Please select the eligibility criteria that correspond to the clinical trial below.
Title: DAPA-LVH - Does Dapagliflozin Regress Left Ventricular Hypertrophy In Patients With Type 2 Diabetes?
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.


Options:
A: Inclusion Criteria:

1. Age ≥ 18 years
2. AHFS as defined by the presence of at least 1 symptom (dyspnea, orthopnea, or edema) AND 1 sign (rales on auscultation, peripheral edema, ascites, pulmonary vascular congestion on chest radiography)
3. AHFS is the primary cause of hospitalization
4. Prior clinical diagnosis of HF
5. Left Ventricular Ejection Fraction(LVEF) ≤ 40% during the preceding 3 months (if no echo within the preceding 3 months, an LVEF ≤ 30% during the preceding three years is acceptable)
6. On evidence-based medication for HF (including beta-blocker and ACE-inhibitor/ARB) or previously deemed intolerant
7. Use of at least 80 mg or furosemide total daily dose (or equivalent) prior to admission for AHFS (a lower dose of a loop diuretic combined with a thiazide will count as an "equivalent")
8. Willingness to provide informed consent

Exclusion Criteria:

1. AHFS due to acute myocarditis or acute Myocardial Infarction
2. Ongoing hemodynamically significant arrhythmias contributing to HF decompensation
3. Inotrope, intra-aortic balloon pump (IABP) or other mechanical circulatory support use at the time of consent. Prior use will not exclude a patient.
4. Current or planned left ventricular assist device therapy in next 180 days
5. United Network for Organ Sharing status 1A or 1B
6. B-type natriuretic peptide(BNP)\< 250 or NT-proBNP\<1,000 (Not required per protocol but if available and too low would be an exclusion; within 48 hours of consent)
7. Hemoglobin (Hgb) \< 8.0 g/dl
8. Glomerular filtration rate(GFR) \< 20 ml/min/1.73 m2 within 48 hours of consent
9. Systolic blood pressure \< 80 mmHg at consent
10. Resting Heart Rate \> 110 at consent
11. Acute coronary syndrome within 4 weeks as defined by electrocardiographic (ECG) changes and biomarkers of myocardial necrosis (e.g. troponin) in an appropriate clinical setting (chest discomfort or anginal equivalent)
12. Percutaneous Coronary Intervention, coronary artery bypass grafting or new biventricular pacing within past 4 weeks
13. Primary hypertrophic cardiomyopathy
14. Infiltrative cardiomyopathy
15. Constrictive pericarditis or tamponade
16. Complex congenital heart disease
17. Non-cardiac pulmonary edema
18. More than moderate aortic or mitral stenosis
19. Intrinsic (prolapse, rheumatic) valve disease with severe mitral, aortic or tricuspid regurgitation
20. Sepsis, active infection (excluding cystitis) or other comorbidity driving the HF decompensation
21. Acute or chronic severe liver disease as evidenced by any of the following: encephalopathy, variceal bleeding, International Normalized Ration (INR) \> 1.7 in the absence of anticoagulation treatment
22. Terminal illness (other than HF) with expected survival of less than 1 year
23. Previous adverse reaction to the study drug
24. Receipt of any investigational product in the previous 30 days.
25. Enrollment or planned enrollment in another randomized therapeutic clinical trial in next 6 months.
26. Inability to comply with planned study procedures
27. Pregnancy or breastfeeding mothers
28. Women of reproductive age not on adequate contraception
29. History of acute or chronic pancreatitis
30. History of symptomatic gastroparesis
31. Familial or personal history of medullary thyroid cancer or multiple endocrine neoplasia type-2 (MEN2)
32. Prior weight-loss surgery (i.e., Roux-en-Y gastric bypass) or other gastric surgery associated with increased endogenous GLP-1 production
33. Prior or ongoing treatment with GLP-1 receptor agonists
34. Ongoing treatment with dipeptidyl peptide-IV inhibitors (1 week washout required)
35. Ongoing treatment with thiazolidinedione
36. Oxygen-dependent chronic obstructive pulmonary disease
37. Diabetic patients with history of 2 or more severe hypoglycemia, Diabetic Ketoacidosis(DKA) or hyperglycemic, hyperosmotic nonketotic coma in the preceding 12 months.
38. Diagnosis of Type 1 Diabetes Mellitus

40. If diabetic, inadequate glycemic control with glucose level \> 300 mg/dL within 24 hours of randomization
B: 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.
C: Inclusion criteria:

1. Diagnosis of type 2 diabetes mellitus prior to informed consent
2. Male or female patients on diet and exercise regimen who are drug naive or pre treated with any background therapy. Antidiabetic therapy has to be unchanged for 12 weeks prior to randomization.
3. Glycosylated haemoglobin (HbA1c) of \>= 7.0% and \<=10% for patients on background therapy or HbA1c \>= 7.0% and \<= 9.0% for drug naive patients
4. Age \>= 18 years
5. Body Mass index \<= 45 at Visit 1
6. Signed and dated informed consent
7. High cardiovascular risk

Exclusion criteria:

