Mazdutide for Adults With Prediabetes: A Randomized, Double-Blind, Placebo-Controlled Trial (DREAM-PRE)

BACKGROUND AND RATIONALE Prediabetes - encompassing impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and elevated HbA1c (5.7-6.4%) - affects an estimated 352 million adults globally, with China bearing the highest absolute burden. Without intervention, approximately 5-10% of individuals with prediabetes progress to type 2 diabetes (T2D) annually. Reversal to Normal Glucose Regulation (NGR) is achievable but underexplored as a primary clinical endpoint.

Mazdutide (IBI362) is a GLP-1 receptor/glucagon receptor (GLP-1R/GCGR) dual agonist. Beyond GLP-1R-mediated glucose-dependent insulin secretion and appetite suppression, GCGR co-agonism enhances hepatic fatty acid oxidation and energy expenditure. This dual mechanism may address the overlapping pathophysiology of prediabetes - beta-cell dysfunction, insulin resistance, ectopic lipid accumulation, and excess adiposity - more comprehensively than GLP-1R monoagonists alone.

SCIENTIFIC RATIONALE FOR DOSE SELECTION Two maintenance doses are evaluated: 4 mg and 6 mg once weekly. Both doses demonstrated clinically meaningful HbA1c reduction and weight loss in prior trials (DREAMS-1, DREAMS-2) in patients with type 2 diabetes. The 4 mg dose represents a potentially efficacious and better-tolerated option, while the 6 mg dose achieves maximal receptor engagement. Comparing both doses against placebo in a prediabetes population allows dose-response characterization and informs optimal dosing for future prevention trials.

DISEASE MODIFICATION HYPOTHESIS The primary endpoint (NGR at Week 24) captures complete metabolic normalization across three glycemic domains simultaneously. Secondary assessment at Week 48 (24 weeks after treatment discontinuation) tests whether treatment induces durable disease modification - restoration of beta-cell function and insulin sensitivity - rather than pharmacological glucose suppression alone. The Disposition Index (product of insulin secretion and insulin sensitivity) serves as the key mechanistic secondary endpoint.

LIFESTYLE INTERVENTION BACKGROUND All participants receive standardized lifestyle intervention consistent with Chinese guidelines for prediabetes management, providing an active background that reflects real-world clinical practice and enhances external validity.

Inclusion criteria

• Voluntarily signed written informed consent prior to any study procedures
• Age 18 to 75 years (inclusive) at the time of signing informed consent; male or female
• Prediabetes confirmed by central laboratory at screening, meeting at least one of the following criteria per Chinese Diabetes Society (CDS) standards, and not meeting diagnostic criteria for diabetes:

• Impaired Glucose Tolerance (IGT): 75g OGTT 2-hour plasma glucose

• 7.8 mmol/L and <11.1 mmol/L
• Impaired Fasting Glucose (IFG): fasting plasma glucose ≥6.1 mmol/L and <7.0 mmol/L
• Elevated HbA1c: 5.7% ≤ HbA1c < 6.5% (39-48 mmol/mol)
• BMI ≥22.0 kg/m² at screening
• Self-reported body weight change <10% within 3 months prior to screening; not currently participating in any organized weight-loss program
• Able to understand study requirements, complete all planned visits and examinations, self-administer once-weekly subcutaneous injections, and use the study app for daily monitoring

