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

Diabetes Mellitus, Type 2 Clinical Trial

— METNODTHYR  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04298684
• Other study ID #: PAP_RI1_2019/1
• Secondary ID: 2019-000676-42
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: January 1, 2021
• Est. completion date: July 1, 2024

Study information

• Verified date: September 2020
• Source: Centre Hospitalier Universitaire de Pointe-a-Pitre
• Contact: Valerie VS HAMONY SOTER
• Phone: +590590934686
• Email: valerie.soter[@]chu-guadeloupe.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 90
• Est. completion date: July 1, 2024
• Est. primary completion date: February 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Thyroid Diseases
• Thyroid Nodule
• Thyroid Nodule (Benign)

Intervention

Drug:
• METFORMIN
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.
• Sitagliptin
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.

Locations

Country	Name	City	State
France	CHU Bordeaux	Bordeaux
France	CHU Limoges	Limoges
Guadeloupe	University Hospital Center of Guadeloupe	Pointe-à-Pitre
Réunion	CHU de la Réunion	Saint-Pierre

Sponsors (1)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire de Pointe-a-Pitre

Countries where clinical trial is conducted

France,  Guadeloupe,  Réunion, 

References & Publications (24)

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* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Health Insurance. Relevance of care: an analysis of thyroidectomy practice in adults, information point of October 22, 2013.