Dapagliflozin, Cardio-Metabolic Risk Factors and Type-2 Diabetes

NCT03377335 | Unknown Phase 4

• 1 other identifier: ESR-16-12388
• Study Type: interventional
• Target: 186
• Locations: 1 country
• Sites: 1

Brief Summary

Dapagliflozin is a member of the sodium-glucose cotransporter-2 (SGLT2) inhibitor class antidiabetes agents which produces significant and sustained reductions in glycemic parameters in patients with type 2 diabetes (T2DM). However, its non-glycemic effects are still largely unknown. The investigators will evaluate for the first time the effect of dapagliflozin on multiple cardio-metabolic risk markers in one study. So far, no data on the effects of dapagliflozin as well as other SGLT-2 inhibitors on subclinical atherosclerosis, endothelial function, inflammatory markers, cytokines and atherogenic lipoproteins is available. In addition, the investigators will examine microRNAs (miRNAs) implicated in the development and progression of atherosclerotic disease. Again, no data is currently available on dapaglifozin's as well as other SGLT-2 inhibitors' effects on miRNAs. The results of this study will show for the first time the potential multiple, non-glycemic effects of dapagliflozin, reducing multiple cardio-metabolic risk markers, which will ultimately lead to decreased CV risk. In addition, specific mechanisms of the dapagliflozin cardiovascular action will be investigated. Finally, the results of this study may pave the way for personalized therapy (using the results on miRNAs).

Conditions

Type 2 Diabetes Mellitus

Keywords

Dapagliflozin; Type 2 diabetes mellitus; Carotid intima-media thickness; Endothelial dysfunction; Atherogenic lipoproteins; Inflammatory markers; microRNAs

Outcome Measures

Primary Outcomes (1)

• Subclinical atherosclerosis

  To assess the effects of dapagliflozin on subclinical atherosclerosis, as assessed by carotid intima-media thickness (cIMT).

  Change from baseline to 6 months of the treatment

Secondary Outcomes (5)

• Endothelial dysfunction

  Change from baseline to 6 months of the treatment

• Oxidative stress

  Change from baseline to 6 months of the treatment

• Atherogenic lipoproteins

  Change from baseline to 6 months of the treatment

• Inflammatory markers

  Change from baseline to 6 months of the treatment

• microRNAs

  Change from baseline to 6 months of the treatment

Study Arms (2)

Dapagliflozin

EXPERIMENTAL

Dapagliflozin (10mg daily) as add-on to metformin (stable doses ranging from 1500 to 3000 mg daily). The total duration of treatment is 6 months.

Drug: Dapagliflozin 10mg

Metformin alone

PLACEBO COMPARATOR

Metformin alone (stable doses ranging from 1500 to 3000 mg daily). The total duration of treatment is 6 months.

Drug: Metformin

Interventions

Dapagliflozin 10mg DRUG

The subjects in this arm will receive dapagliflozin (10mg daily) as add-on to metformin therapy (doses ranging from 1500 to 3000 mg daily). Number of patients to be randomized: 93 Number of patients expected to complete the study: \>87 All the other medications (including lipid-lowering, anti-hypertensive and anti-platelet agents) will be maintained at fixed doses during the treatment.

Also known as: Forxiga®

Dapagliflozin

Metformin DRUG

All the subjects in this arm will be on metformin therapy only (doses ranging from 1500 to 3000 mg daily). Number of patients to be randomized: 93 Number of patients expected to complete the study: \>87 All the other medications (including lipid-lowering, anti-hypertensive and anti-platelet agents) will be maintained at fixed doses during the treatment.

Also known as: Glucophage®

Metformin alone

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• men and women with T2DM;
• age \>18;
• BMI ≥20 kg/m\^2;
• HbA1c 7.0-9.0 %;
• receiving metformin therapy at least 1500 mg/day for at least 8 weeks before screening;
• plasma triglycerides \<400 mg/dL, plasma LDL-cholesterol \< 250 mg/dL;
• stabile daily dose(s) of hypolipidemic drugs (statins, ezetimibe) for at least 7 weeks prior to the day of randomization;
• adequately controlled blood pressure (≤140/90 mmHg) to be maintained during the study according to Standard of Care;
• able to swallow whole tablets.

You may not qualify if:

• pregnancy or willingness to became pregnant;
• severe liver dysfunction (alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 3 times upper limit of normal);
• renal failure with glomerular filtration rate (eGFR) \<60 ml/min/1.73m\^2;
• major cardiovascular event (myocardial infarction, stroke or hospitalization for unstable angina and/or transient ischaemic attack) within 12 weeks before screening;
• severe infections (such as HIV and HCV);
• any malignancy within 5 years before screening.

Sponsors & Collaborators

• University of Palermo: lead
• AstraZeneca: collaborator
• University of Catania: collaborator

Study Sites (1)

University Hospital of Palermo

Palermo, 90127, Italy

Location

Related Publications (12)

• Rizzo M, Rizvi AA, Patti AM, Nikolic D, Giglio RV, Castellino G, Li Volti G, Caprio M, Montalto G, Provenzano V, Genovese S, Ceriello A. Liraglutide improves metabolic parameters and carotid intima-media thickness in diabetic patients with the metabolic syndrome: an 18-month prospective study. Cardiovasc Diabetol. 2016 Dec 3;15(1):162. doi: 10.1186/s12933-016-0480-8.

