None listed
Conditions
Brief summary
This study will help to better understand the effect of empagliflozin on the sympathetic nervous system in people who have preexisting cardiovascular disease. The sympathetic nervous system regulates heart rate, controls blood pressure, regulates sweating and release of glucose from the liver. The primary aim is to answer this question: *What effect does empagliflozin have overall on the sympathetic nervous system? The secondary aims are to answer these questions: *What effects does empagliflozin have on the sympathetic nervous system activity in the heart, kidney, muscle and sweat gland? *What effects does empagliflozin have on pressure in the heart and on heart muscle contraction and relaxation? *What effects does empagliflozin have on glucose and metabolite levels? The study is a randomised trial with 18 people per arm: *Group 1 empagliflozin *Group 2 placebo Total length of study participation will be approximately 19 weeks, i.e. a screening period and baseline assessment period that will last up to 3 weeks, a treatment period lasting 12 weeks, and a safety followup period lasting 4 weeks. There will be up to 9 study visits. During this study, there will be medical history and medication reviews, physical examination, assessment of blood pressure, heart rate and weight, collection of blood and urine. To answer the primary aim, there will be baseline and end of treatment kidney and heart noradrenaline spillover studies and arteriovenous metabolite gradient sampling. This involves sampling from a vein in the back of the hand or arm, from a small tube in the artery in the arm, and from a catheter placed via a vein in the arm, to sample the blood in the heart vein, kidney vein and liver vein. To assess accurately the rate of noradrenaline release from the heart and the kidneys into the bloodstream, a small amount of a radioactive substance will be infused continuously at a low rate through the tube in the arm vein. In the same tube, there will be infused a chemical called para aminohippuric acid (PAH) to measure the kidney blood flow. To answer the secondary aims, there will be baseline and end of treatment tests of electrocardiogram, echocardiogram (heart ultrasound), questionnaires on general health, anxiety and depression, Sudoscan (nerve activity related to sweating), ankle brachial index (which assesses the blood pressure in all 4 limbs), nerve activity testing in the calf muscle, and a maximum exercise capacity test on a stationary bicycle.
Interventions
Empagliflozin. Dose = 25 mg once a day, Duration = 12 weeks. Mode of administration = oral tablet.
Adherence will be monitored at study visits by empty drug packet return and pill counting of any returned study drug.
Sponsors
Baker Heart and Diabetes Institute
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
7C is changed: Age greater or equal to 50 years with 2 or more of the following risk factors at Visit 1: duration of type 2 diabetes greater or equal to 10 years; participant is on at least one anti-hypertensive medication prescribed by a doctor for blood-pressure lowering; the average of 3 readings of systolic blood pressure at Visit 1 is greater than 140 mm Hg; documented albuminuria within 12 months of Visit 1 (defined as at least one urine albumin to creatinine ratio greater or equal to 3 mg/mmol in the last 12 months, with at least one other abnormal albumin to creatinine ratio greater or equal to 3 mg/mmol documented in the history); documented HDL-cholesterol less than 1.0 mmol/L within 12 months of Visit 1; low-density lipoprotein cholesterol (LDL-Cl) greater than 3.36 mmol/L) within last 12 months (verified by documentation of laboratory value LDL-C greater than 3.36 mmol/L); on lipid-lowering therapy prescribed by a doctor.
