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

Not Applicable

Not yet recruiting

• Conditions: Dementia, Mild; Mild Cognitive Impairment; Type 2 Diabetes
• Interventions: Drug: Mazdutide; Drug: Placebo

• Registration Number: NCT07083154
• Lead Sponsor: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School

Brief 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.

Detailed 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 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.

Study Timeline

• Study First Submitted: 2025-07-04
• Study First Submitted QC: 2025-07-15
• Study First Posted: 2025-07-24
• Status Verified: 2025-09
• Last Update Submitted: 2025-09-01
• Last Update Posted: 2025-09-08
• Study Start: 2025-10-01
• Primary Completion: 2029-08-01
• Study Completion: 2029-08-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 420

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 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. With current or history of clinically significant psychiatric disorders within the past 2 years, including but not limited to: schizophrenia, bipolar disorder, major depressive disorder, generalized anxiety disorder, or personality disorders.

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Mazdutide group	Mazdutide	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.
Placebo group	Placebo	Participants will receive weekly subcutaneous injections of matched placebo, in addition to their existing glucose-lowering therapy.

Primary Outcome Measures

Name	Time	Method
Integrated Alzheimer's Disease Rating Scale (iADRS) Score Change	From Baseline to Week 76	The change in Integrated Alzheimer's Disease Rating Scale (iADRS) scores from baseline to Week 76 will be compared between the treatment group and the placebo group to assess the drug's potential to improve or slow cognitive decline. iADRS is a composite endpoint that integrates cognitive and functional assessments (scores from Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) and Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living（ADCS-iADL）) to generate a total score (range: 0-144).; The calculation formula is: iADRS score = (85 - ADAS-Cog13 score) + ADCS-iADL score; A lower score indicates more severe cognitive and functional impairment.

