SGLT-2 Inhibition, Metabolomics and Cardiovascular/Kidney Disease

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

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.

Study Overview

• Status: Unknown
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Dapagliflozin 10 mg; Drug: Placebo Oral Tablet

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jose Carlos Fernandez-Garcia, MD, PhD; Phone Number: +34951034016; Email: josecarlosfdezgarcia@hotmail.com

Study Locations

• Spain
  • Malaga, Spain, 29010
    • Virgen de la Victoria University Hospital. Endocrinology Department
    • Contact: Jose Carlos Fernández García, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud
• Investigators: Principal Investigator: Jose Carlos Fernandez-Garcia, MD, PhD, Virgen de la Victoria Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): May 1, 2019
• Primary Completion (Anticipated): December 1, 2019
• Study Completion (Anticipated): April 1, 2020

Study Registration Dates

• First Submitted: April 11, 2019
• First Submitted That Met QC Criteria: April 15, 2019
• First Posted (Actual): April 18, 2019

Study Record Updates

• Last Update Posted (Actual): April 23, 2019
• Last Update Submitted That Met QC Criteria: April 22, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Dapagliflozin; Metabolomics
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: FIM-DAPA-2018-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No