Exclusion criteria

• Confirmed diabetes at screening (FPG ≥7.0 mmol/L, OGTT 2h-PG ≥11.1 mmol/L, or HbA1c ≥6.5%); or prior confirmed diagnosis of type 1 diabetes, type 2 diabetes, or other specific types of diabetes. Prior gestational diabetes in whom blood glucose has returned to prediabetes levels after delivery is NOT grounds for exclusion.
• Continuous use of any antidiabetic medication for more than 7 days within 3 months prior to screening, including: biguanides (metformin), alpha-glucosidase inhibitors (acarbose, voglibose, miglitol), sulfonylureas (glimepiride, gliclazide, glipizide, glibenclamide), glinides (repaglinide, nateglinide), thiazolidinediones (pioglitazone, rosiglitazone), DPP-4 inhibitors (sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin), SGLT2 inhibitors (dapagliflozin, empagliflozin, canagliflozin, ertugliflozin), insulin (any formulation), or traditional Chinese medicine with confirmed glucose-lowering indication.
• Use of any of the following within 6 months prior to screening (regardless of duration): GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide, exenatide, lixisenatide, benaglutide, etc.), GIP/GLP-1 dual agonists (tirzepatide, etc.), any dual or triple agonist containing GLP-1R and/or GCGR components (including mazdutide), or any GLP-1 class investigational drug in clinical development.
• Use of any prescription weight-loss medication within 3 months prior to screening (regardless of duration), including orlistat, naltrexone/bupropion combination, phentermine/topiramate combination, or any weight-loss drug approved in China or in clinical development. Over-the-counter dietary supplements are not excluded but must be recorded.
• Spontaneous body weight change ≥10% within 3 months prior to screening (based on self-report and/or available medical records), or currently participating in any organized weight-loss program (including commercial weight-loss plans or weight-loss interventions in other clinical trials).
• Prior bariatric or metabolic surgery including Roux-en-Y gastric bypass, sleeve gastrectomy, adjustable gastric banding, biliopancreatic diversion, intragastric balloon placement, or other bariatric surgery.
• Prior history of acute pancreatitis (confirmed by imaging or surgery) or chronic pancreatitis; or serum amylase >3× ULN or serum lipase >3× ULN at screening.
• Personal history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN2); first-degree family history of MTC or MEN2; or serum calcitonin ≥50 ng/L at screening.
• Any of the following within 6 months prior to screening: acute myocardial infarction (STEMI or NSTEMI), ischemic or hemorrhagic stroke, transient ischemic attack (TIA), coronary revascularization (PCI or CABG), or hospitalization for unstable angina.
• NYHA Class III or IV heart failure. (NYHA Class I and II are not grounds for exclusion.)
• Clinically significant arrhythmia on 12-lead ECG at screening, including:

Mobitz Type II or third-degree atrioventricular block, sustained ventricular tachycardia (≥30 seconds or requiring cardioversion), QTcF >500 ms, or resting heart rate <50 bpm (in subjects not using beta-blockers or calcium channel blockers).

• Uncontrolled hypertension: confirmed mean systolic blood pressure ≥180 mmHg and/or mean diastolic blood pressure ≥110 mmHg on repeated measurements at screening despite antihypertensive therapy. Subjects with controlled blood pressure on a stable antihypertensive regimen (stable for ≥4 weeks prior to screening) are allowed to enroll.
• ALT >3× ULN, AST >3× ULN, or total bilirubin >2× ULN at screening (except confirmed Gilbert's syndrome with normal direct bilirubin).
• eGFR (CKD-EPI) <45 mL/min/1.73 m² at screening. Subjects with eGFR 45-60 mL/min/1.73 m² may enroll with enhanced renal function monitoring.
• Any of the following gastrointestinal conditions: known gastroparesis (confirmed by gastric emptying study or clinical diagnosis), inflammatory bowel disease (Crohn's disease or ulcerative colitis, active or remission), short bowel syndrome, prior gastrointestinal surgery likely to affect drug absorption (excluding simple appendectomy and laparoscopic cholecystectomy), or other serious gastrointestinal disease likely to significantly affect drug tolerability or absorption.
• Diagnosis or active treatment of any malignancy within 5 years prior to screening.
• Positive urine pregnancy test at screening, currently breastfeeding, or planning pregnancy during the 48-week study period.
• Known allergy to mazdutide or any excipient in its formulation; or prior serious allergic reaction to any GLP-1 class drug (defined as angioedema, anaphylactic shock, or allergic reaction requiring hospitalization).
• Participation in any other interventional clinical trial within 3 months prior to screening (excluding purely observational or epidemiological studies not involving investigational drugs or devices), or currently enrolled in any other clinical trial.
• Currently on long-term systemic corticosteroids (expected continuous use >14 days, oral or intravenous); or currently using drugs known to significantly affect body weight or glucose metabolism that cannot be discontinued or substituted, including antipsychotics (olanzapine, clozapine, quetiapine, etc.), valproate sodium, or lithium.
• History of alcohol abuse within 1 year prior to screening, defined as daily consumption >3 standard drink units (men) or >2 standard drink units (women) sustained for >3 months (1 standard drink unit ≈ 10g pure alcohol).