Does Dapagliflozin Regress Left Ventricular Hypertrophy In Patients With Type 2 Diabetes? (DAPA-LVH)

• ClinicalTrials.gov Identifier: NCT02956811
• Recruitment Status: Completed
• First Posted: November 7, 2016
• Last Update Posted: July 9, 2019
• Sponsor: University of Dundee
• Collaborators: NHS Tayside; AstraZeneca
• Information provided by (Responsible Party): University of Dundee

Study Description

Brief Summary:

Left ventricular hypertrophy (LVH) is common in people with type 2 diabetes (70%) and is the strongest independent risk factor for cardiovascular events and all-cause mortality that there is. It is worse than triple vessel coronary disease. LVH often occurs in patients with "normal" blood pressures (BP). Apart from BP, the other three main factors causing LVH are insulin resistance, obesity and cardiac preload. Dapagliflozin reduces ALL four factors known to promote LVH i.e. Dapagliflozin reduces weight, glycaemia, preload and blood pressure and is therefore the ideal agent to reduce LVH since it uniquely attacks all four known mediators of LVH. This trial will investigate the ability of dapagliflozin to regress LVH in 64 participants with normotensive diabetes. This will be done by seeing if dapagliflozin reduces left ventricular mass as measured by cardiac magnetic resonance imaging (MRI). This trial may identify a novel way to reduce the strong independent risk factor of LVH which often persists despite optimum medical therapy in patients with diabetes. If dapagliflozin does reduce LVH, this would be a key sign of which subgroup of patients with diabetes (those with LVH) should be especially targeted with dapagliflozin.

64 participants with type 2 diabetes and LVH will be recruited through the Scottish Diabetes Research Network (SDRN), Scottish Primary Care Research Network (SPCRN) and other routes, in this single centre study. Participants will be randomised to receive either 10mg dapagliflozin or placebo daily for 12 months. Cardiac MRI will be performed at baseline and at 12 months, this will be assessed for the primary outcome of change in left ventricular mass. Secondary outcomes will examine change in 24 hour blood pressure and weight.

Condition or disease	Intervention/treatment	Phase
Type 2 Diabetes; Left Ventricular Hypertrophy	Drug: Dapagliflozin; Drug: Placebo	Phase 4

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Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 66 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: DAPA-LVH - Does Dapagliflozin Regress Left Ventricular Hypertrophy In Patients With Type 2 Diabetes?
• Actual Study Start Date: February 14, 2017
• Actual Primary Completion Date: March 14, 2019
• Actual Study Completion Date: April 2, 2019

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Active; Dapagliflozin 10mg once daily for 12 months	Drug: Dapagliflozin; SGLT2 inhibitor; Other Name: Forxiga
Placebo Comparator: Placebo; Placebo 10mg once daily for 12 months	Drug: Placebo; Matching Placebo

Outcome Measures

Primary Outcome Measures :

1. Change in left ventricular (LV) Mass by Cardiac MRI at 52 weeks [ Time Frame: Baseline and 52 weeks ]
   To see if Dapagliflozin reduces LV mass more than placebo in participants with type 2 diabetes and LV hypertrophy

Secondary Outcome Measures :

1. Change in 24 hour blood pressure (BP) recording at 52 weeks [ Time Frame: Baseline and 52 weeks ]
   To confirm expected effect of dapagliflozin on BP
2. Change in Office blood pressure (BP) at 4, 17, 34 and 52 weeks [ Time Frame: Baseline, 4, 17, 34 and 52 weeks ]
   To confirm expected effect of dapagliflozin on BP
3. Change in Body mass index at 4, 17, 34 and 52 weeks [ Time Frame: Baseline 4, 17, 34 and 52 weeks ]
   To confirm expected effect of dapagliflozin on body mass index
4. Change in waist/hip ratio at 4, 17, 34 and 52 weeks [ Time Frame: Baseline 4, 17, 34 and 52 weeks ]
   To confirm expected effect of dapagliflozin on waist/hip ratio
5. Change in waist circumference at 4, 17, 34 and 52 weeks [ Time Frame: Baseline 4, 17, 34 and 52 weeks ]
   To confirm expected effect of dapagliflozin on waist circumference
6. Change in visceral fat massed with Abdominal MRI at 52 weeks [ Time Frame: Baseline and 52 weeks ]
   To assess the effect of dapagliflozin on visceral fat mass.
7. Change in HbA1c at 4, 17, 34 and 52 weeks [ Time Frame: Baseline, 4, 17, 34 and 52 weeks ]
   To assess the effects of dapagliflozin on HbA1c
8. Number of patients with adverse events related to treatment [ Time Frame: 4, 17, 34 and 52 weeks ]
   Urinary symptoms and hypotensive symptoms will assess the tolerability of dapagliflozin in this patient group
9. Number of participants with abnormal laboratory values [ Time Frame: 4, 17, 34 and 52 weeks ]
   Liver function tests will assess the tolerability of dapagliflozin in this patient group
10. Change in Fasting Insulin Resistance Index (FIRI) at 4, 17, 34 and 52 weeks [ Time Frame: Baseline, 4, 17, 34 and 52 weeks ]
    To assess the effects of dapagliflozin on FIRI
11. Change in B-type Natriuretic Peptide (BNP) at 4, 17, 34 and 52 weeks [ Time Frame: Baseline, 4, 17, 34 and 52 weeks ]
    To assess the effects of dapagliflozin on BNP
12. Change in uric acid at 4, 17, 34 and 52 weeks [ Time Frame: Baseline, 4, 17, 34 and 52 weeks ]
    To assess the effects of dapagliflozin on uric acid
13. Change in diastolic function and global longitudinal strain [ Time Frame: Baseline and 52 weeks ]
    To assess the effect of dapagliflozin on left ventricular diastolic function

