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

Plain English Summary

GLP-1/GCG Dual Agonist in Type 2 Diabetes With Early Dementia (LIGHT-COG Study) is a Phase 3 clinical trial sponsored by The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School studying Dementia, Mild, Mild Cognitive Impairment, Type 2 Diabetes. Tests the effectiveness of Mazdutide, a GLP-1/GCG dual receptor agonist, in managing cognitive decline in type 2 diabetes patients with early dementia. For patients aged 50-75 with mild cognitive impairment or early dementia and well-controlled type 2 diabetes. Participation involves weekly injections of Mazdutide or placebo for 76 weeks, with regular cognitive assessments. Alternative treatments include lifestyle changes, oral antidiabetic drugs, and non-pharmacological therapies. The trial aims to enroll 420 participants.

Official Summary

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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Eligible if aged 50-75, with type 2 diabetes and early dementia symptoms, and stable health conditions. Not eligible if you have other neurodegenerative diseases, unstable psychiatric conditions, or recent stroke. Must be able to comply with study requirements and have a stable weight and glycemic control. Women of childbearing potential must use effective contraception. This trial is studying Dementia, Mild, Mild Cognitive Impairment, Type 2 Diabetes, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcome measures the impact of Mazdutide on cognitive function, providing hope for improved quality of life for participants. The specific primary outcome measures are: Integrated Alzheimer's Disease Rating Scale (iADRS) Score Change (From Baseline to Week 28, 52 and 76). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial aims to fill the gap in treatment options for cognitive decline in type 2 diabetes patients with early dementia. As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Dementia, Mild, Mild Cognitive Impairment, Type 2 Diabetes, where improved treatment options are needed.

Investor Insight

The large market size and growing need for effective treatments make this trial significant, with a high probability of approval. Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage.

Is This Trial Right for Me?

Ask your doctor if you have any of the conditions listed in the inclusion criteria. Participation involves weekly injections and regular cognitive assessments. This trial is currently recruiting participants. The trial is being conducted at 8 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: QUADRUPLE
• Enrollment: 420 participants

Interventions

• DRUG: Mazdutide — Mazdutide injection (pre-filled auto-injector pen) is administered subcutaneously at the same time each week. The starting dose is 2.0 mg administered once weekly (QW). Based on individual patient tolerance, the dose should be gradually increased to the target therapeutic dose of 4.0 mg QW over a period of 4 to 12 weeks. The protocol permits adaptive dose escalation up to 6.0 mg weekly when clinically indicated. For participants unable to tolerate dose increases, treatment continue at their maxi
• DRUG: Placebo — Placebo injection (pre-filled auto-injector pen) is administered subcutaneously at the same time each week. The starting dose is 2.0 mg administered once weekly (QW). Based on individual patient tolerance, the dose should be gradually increased to the target therapeutic dose of 4.0 mg QW over a period of 4 to 12 weeks. The protocol permits adaptive dose escalation up to 6.0 mg weekly when clinically indicated. For participants unable to tolerate dose increases, treatment continue at their maximu

Primary Outcomes

• Integrated Alzheimer's Disease Rating Scale (iADRS) Score Change (From Baseline to Week 28, 52 and 76)

Secondary Outcomes

• Mini-Mental State Examination (MMSE) Score Change (From Baseline to Week 28, 52 and 76)
• Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) Score Change (From Baseline to Week 28, 52 and 76)
• Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) Score Change (From Baseline to Week 28, 52 and 76)
• Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL) Score Change (From Baseline to Week 28, 52 and 76)
• Change in Total Brain Volume (From Baseline to Week 76)

Full Eligibility Criteria

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

Trial Locations

• Department of Endocrinology, Xiangya Hospital of Central South University, Changsha, Hunan, China
• Department of Endocrinology, Changzhou No.2 People's Hospital, Changzhou, Jiangsu, China
• Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
• Department of Endocrinology, Endocrine and Metabolic Disease Medical Center,Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
• Department of Endocrinology, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu, China
• The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
• Department of Endocrinology, Shanghai General Hospital, Shanghai, Shanghai Municipality, China
• Department of Endocrinology, Huadong Hospital Affiliated to Fudan University, Shanghai, China

Frequently Asked Questions

Related Conditions

• Alzheimer's disease, mild cognitive impairment, type 2 diabetes, dementia, cognitive dysfunction, neurodegenerative diseases, psychiatric disorders, stroke, and metabolic disorders.

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