Background
Left ventricular hypertrophy
Sodium glucose linked co-transporter2 [SGLT2] inhibitors and their potential to regress LVH
Methods
Study design
Visit | 1 Screening | 2 Baselinea
| 3 follow-upa
| 4 Follow-upa
| 5 Follow-upa
| 6 Last visita
|
---|---|---|---|---|---|---|
Timeline - weeks | 0 to − 4 | 0 Within 4 weeks of screening visit | 4b [+/− 1 week] | 17 [+/− 4 weeks] | 34 [+/− 4 weeks] | 52 [+/− 4 weeks] |
Informed Consent | X | |||||
Medical History | X | |||||
Demographics | X | |||||
Concomitant Medications | X | X | X | X | X | X |
Physical Examination | X | |||||
Height & weight | X | |||||
BP & P | X | X | X | X | X | X |
Temperature | X | |||||
ECG | X | |||||
Echoc
| X | X | ||||
Safety Bloodsd
| X | X | X | X | X | X |
Inclusion/Exclusion | X | |||||
Pregnancy Testing if applicablee
| X | X | X | X | X | X |
Research Blood Sample f
| X | X | X | X | X | |
Genetic blood sample | X | |||||
24 h BP | X | X | ||||
Cardiac & abdominal MRIg
| X | X | ||||
Waist & hip measurement | X | X | X | X | X | |
Adjustment of diabetes medication | X | X | X | X | ||
Adjustment of anti-hypertensive medication | X | X | X | X | ||
Record Adverse Events | X | X | X | X | X | |
Randomisation | X | |||||
Dispense Trial Drugs | Xh
| X | X | X | ||
Return trial drugs | X | X | X | X |
Study population
-
Diagnosed with type 2 diabetes mellitus based on the current American Diabetes Association guidelines.
-
Aged 18–80 years
-
Body Mass Index ≥ 23 kg/m2
-
HbA1c 48-85 mmol/mol [last known result within in the previous 6 months]
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BP < 145/90 mmHg. Office BP at screening visit will be used however if this is above the inclusion criteria then the 24 h recording at screening visit will be used to confirm that in the opinion of the PI the BP is adequately controlled.
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Echocardiographic LV hypertrophy (defined as either an LV mass index of >115 g/m2 for men and > 95 g/m2 for women indexed to body surface area or > 48 g/m2.7 or 44 g/m2.7 when indexed to height2.7)
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Women of childbearing potential* [WoCBP] must agree to take precautions to avoid pregnancy throughout the trial and for 4 weeks after intake of the last dose
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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].
-
Participants with type 1 diabetes mellitus
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Participants who have previously had an episode of diabetic ketoacidosis.
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Serum Potassium or Sodium results outwith the normal range
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Diagnosis of clinical heart failure
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History of human immunodeficiency virus
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LV systolic dysfunction [LVEF < 45%] [last known result within in the previous 6 months]
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eGFR < 60 ml/min/1.73m2 [last known result within in the previous month] assessed using an abbreviated Modification of Diet in Renal Disease (MDRD) equation and indexed to 1.73m2.
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Known liver function tests > 3 times upper limit of normal [based on last measures and documented laboratory measurement in the previous 6 months]
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Body weight > 150Kg [unable to fit into a MRI scanner]
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Contraindications to MRI [e.g. claustrophobia, metal implants, penetrative eye injury or exposure to metal fragments in eye requiring medical attention]
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Past or current treatment with any SGLT2 inhibitor
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Allergy to any SGLT2 inhibitor or lactose or galactose intolerance
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Current treatment with loop diuretic
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Currently receiving long term [> 30 consecutive days] treatment with an oral steroid
-
Pregnant or breast feeding participants
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Involvement in the planning and/or conduct of the trial [applies to Astra Zeneca or representative staff and/or staff at the trial site].
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Participation in another interventional study [other than observational trials and registries] within 30 days before visit 1.