Secondary Outcome Measures

Name	Time	Method
Mini-Mental State Examination (MMSE) Score Change	From Baseline to Week 76	The change in Mini-Mental State Examination (MMSE) scores from baseline to Week 76 will be compared between the treatment group and the placebo group to assess the drug's potential to improve or slow cognitive decline. It assesses multiple cognitive domains, including orientation, memory, attention and calculation, recall ability, language, and visuospatial skills. The total score ranges from 0 to 30, with higher scores indicating better cognitive function.
Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) Score Change	From Baseline to Week 76	The change in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) scores from baseline to Week 76 will be compared between the treatment group and the placebo group to assess the drug's potential to improve or slow cognitive decline. The score ranges from 0 to 18, with higher scores indicating greater severity of cognitive and functional impairment.
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) Score Change	From Baseline to Week 76	The change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) scores from baseline to Week 76 will be compared between the treatment group and the placebo group to assess the drug's potential to improve or slow cognitive decline. The score ranges from 0 to 85, with higher scores indicating more significant cognitive impairment.
Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL) Score Change	From Baseline to Week 76	The change in Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL) scores from baseline to Week 76 will be compared between the treatment group and the placebo group to assess the drug's potential to improve or slow functional decline. The total score ranges from 0 to 59, with lower scores indicating more severe functional impairment.
Change in Total Intracranial Volume	From Baseline to Week 76	The change in total intracranial volume evaluated by stuctural MRI from baseline to Week 76 will be compared between the treatment group and the placebo group.
Change in Total White Matter Volume	From Baseline to Week 76	The change in total white matter volume evaluated by stuctural MRI from baseline to Week 76 will be compared between the treatment group and the placebo group.
Change in Total Gray Matter Volume	From Baseline to Week 76	The change in total gray matter volume evaluated by stuctural MRI from baseline to Week 76 will be compared between the treatment group and the placebo group.
Change in Cerebrospinal Fluid Volume	From Baseline to Week 76	The change in cerebrospinal fluid volume evaluated by stuctural MRI from baseline to Week 76 will be compared between the treatment group and the placebo group.
Change in Total White Matter Lesion Volume	From Baseline to Week 76	The change in total white matter lesion volume evaluated by stuctural MRI from baseline to Week 76 will be compared between the treatment group and the placebo group.
Change in Cortical Thickness	From Baseline to Week 76	The change in cortical thickness evaluated by stuctural MRI from baseline to Week 76 will be compared between the treatment group and the placebo group.
Change in Subcortical Nuclei Volumes	From Baseline to Week 76	The change in subcortical nuclei volumes evaluated by stuctural MRI from baseline to Week 76 will be compared between the treatment group and the placebo group.
Alterations in Brain Network Activation	From Baseline to Week 76	The alterations in brain network activation (e.g. auditory network, visual network, default mode network, salience network, and sensorimotor network, etc.）evaluated by functional MRI from baseline to Week 76 will be compared between the treatment group and the placebo group.
Change in Blood-Based Neurodegeneration Biomarkers	From Baseline to Week 76	The change in blood-based neurodegeneration biomarkers (includingAmyloid-β (Aβ42/40 ratio), Phosphorylated tau (p-tau217), Glial fibrillary acidic protein (GFAP), and Neurofilament light chain (NfL), etc.）evaluated by Simoa from baseline to Week 76 will be compared between the treatment group and the placebo group.
Change in Aβ Plaque Deposition	From Baseline to Week 76	The change in Aβ plaque deposition evaluated by \[¹⁸F\]florbetaben PET MR from baseline to Week 76 will be compared between the treatment group and the placebo group (subgroup).
Change in Body Weight	From Baseline to Week 76	The change in body weight from baseline to Week 76 will be compared between the treatment group and the placebo group.
Change in BMI	From Baseline to Week 76	The change in body mass index (BMI) from baseline to Week 76 will be compared between the treatment group and the placebo group.
Change in Glycated Hemoglobin	From Baseline to Week 76	The change in Glycated Hemoglobin (HbA1c) from baseline to Week 76 will be compared between the treatment group and the placebo group.
Change in Fasting Blood Glucose	From Baseline to Week 76	The change in fasting blood glucose from baseline to Week 76 will be compared between the treatment group and the placebo group.
Change in Postprandial Blood Glucose	From Baseline to Week 76	The change in postprandial blood glucose from baseline to Week 76 will be compared between the treatment group and the placebo group.
Change in Lipid Profiles	From Baseline to Week 76	The change in lipid profiles (e.g. Total cholesterol, low density lipoprotein-cholesterol, high density lipoprotein-cholesterol, triglycerides, etc.) from baseline to Week 76 will be compared between the treatment group and the placebo group.
Change in Fasting and Postprandial C-peptide	From Baseline to Week 76	The change in Fasting and Postprandial C-peptide from baseline to Week 76 will be compared between the treatment group and the placebo group.
Change in Pancreatic β-cell Function	From Baseline to Week 76	The change in pancreatic β-cell function (e.g. HOMA2-B, HOMA2-S, HOMA2-IR, etc.) from baseline to Week 76 will be compared between the treatment group and the placebo group.
Change in Visceral Adipose Tissue	From Baseline to Week 76	The change in visceral adipose tissue measured by dual-energy X-ray absorptiometry (DEXA) from baseline to Week 76 will be compared between the treatment group and the placebo group.
Change in Liver Fat Content	From Baseline to Week 76	The change in liver fat content assessed via FibroScan® from baseline to Week 76 will be compared between the treatment group and the placebo group.
Change in Liver Stiffness	From Baseline to Week 76	The change in liver stiffness assessed via FibroScan® from baseline to Week 76 will be compared between the treatment group and the placebo group.

Trial Locations

Locations (7)

Department of Endocrinology, Changzhou No.2 People's Hospital; 🇨🇳 Changzhou, Jiangsu, China

Department of Endocrinology, Jiangsu Province Hospital of Traditional Chinese Medicine; 🇨🇳 Nanjing, Jiangsu, China

Department of Endocrinology, Huadong Hospital Affiliated to Fudan University; 🇨🇳 Shanghai, China

Department of Endocrinology, Xiangya Hospital of Central South University; 🇨🇳 Changsha, Hunan, 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, Shanghai General Hospital; 🇨🇳 Shanghai, Shanghai Municipality, China