Efficacy of Metformin Versus Sitagliptin on Benign Thyroid Nodules in Type 2 Diabetes

Study Overview
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Brief Summary
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A 2-years prospective, randomized and multicentric study will be performed to assess the efficacy of metformin compared to sitagliptin on benign thyroid nodules size ≥ 2 cm, in newly diagnosed patients with type 2 diabetes.

Detailed Description
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Previous studies reported that prevalence of thyroid nodules (TN) is increased in patients with insulin resistance (IR) and type 2 diabetes mellitus (T2DM). However, there are no guidelines for the management of TN in this target population. In 2013, the French National Health Insurance reported that thyroid surgery procedures for benign nodules have increased unjustifiably. The impact of such surgery on the patients could be serious, with psychological repercussions and risks of surgical complications and the need of a substitutive lifetime hormonal treatment. The investigators hypothesize that metformin may reduce the need of TN surgery by decreasing benign TN size through a reduction of IR profile. A 2-years multicentric prospective study will be conducted to compare efficacy of metformin versus sitagliptin on benign thyroid nodules size in patients with initial benign thyroid nodules ≥ 2 cm. The percentage of thyroid surgery avoided, IR profile measured by Homeostasis Model Assessment of Insulin Resistance-Index (HOMA-IR-index) and adipokines concentrations will be also collected at inclusion ad at 2 years. The Primary outcome will be the percentage of patients in each group who had at least a 20% decrease in one or more nodules of more than 2 cm at 2 years. Several secondary outcomes will be registered: percentage of thyroid surgery observed in each group at 2 years, number of new TN (≥ 10mm) after 2 years of follow-up , percentage of metabolic syndrome before and after treatment, proportion of subjects with improvement of the HOMA-IR index and adipokine concentrations, plasmatic thyroid-stimulating hormone (TSH), T4 and T3 levels evolution, percentage of insulin like growth factor-1 (IGF-1) and adiponectin receptor expression in thyroid tissues after TN surgery.

Official Title
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Efficacy of Metformin Versus Sitagliptin on Benign Thyroid Nodules Size in Type 2 Diabetes: a 2-years Prospective Multicentric Study

Conditions
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Diabetes Mellitus, Type 2, Thyroid Nodule (Benign)

Intervention / Treatment
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* Drug: METFORMIN
* Drug: Sitagliptin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with T2DM aged 18 to 65 years; Uncomplicated T2DM, evolving for less than 3 years; Patients with HbA1c levels between 7 and 8% (after the run-in period) Patients with at least one TN ≥ 2 cm non-cystic, whose benignity will be confirmed by a fine-needle aspiration cytology performed twice regardless of ultrasound TIRADS score; Naive subjects of any treatment: never received an anti-diabetic treatment OR received an anti-diabetic treatment of less than 30 days since diagnosis OR did not receive an anti-diabetic treatment during the 30 days before screening; Patients with a creatinine clearance > 60 ml/min; Informed and written consent signed by the patient and the investigator; Affiliation to the national social health system or equivalent. Exclusion Criteria: Subjects without adequate or impaired decisional abilities for consent to research and placed under guardianship, trusteeship or safeguard of justice Pregnant or breastfeeding woman Woman of childbearing potential without effective contraception (estroprogestative, presentative, intrauterine device) Suspect thyroid nodules in ultrasound (TIRADS 4 to 5) with confirmation after a fine-needle aspiration cytology; Thyroid function abnormalities or a history of thyroid disease; Thyroid nodules whose size or symptoms (compressive signs) require surgery Ioduria <100ug /L Thyroid autoimmunity: positive anti-peroxidase, thyroglobulin or anti-TSH receptors antibodies Levothyroxine treatment History of cervical radiotherapy or thyroid surgery Type 1 diabetes Insulin deficiency History of hypersensitivity to one of the active substances History of pancreatitis Obesity linked to endocrine disease Presence of severe complications of T2DM (ischemic heart disease, heart failure with reduced left ventricular ejection fraction, severe lower extremity arteritis, gangrene, retinopathy, end-stage renal failure, cerebrovascular accident) HbA1c levels > 8% after the run-in period Liver diseases (liver failure, cirrhosis, viral hepatitis B or C) Acute alcoholic intoxication, chronic alcoholism Psychiatric diseases (depression, schizophrenia) Neurological diseases (epilepsy, demyelinating diseases, etc.) Treatment influencing the morphology or thyroid function: corticosteroids, lithium, iodized products etc. ... Acute conditions that may impair renal function such as: dehydration, severe infection, shock Respiratory failure Metabolic acidosis