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Individuals considered at risk for poor protocol or medication compliance
Randomisation and treatment allocation
Study outcomes
Primary objective and outcome
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To determine if dapagliflozin has any effect on LV diastolic function.
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To determine if as expected dapagliflozin reduces blood pressure [BP]
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To assess the effect of dapagliflozin on left ventricular diastolic function and global longitudinal strain
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To determine if as expected dapagliflozin reduces body weight
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To determine if dapagliflozin reduces visceral fat mass
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To determine if as expected dapagliflozin reduces HbA1C.
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To determine the effect of dapagliflozin on B-type natriuretic peptide [BNP], Uric acid and Fasting Insulin Resistance Index [FIRI]
-
To assess the tolerability of dapagliflozin in this patient group
Sample size and power calculations
Cardiac MRI protocol
Discussion
SGLT2 Inhibitor | Trial Name; Clinical Trial Identifier | Primary Outcome measure | Patient Populationa
| Final Results |
---|---|---|---|---|
Empagliflozin | Empagliflozin Impact on Haemodynamics in Patients with Diabetes and Heart Failure [EMBRACE-HF]. [54] NCT03030222 | Change in pulmonary artery diastolic pressure |
N = 60 10 mg vs placebo Either LVEF 40% or > 40% NHYA II-IV HbA1c ≥ 6.5% and ≤ 11% GFR > 30 ml/min | June 2018 |
Empagliflozin | SGLT2 Inhibition in Diabetic Patients With Heart Failure with Reduced Ejection Fraction [55] NCT02862067 | SGLT2 inhibition effects on cardiorespiratory fitness |
N = 31 10 mg/25 mg standard care LVEF ≤ 50% [in maximum tolerated HF therapy HbA1c 7–10% Age ≥ 18 years GFR > 45 ml/min | June 2018 |
Empagliflozin | EMPagliflozin outcomE tRial in Patients with chrOnic heaRt Failure with Reduced Ejection Fraction [EMPEROR-Reduced] [56] NCT03057977 | Time to first event of adjudicated CV death or adjudicated hospitalisation for HF in patients with HF with reduced ejection fraction |
N = 2850 LVEF ≥ 36to ≤ 40%: NTproBNP ≥ 2500 pg/ml LVEF ≥ 31% to ≤ 35%: NT-proBNP ≥ 1000 pg/ml If LVEF ≤ 30% NT-proBNP ≥ 600 pg/ml Age > 18 years GFR > 20 ml/min | June 2020 |
Dapagliflozin | Dapagliflozin Effect on Symptoms and Biomarkers in Diabetes Patients with Heart Failure [DEFINE-HF] [57] NCT02653482 | Differences in the average reduction of NTproBNP Proportion of patient that achieve a ≥ 5pts increase in heart failure disease specific quality of life score or a ≥ 20% decrease in NTproBNP |
N = 250 10 mg vs placebo LVEF ≤ 40/NHYA II-III HbA1c 6.5–11.0% Age 19–119 years GFR > 45 ml/min BNP ≥ 125 pg/ml and/or NTproBNP ≥ 600 pg/ml | May 2017 |
Dapagliflozin | Study to Evaluate the Effect of dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure With Reduced Ejection Fraction [Dapa-HF]. [58] NCT03036124 | Time to first occurrence of the composite: CV death or hospitalisation for HF or urgent HF visit. |
N = 4500 5/10 mg vs placebo LVEF ≤ 40/NHYA II-IV Age 18 to 130 years GFR > 30 ml/min NTproBNP ≥ 600 pg/ml | December 2019 |
