SGLT-2 Inhibition, Metabolomics and Cardiovascular/Kidney Disease

Study Overview
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Brief Summary
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This study evaluates the metabolomics changes associated with dapagliflozin treatment in patients with type 2 diabetes mellitus (T2DM). The participants in the study will be randomized to receive 10 mg dapagliflozin or placebo once daily for 12 weeks.

Detailed Description
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In this study, we hypothesize that metabolomics changes that occur in patients with T2DM after initiating SGLT2i (sodium-glucose cotransporter 2 inhibitors) treatment may be responsible for the beneficial cardiovascular and kidney effects observed in clinical trials with SGLT2i. Also, we propose that the study of the specific metabolome associated with the treatment with SGLT2i could help identify the possible metabolites and molecules that reduce CVD (cardiovascular disease) and renal disease in patients with T2DM. The participants in the study will be randomized to receive 10 mg dapagliflozin or placebo once daily of for 12 weeks. Besides, all participants will be advised to engage in 150 min or more of moderate-to vigorous intensity physical activity per week, spread over at least 3 days/week, with no more than 2 consecutive days without activity and to engage in 2-3 sessions/week of resistance exercise on nonconsecutive days. Moreover, these patients will be advised to follow a lifestyle program that achieve a 500-750 kcal/day energy deficit or provide≈1,200-1,500 kcal/day for women and 1,500-1,800 kcal/day for men, adjusted for the individual's baseline body weight.

Official Title
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SGLT-2 Inhibition and Cardiovascular Disease. Metabolomics Study of Potential Factors Involved in Cardio- and Nephroprotection

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Dapagliflozin 10 mg
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-75. BMI 27-39.9 kg/m2. T2DM on treatment with metformin and inadequate metabolic control (defined as HbA1c≥6.5 -7%). Exclusion Criteria: Pregnancy (all women of child-bearing age, unless on treatment with contraceptive methods, will undergo a pregnancy test) Breastfeeding Intolerance/allergy to dapagliflozin. Treatment with antidiabetic drug other than metformin. Impaired kidney function: Estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2 (calculated using the CKD-EPI formula). Patients with established cardiovascular disease. Previous or current history of cancer of any kind. Uncontrolled hypertension (systolic blood pressure≥160 mmHg or diastolic blood pressure≥110 mmHg, despite adequate antihypertensive treatment). History of liver tumour or acute or chronic liver disease with impaired liver function: total bilirubin levels> 2.0 mg / dl or GOT/GPT levels three times higher than normal upper limit. Known HIV infection or active HBV or HCV infection. Other serious underlying diseases, which could affect the patient's ability to participate in the study. Reduced life expectancy (<12 months) due to advanced or terminal concomitant diseases. In addition, female patients of child-bearing age will be advised to use contraceptive methods during the study period, given the contraindication of dapagliflozin and metformin during pregnancy as per normal clinical practice.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomized in a 1:1 ratio
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin<br>Dapagliflozin 10 mg daily (orally) | Drug: Dapagliflozin 10 mg<br>* Dapagliflozin 10 mg daily in a green, plain, diamond shaped, film coated tablet (orally)<br>* Other names: Farxiga 10 mg;|
| Placebo Comparator: Placebo<br>Matching placebo for dapagliflozin daily (orally). Does not contain active ingredient | Drug: Placebo Oral Tablet<br>* Green, plain, diamond shaped, film coated tablet (orally). Does not contain active ingredient<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolomics changes in blood | Targeted and quantitative analysis by ultra-high-resolution liquid chromatography coupled to triple quadrupole mass spectrometry (UHPL-QqQ/MS). Analysis of specific families of metabolites selected from hypotheses generated by previous exploratory studies: changes in acylcarnitines and other intermediates of mitochondrial β-oxidation and the urea cycle, branched-chain amino acids and biogenic amines | From baseline to week 12 | 
| Metabolomics changes in urine | Targeted and quantitative analysis by ultra-high-resolution liquid chromatography coupled to triple quadrupole mass spectrometry (UHPL-QqQ/MS). Analysis of specific families of metabolites selected from hypotheses generated by previous exploratory studies: changes in acylcarnitines and other intermediates of mitochondrial β-oxidation and the urea cycle, branched-chain amino acids and biogenic amines | From baseline to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BMI (body mass index) changes | Measured by body composition analysis | From baseline to to week 12 | 
| Changes in insulin resistance | Measured as HOMA-IR (homeostatic model assessment of insulin resistance) | From baseline to to week 12 | 
| Changes in metabolic control | Measured as HbA1c (glycated hemoglobin) | From baseline to to week 12 | 
| Changes in Quality of Life: 36-Item Short Form Health Survey (SF-36) questionnaire | The SF-36 has eight scaled scores: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. The scores are weighted sums of the questions in each section. Scores range from 0 - 100, lower scores indicate more disability, and higher scores indicate less disability | From baseline to to week 12 | 
| Changes in albuminuria | Modifications in albuminuria, measured as albumin excretion rate (AER) | From baseline to to week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metabolomics, Dapagliflozin