Exclusion criteria
1) History of type 1 diabetes. 2) Uncontrolled hyperglycaemia with fasting plasma glucose level > 13.3 mmol/L during screening and confirmed by a second measurement performed on a separate day. 3) History of 1 or more episodes of ketoacidosis or hyperosmolar state/coma requiring hospitalisation within the 6 months prior to Visit 1. 4) Ongoing therapy with an SGLT2 inhibitor or pioglitazone. 5) Previously intolerant of an SGLT2 inhibitor. 6) Acute coronary syndrome, stroke or TIA within 2 months prior to Visit 1. 7) On monoamine oxidase inhibitors or tricyclic antidepressants. 8) Diagnosed hypertrophic obstructive cardiomyopathy, dilated cardiomyopathy or restrictive cardiomyopathy. 9) New York Heart Association class III or IV heart failure. 10) Valvular heart disease, moderate or severe, i.e. Stage B moderate or severe, Stage C or Stage D, as defined by the current American Heart Association clinical guidelines9. 11) Current smoker. 12) Indication of liver disease, defined by serum levels of either ALT, AST, or alkaline phosphatase above 3 x upper limit of normal (ULN) at Visit 1 or bilirubin above 1.5 x the ULN measured at Visit 1. 13) Planned cardiac surgery or angioplasty within 19 weeks of Visit 1 14) Bariatric surgery within the past two years, or history of other gastrointestinal surgeries that induce chronic malabsorption. 15) Treatment with anti-obesity drugs 3 months prior to Visit 1 (e.g. orlistat, zonisamide, topiramate, phentermine, lorcaserin, bupropion, naltrexone, either alone or in combination for the purpose of weight loss) or any other treatment at the time of screening (e.g. aggressive diet regimen, etc.) leading to unstable body weight. Unstable body weight is defined as more than 5 kg self-reported change within the 3 months before Visit 1. 16) Have any haematological condition that may interfere with HbA1c measurement (e.g. haemolytic anaemias, haemoglobinopathy). 17) History of an active or untreated malignancy, or in remission from a clinically significant malignancy (other than basal or squamous cell skin cancer, in situ carcinoma of the cervix, or in situ prostate cancer) for less than 5 years prior to Visit 1, or are receiving or planning to receive therapy for cancer, at Visit 1. 18) Are receiving chronic (>2 weeks or 14 days) systemic glucocorticoid therapy (excluding topical, intra-ocular, intranasal, or inhaled preparations) or have received such therapy within 4 weeks of Visit 1. 19) Change in dosage of thyroid replacement hormone within 6 weeks prior to Visit 1. 20) Other endocrine disorder, with the exception of type 2 diabetes and hypothyroidism on stable thyroid replacement dose. 21) Pre-menopausal women (last menstruation less than or equal to 1 year prior to informed consent) who: a) are nursing or pregnant or b) 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 for 30 days after end of treatment, and do not agree to submit to periodic pregnancy testing during participation in the trial. 22) Inadequately controlled arterial blood pressure, defined as SBP >160 mmHg at Visit 1 or DBP > 100 mm Hg at Visit 1. 23) Current genito-urinal infection or history of genito-urinal infection within 2 weeks prior to Visit 1 (but not simple asymptomatic bacteriuria). 24) The occurrence of any acute infection requiring systemic antibiotic therapy within the 2 weeks prior to Visit 1, or known infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection. 25) Patients with any rare hereditary condition of galactose intolerance, e.g. galactosaemia. 26) Alcohol or drug abuse within the 3 months prior to Visit 1 that would interfere with trial participation. 27) Administration of any investigational product within 30 days or within 5 half-lives of the investigational agent (whichever is longer) of Visit 1, or currently participating in another trial (involving an investigational drug and/or follow-up). 28) Any condition which, in the opinion of the Investigator, constitutes a risk or contraindication for the participation of the participant in the study, or that could interfere with the study objectives, conduct, or evaluation. This includes participants unlikely to comply with the study protocol (e.g. an inability and unwillingness to participate in adequate training, an uncooperative attitude, inability to return for follow-up visits, or unlikelihood of completing the study). 29) Persons employed by the Sponsor, Boehringer Ingelheim. 30) Persons who are Investigator site personnel directly affiliated with this study and/or their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or adopted. 31) Participants who, in the opinion of the investigator and based on the participant’s comorbid profile, are likely to have a change in dose of GLP-1 receptor agonist during the study.
Outcome results
None listed