit of normal (ULN)
    2. eGFR <45 mL/min/1.73m² (CKD-EPI equation)
    3. Unstable angina, myocardial infarction (MI), or NYHA Class II+ heart failure within 3 months

11. Known/suspected hypersensitivity to the investigational product or related compounds

12. Pregnancy, lactation, or women of childbearing potential not using highly effective contraception.

13. MRI contraindications (e.g., metal implants, claustrophobia).

14. Participation in other clinical trials within 3 months, involving an investigational medicinal product or enrollment in any other type of medical research judged not to be scientifically or medically compatible with this study.

15. Any other condition deemed by the investigator to compromise safety or interfere with study assessments.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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432 participants in 2 patient groups, including a placebo group

Mazdutide group

Experimental group

Description:

Participants will receive weekly subcutaneous injections of mazdutide (starting at 2.0 mg, with stepwise dose escalation to a target maintenance dose of 4.0 mg and optional adaptive increase to 6.0 mg if necessary and tolerated) , in addition to their existing glucose-lowering therapy.

Treatment:

Drug: Mazdutide

Placebo group

Placebo Comparator group

Description:

Participants will receive weekly subcutaneous injections of matched placebo, in addition to their existing glucose-lowering therapy.

Treatment:

Drug: Placebo