Effect of Low Dose Combination of Linagliptin + Metformin to Prevent Diabetes

Study Overview
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Brief Summary
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Type 2 diabetes is a chronic disease that has reached global epidemic proportions due to the growing number of patients in all countries; It has become the disease that causes more chronic and acute complications to patients, unfortunately, when the diagnosis of type 2 diabetes is made patients are identified at very advanced stages of the disease. For all the above, the best strategies will be those that are aimed at early stages of the disease, and the investigators are convinced that the use the combination of drugs with additive pathophysiological effect plus cardiovascular protection in early stages, will have better results, lasting and with greater results impact on the natural history of the disease that throws measures that may have an applicability in clinical practice, in order to contribute to the control of this pathology. Therefore, the combination of medications with different mechanisms of action, in low doses, could be a useful strategy not only to prevent type 2 diabetes, but also to prevent macro and microvascular complications early. The goal of this clinical trial is to evaluate the effect of low doses of linagliptin + metformin vs metformin alone on physiopathological parameters, such as glucose metabolism, insulin resistance, insulin secretion and pancreatic beta cell function in patients with impaired fasting glucose plus impaired glucose tolerance, during 12 months.

Detailed Description
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The main goal of this clinical trial is to compare the effect of two different treatments during 12 months: Lifestyle modification program + metformin 1700mg every 24 hours. Lifestyle modification program + linagliptin (2.5mg) and metformin (1700mg) every 24 hours. on the following parameters, after 12 months of treatment: Glucose metabolism, evaluated by the oral glucose tolerance Insulin resistance, evaluated by the oral glucose tolerance in 100% of the patients Insulin secretion, evaluated by the oral glucose tolerance in 100% of the patients Pancreatic beta cell function, evaluated by the oral glucose tolerance in 100% of the patients Cardiovascular function, evaluated by ejection fraction measurement, diastolic and systolic preloads measured by standard echocardiography. All the patients will have a basal evaluation with an oral glucose tolerance test, lipid profile, body composition. After the basal evaluation, if the patients result with prediabetes (FASTING IMPAIRED GLUCOSE/IMPAIRED GLUCOSE TOLERANCE) and have at least 2 risk factors, they will be invited to the intervention phase where they will be randomized to one of the two treatment groups. Patients will have a follow-up visit every month to review the adherence to the lifestyle modification program and to the medication. After 6 months, patients will repeat the same evaluation performed as the basal evaluation.

Official Title
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Effect of Low Dose Combination of Linagliptin and Metformin to Improve Pancreatic Beta Cell Function, Insulin Resistance and Cardiovascular Function in Patients With Prediabetes and Overweight/Obesity: Randomizer Clinical Trial

Conditions
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Prediabetic State, Insulin Resistance

Intervention / Treatment
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* Combination Product: Linagliptin + metformin
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with prediabetes, defined for the existence of one or both of the following conditions: 1) impaired fasting glucose (Fasting glucose between 100 and 125 mg/dL), 2) impaired glucose tolerance (Glucose between 140 and 199 mg/dL at the 2 hours of the Oral Glucose Tolerance test (OGTT) Patients who accept to participate in the study and sign the informed consent letter. Exclusion Criteria: Patients with diagnosed Type 2 Diabetes Mellitus previously or detected during the OGTT Patients in actual treatment or during the last 3 months with metformin, pioglitazone or another antidiabetic drug, including insulin. Serum creatinine > 1.6 mg/dL Hypertriglyceridemia very high (>500 mg/dL) Pregnant women Altered arterial hypertension (Systolic > 180 mmHg or Diastolic >105 mmHg) Excessive alcohol intake, acute or chronic Medications or medical conditions that affect glucose homeostasis (thiazides, beta blockers, glucocorticoids for systemic use, weight-reducing drugs or anorexigenics, Cushing's syndrome, Thyrotoxicosis.

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: 1:1 ratio allocation
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Linagliptin + Metformin plus lifestyle<br>Patients are randomized to receive for 12 months Linagliptin 2.5mg + metformin 1700mg every 24 hours. The start of the dose in this group will be gradual so that at the month of treatment the patient can be with the full doses. Together with this, patients will receive a lifestyle modification program seeking to reduce 5-7% of body weigh and increase physical activity to 90-150min/week. | Combination Product: Linagliptin + metformin<br>* Linagliptin-Metformin 2.5/1700mg daily plus a lifestyle modification program based on nutritional assesment, physical activity prescription and general counseling<br>* Other names: low doses of Linagliptin + metformin;|
| Active Comparator: Metformin plus lifestyle<br>Patients are randomized to receive for 12 months Metformin 1700mg every 24 hours. The start of the dose in this group will be gradual so that at the month of treatment the patient can be with the full doses. Together with this, patients will receive a lifestyle modification program seeking to reduce 5-7% of body weigh and increase physical activity to 90-150min/week. | Drug: Metformin<br>* Metformin 1700mg daily plus a lifestyle modification program based on nutritional assesment, physical activity prescription and general counseling<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from basal fasting and 2 hours glucose levels during the oral glucose tolerance test at 12 months | Fasting and post-2 hours glucose values (mg/dl) during the oral glucose tolerance test | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from basal pancreatic beta cell function at 12 months | Evaluated with the Disposition index (DI), obtained from measurements of glucose and insulin during the oral glucose tolerance test. A higher value in the DI meas a better pancreatic beta cell function. There are not minimum and maximum levels | 12 months | 
| Change from basal insulin sensitivity at 12 months | Insulin sensitivity evaluated with the Matsuda Index, obtained with the insulina and glucose measurements during the oral glucose tolerance test. Matsuda index is reported in arbitrary units, and a higher value means a better insulin sensitivity. There are not minimum and maximum levels | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prediabetes