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Provision of informed consent before any trial specific procedures.
2. Diagnosed with type 2 diabetes mellitus based on the current American Diabetes Association guidelines.
3. Aged >18 and <80 years
4. Body Mass Index ≥23
5. HbA1c 48-85mmol/mol (last known result within in the previous 6 months)
6. Blood pressure <145/90mmHg. Office BP at screening visit will be used however if this is above the inclusion criteria then the 24 hour or 16 hour recording at screening visit will be used to confirm that in the opinion of the PI the BP is adequately controlled.
7. Echocardiographic left ventricular (LV) hypertrophy (defined as an LV mass index of >115g/m2 for men and >95g/m2 for women indexed to body surface area or >48g/m2.7 or >44g/m2.7 when indexed to height) within the previous 6 months.
8. Women of childbearing potential must agree to take precautions to avoid pregnancy throughout the trial and for 4 weeks after intake of the last dose.

Exclusion Criteria:

1. 1. Any condition that in the opinion of the investigator may render the participant unable to complete the trial including non CV disease (e.g. active malignancy).
2. Participants with type 1 diabetes mellitus
3. Participants who have previously had an episode of diabetic ketoacidosis.
4. Serum Potassium or Sodium results outwith the normal range
5. Diagnosis of clinical heart failure
6. History of human immunodeficiency virus
7. LV systolic dysfunction (LVEF <45%) (last known result within in the previous 6 months)
8. eGFR <45ml/min (last known result within in the previous month)
9. Known liver function tests >3 times upper limit of normal (based on last measures and documented laboratory measurement in the previous 6 months)
10. Body weight >150Kg (unable to fit into a MRI scanner)
11. Contraindications to MRI (e.g. claustrophobia, metal implants, penetrative eye injury or exposure to metal fragments in eye requiring medical attention)
12. Past or current treatment with any SGLT2 inhibitor
13. Allergy to any SGLT2 inhibitor or lactose or galactose intolerance
14. Current treatment with loop diuretic
15. Currently receiving long term (>30 consecutive days) treatment with an oral steroid
16. Pregnant or breast feeding participants
17. Involvement in the planning and/or conduct of the trial (applies to Astra Zeneca or representative staff and/or staff at the trial site).
18. Participation in another interventional study (other than observational trials and registries) within 30 days before visit 1.
19. Individuals considered at risk for poor protocol or medication compliance.

Contacts and Locations

Locations

United Kingdom

Ninewells Hospital

Dundee, United Kingdom

Sponsors and Collaborators

University of Dundee

NHS Tayside

AstraZeneca

Investigators

• Study Director: Allan Struthers, MD, FRCP; University of Dundee
• Principal Investigator: Chim Lang, MD, FRCP; University of Dundee
• Study Director: Graeme Houston, FRCR, MBBCh; University of Dundee
• Study Director: Rory McCrimmon, MBChB, MRCP; University of Dundee

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Brown AJM, Lang C, McCrimmon R, Struthers A. Does dapagliflozin regress left ventricular hypertrophy in patients with type 2 diabetes? A prospective, double-blind, randomised, placebo-controlled study. BMC Cardiovasc Disord. 2017 Aug 23;17(1):229. doi: 10.1186/s12872-017-0663-6.

• Responsible Party: University of Dundee
• ClinicalTrials.gov Identifier: NCT02956811 History of Changes
• Other Study ID Numbers: 2015DM07; 2016-000715-33 ( EudraCT Number )
• First Posted: November 7, 2016
• Last Update Posted: July 9, 2019
• Last Verified: July 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Dundee:

Type 2 Diabetes; Left Ventricular Hypertrophy; Dapagliflozin

Additional relevant MeSH terms:

Hypertrophy, Left Ventricular; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypertrophy; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Pathological Conditions, Anatomical; Cardiomegaly; Heart Diseases; Cardiovascular Diseases; 2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol; Sodium-Glucose Transporter 2 Inhibitors; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Physiological Effects of Drugs