1. Uncontrolled hyperglycaemia with a glucose level \>240 mg/dl (\>13.3 mmol/L) after an overnight fast during placebo run-in and confirmed by a second measurement (not on the same day)
2. Indication of liver disease, defined by serum levels of either alanine aminotransferase (ALT), aspartate aminotransferase ALT or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined at screening and/or run in.
3. Planned cardiac surgery or angioplasty within 3 months
4. Impaired renal function, defined as Glomerular Filtration Rate \<30 ml/min (severe renal impairment, Modification of Diet in Renal Disease formula) during screening or run in.
5. Bariatric surgery within the past two years and other gastrointestinal surgeries that induce chronic malabsorption
6. Blood dyscrasias or any disorders causing haemolysis or unstable Red Blood Cell (e.g. malaria, babesiosis, haemolytic anemia)
7. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years
8. Contraindications to background therapy according to the local label
9. Treatment with anti-obesity drugs (e.g. sibutramine, orlistat) 3 months prior to informed consent or any other treatment at the time of screening (i.e. surgery, aggressive diet regimen, etc.) leading to unstable body weight
10. Current treatment with systemic steroids at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled endocrine disorder except type 2 diabetes mellitus
11. Pre-menopausal women (last menstruation \<+ 1 year prior to informed consent) who:

    * are nursing or pregnant or
    * are of child-bearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the study and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable methods of birth control include tubal ligation, transdermal patch, intra uterine devices/systems, oral, implantable or injectable contraceptives, sexual abstinence, double barrier method and vasectomised partner
12. Alcohol or drug abuse within the 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to study procedures or study drug intake
13. Participation in another trial with an investigational drug within 30 days prior to informed consent
14. Any other clinical condition that would jeopardize patients safety while participating in this clinical trial
15. Acute coronary syndrome, stroke or TIA within 2 months prior to informed consent
D: Inclusion Criteria:

* Diagnosed with type 2 diabetes mellitus
* Is on one of the following diabetes treatment regimens that is stable for at least 12 weeks (except for pioglitazone for at least 16 weeks) and is within the associated A1C range for that treatment regimen:

  1. A1C \>= 6.5% and \<= 10.0% (\>=48 mmol/mol and \<=86 mmol/mol) on: (a) diet or exercise alone (not on antihyperglycemic agent \[AHA\] for \>= 12 weeks) OR (b) monotherapy with metformin (MF), pioglitazone (PIO) or an alpha-glucosidase inhibitor (AGI) or a sodium-glucose cotransporter inhibitor (SGLT2i) OR (c) dual combination therapy with MF, PIO, AGI or SGLT2i OR
  2. A1C \>= 7.0% and \<=10.0% (\>=53 mmol/mol and \<=86 mmol/mol) on (a) monotherapy with a sulfonylurea or meglitinide OR (b) dual combination therapy with a sulfonylurea or a meglitinide and MF, PIO, AGI, or SGLT2i OR
  3. A1C \>=7.0% and \<=10.0% (\>=53 mmol/mol and \<=86 mmol/mol) on one of the following insulin regimens (with or without metformin): (a) basal insulin (e.g.; insulin glargine, insulin detemir, NPH insulin, degludec) OR (b) prandial insulin (e.g. regular, aspart, lispro, glulisine) OR (c) basal/prandial insulin regimen consisting of multiple dose insulin injections of basal and prandial insulin or the use of pre-mixed insulin (e.g., Novolog 70/30®, Novolin 70/30®, Humalog 75/25®, or Humulin 70/30®
* Pre-existing vascular disease (coronary artery disease, ischemic cerebrovascular disease, atherosclerotic peripheral artery disease)
* (1) Male; (2) female not of reproductive potential; or (3) female of reproductive potential who agrees to remain abstinent or use alone or in conjunction with their partner 2 methods of contraception to prevent pregnancy during the study and for 21 days after the last dose of study drug.

Exclusion Criteria:

* History of type 1 diabetes mellitus or a history of ketoacidosis
* Treated with rosiglitazone, a dipeptidyl peptidase-IV (DPP-4) inhibitor, or a glucagon-like peptide-1 (GLP-1) receptor agonist within 12 weeks prior to study participation or previously treated with omarigliptin
* On a weight loss program and is not in the maintenance phase or has been on a weight loss medication in the past 6 months or has undergone bariatric surgery within 12 months prior to study participation
* Medical history of active liver disease (other than non-alcoholic hepatic steatosis), including chronic active hepatitis B or C, primary biliary cirrhosis, or symptomatic gallbladder disease
* Human immunodeficiency virus (HIV) as assessed by medical history
* New or worsening coronary heart disease, congestive heart failure, myocardial infarction, unstable angina, coronary artery intervention, stroke, or transient ischemic neurological disorder within the past 3 months
* History of malignancy \<=5 years prior to study participation, except for adequately treated basal cell or squamous cell skin cancer, or in situ cervical cancer
* Clinically important hematological disorder (such as aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia)
* Pregnant or breast feeding, or is expecting to conceive or donate eggs during the trial, including 21 days following the last dose of study drug

Answer: B