Clinical trial NCT04298684: Efficacy of Metformin Versus Sitagliptin on Benign Thyroid Nodules in Type 2 Diabetes
Official title: Efficacy of Metformin Versus Sitagliptin on Benign Thyroid Nodules Size in Type 2 Diabetes: a 2-years Prospective Multicentric Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Thyroid Nodule (Benign)
Keywords: type 2 diabetes mellitus
thyroid nodule
metformin
insulin resistance
Lead sponsor: Centre Hospitalier Universitaire de la Guadeloupe
Sponsor class: OTHER
First posted: 2020-03-06
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: PREVENTION

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: 24 months
Secondary outcomes:
measure: Percentage of thyroid surgery observed in each group at 2 years.
timeFrame: 24 months after treatment initiation
measure: Number of new TN (≥ 10mm) after 2 years of follow-up
timeFrame: Baseline and 24 months after treatment initiation
measure: Change between percentage of metabolic syndrome before and after treatment according to the NCEP ATP III definition
timeFrame: Baseline, every 6 months after treatment initiation until 24 months
measure: Proportion of subjects with improvement of the HOMA-IR index
timeFrame: Baseline, every 6 months after treatment initiation until 24 months
measure: Proportion of subjects with improvement of adipokine concentrations
timeFrame: Baseline and 24 months after treatment initiation
measure: Plasmatic thyroid hormon levels
timeFrame: Baseline, every 6 months after treatment initiation until 24 months
measure: Percentage of IGF-1 receptor expression in thyroid tissues after TN surgery
timeFrame: through study completion, an average of 1 year
measure: Percentage of adiponectin receptor expression in thyroid tissues after TN surgery
timeFrame: through study completion, an average of 1 year
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Limoges
country: France
facility: CHU Limoges
city: Pointe-à-Pitre
country: Guadeloupe
facility: University Hospital Center of Guadeloupe
city: Saint-Pierre
country: Réunion
facility: CHU de la Réunion
Study officials:
affiliation: CHU de la Guadeloupe
name: Fritz-Line FLV VELAYOUDOM, MD
role: STUDY_DIRECTOR
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