Dapagliflozin | Safety and Effectiveness of SGLT2 inhibitors in Patients with Heart Failure and Diabetes [REFORM] [59] NCT02397421 | Change in LV end systolic volume or LV end diastolic volume as determined by CMRI |
N = 56 10 mg vs placebo. LVEF < 50%/NYHA I-II HbA1c > 6% Age 18 to 75 years GFR > 45 ml/min | August 2017 |
Canagliflozin | A Randomised Active-Control Double-Blinded Study to Evaluate the Treatment of Diabetes in Patients with Systolic Heart Failure. [60] NCT02920918 | Change from baseline aerobic exercise capacity Change from baseline ventilator efficiency |
N = 88 LVEF ≤ 40%/NYHAII-III HbA1C 6.5%–10% Age ≥ 18 years GFR >50 ml/min | November 2018 |
SGLT 2 Inhibitor | Trial Name; Clinical Trial Identifier | Primary Outcome Measure | Patient Populationa
| Final Results |
---|---|---|---|---|
Empagliflozin | Effects of Empagliflozin on Left Diastolic Function Compared to Usual Care in Type 2 Diabetics [EmDia]. [61] NCT02932436 | Difference in E/E’ ratio measured by echocardiography |
N = 264 10 mg vs placebo Age 18–84 years HbA1C ≥ 7–10% on diabetic therapy or ≥ 7–9% diet controlled GFR > 60 ml/min | October 2017 |
Empagliflozin | SGLT2 Inhibition and Left Ventricular Mass [EMPATROPHY] [62]; NCT 02728453 | Change in ventricular mass assessed using CMRI |
N = 60 25 mg vs 2-4 mg Glimepiride LVEF ≥ 45% Age ≥ 40 and < 80 years Office BP ≤ 150/95 mmHg HbA1C 6.5–9% GFR > 60 ml/min | April 2018 |
Empagliflozin | Effects of Empagliflozin on Cardiac Structure in Patients with Type 2 Diabetes [EMPA-HEART] [63] NCT02998970 | Left Ventricular Mass changes measured by CMRI at 24 weeks |
N = 90 10 mg vs placebo LVEF > 30% Age ≥ 40 and ≤ 80 years HbA1C 6.5- ≤ 10% GFR > 60 ml/min | June 2017 |
Dapagliflozin | Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Type 2 Diabetes or Pre-diabetes, and PRESERVED Ejection Fraction; [64] NCT030302235 | Changes from baseline in NTproBNP |
N = 320 10 mg vs placebo LVEF ≥ 45% Age 19 to < 119 years HbA1C ≥ 5.7 - < 11% GFR < 30 ml/min | March 2019 |
Dapagliflozin | Does Dapagliflozin Regress Left Ventricular Hypertrophy in Patients with Type 2 Diabetes; [65] NCT02956911 | Left Ventricular Mass changes measured by CMRI at 52 weeks |
N = 64 10 mg vs placebo LVEF ≥ 45% Age ≥ 18 and ≤ 75 years HbA1C ≥ 7 - < 10% GFR > 60 ml/min | May 2019 |
SGLT2 Inhibitor | Trial Name; Clinical Trial Identifier | Primary Outcome Measure | Patient Populationa
| Final Results |
---|---|---|---|---|
Dapagliflozin | Dapagliflozin Effect on Cardiovascular Events. [DECLARE TIMI 58]; [66] NCT 01730534 | CV Death, non-fatal MI, non-fatal ischaemic stroke |
N = 17,276 10 mg vs placebo HbA1C range not specified Age ≥ 40 years High CV risk | 2019 [Estimated] |
Canagliflozin | Canagliflozin Cardiovascular Assessment Study. CANVAS]; [67] NCT 01032629 | CV Death, non-fatal MI, non-fatal ishaemic stroke |
N = 4422 100 mg/300 mg vs placebo HbA1C 7–10.5% Age ≥ 30 years High CV risk | June 2017 |
Canagliflozin | Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy [CREDENCE] [68]; NCT 02065791 | Time to first occurrence of an event in the primary composite of endpoint of ESKD, doubling of serum creatinine, renal or CV death. |
N = 4200 100 mg vs placebo HbA1c 6.5–12% Age > 30 years GFR ≥ 30 to < 90 ml/min | June 2019 |