Levothyroxine as Adjuvant to a Hypocaloric Diet for the Treatment of Obesity.

Summary

Obesity is a chronic disease with high relapse rates after initial weight loss. Thyroid hormones modulate energy expenditure, body composition, and thermogenesis; higher TSH within the reference range and subclinical hypothyroidism have been associated with adverse metabolic profiles and weight gain. These signals suggest the thyroid axis could influence weight-loss response and subsequent regain. Levothyroxine (LT4) is widely used for hypothyroidism; evaluating its adjuvant role in obesity management is clinically relevant.

This is a phase III, randomized, double-blind, placebo-controlled, multicentre clinical trial conducted in five Spanish hospitals. A total of 286 adults (25-60 years) with grade I-II obesity will be enrolled if they have subclinical hypothyroidism (TSH 5-10 mIU/L with normal peripheral hormones) or are euthyroid with TSH in the highest tertile of the reference range. Participants are randomized 1:1, stratified by age, sex, and BMI.

Intervention: LT4 88 µg once daily or matching placebo for 9 months. During months 0-3, all participants receive a structured hypocaloric Mediterranean diet (≈600 kcal/day deficit; macronutrients 45% carbohydrates, 35% fats, 20% proteins) plus standardized physical-activity advice. From months 3-9, lifestyle support continues with a normocaloric Mediterranean diet. Physical-activity guidance targets ≥150 min/week of moderate-to-vigorous activity (spread over ≥3 days) and 2-3 resistance sessions/week.

Primary endpoint (3 months): change in body weight (kg and %) and body composition (BMI, waist/hip circumferences, fat mass, fat-free mass, total body water by bioimpedance) comparing LT4 versus placebo under the same lifestyle program. The study is powered for n=286.

Key secondary endpoints (up to 9 months): prevention of weight regain; changes in obesity stage; cardiometabolic markers (lipids, glucose/HbA1c, HOMA-IR, adipokines, inflammation, blood-pressure patterns); resting energy expenditure by indirect calorimetry; objectively measured physical activity by accelerometry; cardiac parameters (ECG) and safety; quality of life (EuroQol-5D). Mechanistic substudies assess adipose-tissue metabolic activity (gene/protein expression, browning markers, mitochondrial DNA) and explore gut microbiota, epigenetic signatures, nitrogen balance, and sex-specific differences in response.

Assessments are performed at baseline and follow-up visits through 9 months and include anthropometry, bioimpedance, laboratory panels, indirect calorimetry, ambulatory blood-pressure monitoring, ECG, diet/physical-activity questionnaires, and biobanking of blood, urine, and stool; an adipose-tissue biopsy is obtained in a subsample.

The trial uses intention-to-treat analyses with mixed linear models and is designed with 90% power to detect a clinically meaningful between-group difference in 3-month weight loss; total sample size is 286 (143 per arm). Overall study duration is 21 months (12 months of recruitment plus 9 months of treatment/follow-up); each participant remains in the study for 9 months.

In summary, this trial tests whether adding LT4 88 µg/day to a structured Mediterranean-diet and exercise program enhances early weight loss and helps prevent regain versus placebo in adults with obesity and high-normal TSH or subclinical hypothyroidism, while characterizing metabolic mechanisms and biomarkers of response.

Conditions

• Obesity

Interventions

DRUG

Levothyroxine

Film-coated oral tablets containing levothyroxine 88 mcg, taken once daily for 9 months. All participants receive a structured lifestyle program: months 0-3 hypocaloric Mediterranean diet (\~600 kcal/day deficit) with physical-activity advice; months 3-9 normocaloric Mediterranean diet with continued advice. The IMP is purchased from authorized manufacturers, then reconditioned and relabeled per GMP and supplied blinded for the full study period. Dispensing follows the randomization code; emergency unblinding only via the hospital pharmacy. Store per label (do not store above 25 °C); adherence assessed by pill count and self-report.

DRUG

Placebo

(white, plain, circular), oral once daily for 9 months, no active ingredient. Administered alongside the same lifestyle program as the active arm (months 0-3 hypocaloric Mediterranean diet; months 3-9 normocaloric Mediterranean diet). Placebo is reconditioned and relabeled per GMP to be indistinguishable from levothyroxine; supply is blinded and dispensed per randomization code. Emergency unblinding is performed only by the pharmacy service when medically necessary.

Sponsors & Collaborators

• Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Model

PARALLEL

Eligibility

Min Age

25 Years

Max Age

60 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2025-11-05

Primary Completion

2026-11-30

Completion

2027-05-31

Countries

• Spain

Study Locations