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicenter, prospective open-label study evaluating the efficacy of metformin compared to sitagliptin on benign TN growth in subjects with T2DM. After written approval, subjects with T2DM who meet the eligibility criteria will have a thyroid ultrasound. Subjects with TN of at least 2 cm and 2 benign cytology results after fine-needle aspiration, will be included after a run-in period of 1 month with a daily basal insulin therapy in order to reduce glucotoxicity. If the Hb1Ac levels remain above 8%, the subjects will not be included. After inclusion, a central randomization will allow subjects to benefit from either metformin (group 1) or sitagliptin (group 2). In both cases, the standard nutritional care and physical activity recommendations (150 minutes of physical activity per week) will be recalled. If HbA1c levels > 8% during the follow-up, treatment by gliclazide will be introduce (LP30mg). A follow-up schedule will be given to the included patient for future visits.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin<br>In arm 1, the subjects will receive metformin at the initial dose of 500mg x 2 / day, which will be increased weekly to 500mgx3 / day and then 1gx2 / day in order to obtain the minimum effective dose on glycemic control. | Drug: METFORMIN<br>* After inclusion, a central randomization will allow subjects to benefit from either metformin (group 1) or sitagliptin (group 2). A follow-up schedule will be given to the included patient for future visits. thyroid ultrasonography to analyze the TN evolution in the 2 groups. In arm 1, the subjects will receive metformin at the initial dose of 500mg x 2 / day, which will be increased weekly to 500mgx3 / day and then 1gx2 / day in order to obtain the minimum effective dose on glycemic control. In case of intolerance, the tolerated and effective dose will be taken back provided an effective glycemic control. A classic follow-up will be done every 3 months. Thyroid US and measure of HOMA-IR index will be done every 6 months for 2 years. If the goal of HbA1c will not achieved, a treatment with glicazide will be introduced.<br>|
| Placebo Comparator: Sitagliptin<br>In arm 2, sitagliptin will be prescribed at 100mg / day. A classic follow-up will be done every 3 months. | Drug: Sitagliptin<br>* After inclusion, a central randomization will allow subjects to benefit from either metformin (group 1) or sitagliptin (group 2). A follow-up schedule will be given to the included patient for future visits. thyroid ultrasonography to analyze the TN evolution in the 2 groups. In arm 2, sitagliptin will be prescribed at 100mg / day. A classic follow-up will be done every 3 months. Thyroid US and measure of HOMA-IR index will be done every 6 months for 2 years. If the goal of HbA1c will not achieved, a treatment with glicazide will be introduced.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients in each group who had at least a 20% decrease in one or more nodules of more than 2 cm at 2 years. | Size : The reduction of TN will be evaluated by thyroid ultrasonography. The operator will be the same throughout the follow-up and in each center, with an evaluation every 6 months. A measurement and precise analysis of the TN will be performed. If a TIRADS 4 or 5 classification is described , a new fine-needle aspiration cytology will be performed. A final thyroid ultrasonography evaluation will be performed at 2 years in order to allow the comparison of TN sizes from the pre-inclusion period to the final period. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of thyroid surgery observed in each group at 2 years. | Record the number of thyroid surgeries performed after inclusion for 2 years | 24 months after treatment initiation | 
| Number of new TN (≥ 10mm) after 2 years of follow-up | Detection of new TN (≥ 10mm) by thyroid ultrasonography. The operator will be the same throughout the follow-up and in each center | Baseline and 24 months after treatment initiation | 
| Change between percentage of metabolic syndrome before and after treatment according to the NCEP ATP III definition | Central or abdominal obesity (measured by waist circumference): Men - greater than 40 inches (102 cm) Women - greater than 35 inches (88cm) Triglycerides plasmatic levels greater than or equal to 150 mg/dL (1.7 mmol/L) HDL cholesterol : Men - Less than 40 mg/dL (1.03 mmol/L) Women - Less than 50 mg/dL (1.29 mmol/L) Blood pressure greater than or equal to 130/85 mm Hg Fasting glucose greater than or equal to 110 mg/dL (6.1 mmol/L) | Baseline, every 6 months after treatment initiation until 24 months | 
| Proportion of subjects with improvement of the HOMA-IR index | The HOMA index will be measured after calculation the ratio between the [fasting plasma insulin (Mu / L) X Fasting plasma glucose (mmol / l)] / 22.5 | Baseline, every 6 months after treatment initiation until 24 months | 
| Proportion of subjects with improvement of adipokine concentrations | Among the adipokines, we will measure the plasmatic Leptin, Adiponectin and Vifastin levels | Baseline and 24 months after treatment initiation | 
| Plasmatic thyroid hormon levels | these dosages will allow us to evaluate the changes in the functioning of the nodular thyroid gland during follow-up under either treatment | Baseline, every 6 months after treatment initiation until 24 months | 
| Percentage of IGF-1 receptor expression in thyroid tissues after TN surgery | The analysis of the tissue expression of IGF1 receptors will be performed on thyroid samples after surgery if performed. One sample will be frozen and another will be included in paraffin for further analysis. IGF1 receptors are involved in the insulin and glucose metabolism signaling pathways. Analysis of their expression could help us to understand the possible links between insulin resistance and thyroid nodule. | through study completion, an average of 1 year | 
| Percentage of adiponectin receptor expression in thyroid tissues after TN surgery | The analysis of the tissue expression of adiponectin receptor will be performed on thyroid samples after surgery if performed. One sample will be frozen and another will be included in paraffin for further analysis. Adiponectin receptor are involved in the insulin and glucose metabolism signaling pathways. Analysis of their expression could help us to understand the possible links between insulin resistance and thyroid nodule. | through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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type 2 diabetes mellitus, thyroid nodule, metformin, insulin resistance