  PMID: 27912784 BACKGROUND

• Rizzo M, Chandalia M, Patti AM, Di Bartolo V, Rizvi AA, Montalto G, Abate N. Liraglutide decreases carotid intima-media thickness in patients with type 2 diabetes: 8-month prospective pilot study. Cardiovasc Diabetol. 2014 Feb 22;13:49. doi: 10.1186/1475-2840-13-49.

  PMID: 24559258 BACKGROUND

• Corrado E, Rizzo M, Coppola G, Muratori I, Carella M, Novo S. Endothelial dysfunction and carotid lesions are strong predictors of clinical events in patients with early stages of atherosclerosis: a 24-month follow-up study. Coron Artery Dis. 2008 May;19(3):139-44. doi: 10.1097/MCA.0b013e3282f3fbde.

  PMID: 18418229 BACKGROUND

• Salamone F, Galvano F, Marino Gammazza A, Paternostro C, Tibullo D, Bucchieri F, Mangiameli A, Parola M, Bugianesi E, Li Volti G. Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis. Dig Liver Dis. 2012 Apr;44(4):334-42. doi: 10.1016/j.dld.2011.11.010. Epub 2011 Dec 24.

  PMID: 22197629 BACKGROUND

• Rizzo M, Abate N, Chandalia M, Rizvi AA, Giglio RV, Nikolic D, Marino Gammazza A, Barbagallo I, Isenovic ER, Banach M, Montalto G, Li Volti G. Liraglutide reduces oxidative stress and restores heme oxygenase-1 and ghrelin levels in patients with type 2 diabetes: a prospective pilot study. J Clin Endocrinol Metab. 2015 Feb;100(2):603-6. doi: 10.1210/jc.2014-2291. Epub 2014 Nov 13.

  PMID: 25393640 BACKGROUND

• Berneis K, Rizzo M, Berthold HK, Spinas GA, Krone W, Gouni-Berthold I. Ezetimibe alone or in combination with simvastatin increases small dense low-density lipoproteins in healthy men: a randomized trial. Eur Heart J. 2010 Jul;31(13):1633-9. doi: 10.1093/eurheartj/ehq181. Epub 2010 Jun 6.

  PMID: 20525999 BACKGROUND

• Mikhailidis DP, Elisaf M, Rizzo M, Berneis K, Griffin B, Zambon A, Athyros V, de Graaf J, Marz W, Parhofer KG, Rini GB, Spinas GA, Tomkin GH, Tselepis AD, Wierzbicki AS, Winkler K, Florentin M, Liberopoulos E. "European panel on low density lipoprotein (LDL) subclasses": a statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses. Curr Vasc Pharmacol. 2011 Sep;9(5):533-71. doi: 10.2174/157016111796642661.

  PMID: 21595628 BACKGROUND

• Barbagallo I, Parenti R, Zappala A, Vanella L, Tibullo D, Pepe F, Onni T, Li Volti G. Combined inhibition of Hsp90 and heme oxygenase-1 induces apoptosis and endoplasmic reticulum stress in melanoma. Acta Histochem. 2015 Oct;117(8):705-11. doi: 10.1016/j.acthis.2015.09.005. Epub 2015 Oct 19.

  PMID: 26493719 BACKGROUND

• Cengiz M, Yavuzer S, Kilickiran Avci B, Yuruyen M, Yavuzer H, Dikici SA, Karatas OF, Ozen M, Uzun H, Ongen Z. Circulating miR-21 and eNOS in subclinical atherosclerosis in patients with hypertension. Clin Exp Hypertens. 2015;37(8):643-9. doi: 10.3109/10641963.2015.1036064. Epub 2015 Jun 26.

  PMID: 26114349 BACKGROUND

• Tziomalos K, Athyros VG, Karagiannis A. Editorial: Vascular Calcification, Cardiovascular Risk and microRNAs. Curr Vasc Pharmacol. 2016;14(2):208-10. doi: 10.2174/157016111402160208150816.

  PMID: 26864445 BACKGROUND

• Signorelli SS, Volsi GL, Pitruzzella A, Fiore V, Mangiafico M, Vanella L, Parenti R, Rizzo M, Volti GL. Circulating miR-130a, miR-27b, and miR-210 in Patients With Peripheral Artery Disease and Their Potential Relationship With Oxidative Stress. Angiology. 2016 Nov;67(10):945-950. doi: 10.1177/0003319716638242. Epub 2016 Jul 11.

  PMID: 26980776 BACKGROUND

• Peng H, Zhong M, Zhao W, Wang C, Zhang J, Liu X, Li Y, Paudel SD, Wang Q, Lou T. Urinary miR-29 correlates with albuminuria and carotid intima-media thickness in type 2 diabetes patients. PLoS One. 2013 Dec 9;8(12):e82607. doi: 10.1371/journal.pone.0082607. eCollection 2013.

  PMID: 24349318 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

dapagliflozin; Metformin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: December 9, 2017
• First Posted: December 19, 2017
• Study Start: December 22, 2017
• Primary Completion: December 1, 2018
• Study Completion: January 1, 2019
• Last Updated: February 26, 2018

Record last verified: 2017-12

Locations

IT (1)