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

Efficacy, Safety, and Tolerability of a GLP-1/GCG Dual Receptor Agonist in Type 2 Diabetes With Early Dementia: A Multicenter, Randomized, Parallel-group, Double-blind, Placebo-controlled Trial

The LIGHT-COG study is a 76-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial. A total of 420 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.

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 420 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. During the study period, if a subject's study drug has been titrated to the maximum tolerated dose or the maximum protocol-specified dose (6 mg), and glycemic control remains suboptimal (fasting venous blood glucose or fingertip capillary blood glucose > 8.5 mmol/L on two consecutive measurements) during follow-up, individualized rescue therapy may be initiated upon the investigator's judgment. The choice of rescue regimen should be based on the investigator's comprehensive assessment of the subject's specific condition, including but not limited to glycemic levels, complications, hepatic and renal function, and risk of hypoglycemia. Optional rescue medications include insulin glargine, metformin, gliclazide modified-release, and acarbose. The investigator shall closely monitor the response to rescue therapy. The study should be terminated if any of the following occurs: inadequate glycemic control after rescue therapy, intolerance to rescue medications, or any other situation necessitating withdrawal as judged by the investigator. All decision-making basis, selection of rescue regimen, and efficacy evaluations must be thoroughly documented.

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 treatment regimen for cognitive impairment for at least 3 months prior to screening and commit to its continuation throughout the study period, meeting one of the following criteria:

   1. No treatment: Not receiving any pharmacological or non-pharmacological interventions for cognitive impairment;
   2. Non-pharmacological therapy only: Engaged exclusively in non-drug interventions (e.g., cognitive training);
   3. Pharmacological therapy: Using approved symptomatic cognitive-enhancing medications (e.g., cholinesterase inhibitors, NMDA receptor antagonists), excluding disease-modifying therapies for Alzheimer's disease (AD).

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 other neurodegenerative diseases that may affect cognition, excluding Alzheimer's disease, 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), etc.

2. Current diagnosis of a poorly controlled or unstable psychiatric disorder (including but not limited to schizophrenia, bipolar disorder, major depressive disorder, generalized anxiety disorder, personality disorders, etc.), which, in the investigator's judgment, may interfere with study assessments, affect treatment compliance, or increase participant risk.

3. With a Patient Health Questionnaire-9 (PHQ-9) score ≥10 at screening, or a Generalized Anxiety Disorder Scale-7 (GAD-7) score ≥10 at screening.

4. History of stroke (ischemic/hemorrhagic), transient ischemic attack (TIA), or epileptic seizure within 3 months prior to screening; Current or prior diagnosis of central nervous system (CNS) disorders that may impair cognitive function, including but not limited to:

   CNS infections, Intracranial tumors, Metabolic encephalopathy, Neurological disorders due to malnutrition, or Severe traumatic brain injury.

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

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

7. Regular use (>2 doses/week) of moderate-to-strong anticholinergic drugs within 4 weeks prior to screening; Use within 3 months prior to screening of: Anti-Parkinsonian drugs, Antiepileptic drugs, Antipsychotics, Morphine and opioid analgesics (Exemption: Short-term use [<5 days] for surgery/acute injury, if completed >4 weeks before screening); Use within 4 weeks prior to screening of: CNS stimulants; Medical/recreational cannabis, cannabinoids, or cannabidiol (CBD).a. Moderate/high anticholinergics, antiparkinsonian/antiepileptic drugs.

8. 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).

9. 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

10. Uncontrolled or potentially unstable diabetic retinopathy/maculopathy.

11. Severe organ dysfunction, including:

    1. ALT/AST >3× 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

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

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

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

15. 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.

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