Heart failure is correlated with increased mortality. In the elderly population, heart failure is frequent, and particularly elderly patients with obesity, cardiovascular disorders, or chronic kidney disease are at increased risk of developing heart failure. Therefore, focus on prevention of heart failure in elderly and obese patients with existing cardiovascular or kidney disease is important.
In addition to increasing the risk of heart failure, obesity disposes to many other chronic diseases, e.g. type 2 diabetes mellitus and hypertension. It is further associated with a reduced quality of life, increased burden of hospitalizations and a reduced length of life.
Worldwide obesity is a growing epidemic. Despite the growing recognition of the problem, obesity rates continue to increase around the world. Obesity affects every segment of the population, and recently we have shown that 33 % of elderly Danish patients aged 60 years or older with cardiovascular disease have a body mass index > 28 kg/m2.
Whether heart failure prevention is possible in elderly and obese patients is unknown. Treatment with a sodium-glucose cotransporter 2 (SGLT2) inhibitor has an intriguing perspective. The class of drugs reduces the risk of cardiovascular death in patients with type 2 diabetes, with and without known heart failure (6-8). In recent studies, the SGLT2 inhibitors Empagliflozin (Jardiance ®) and Dapagliflozin (Forxiga ®) significantly reduced the risk of cardiovascular death, heart failure hospitalizations and total hospitalizations for patients with heart failure with reduced ejection fraction, with and without type 2 diabetes.
At present, the precise mode of action is unknown, but several mechanisms have been proposed and include a diuretic effect, erythropoietin secretion, an effect on blood pressure, a metabolic effect, a reduction in left ventricular (LV) mass and an increase in plasma concentrations of ketones. Obesity as a condition is associated with hypertension, hypervolemia, low grade inflammation and metabolic disturbances for example increased epi- and pericardial fat and an increased risk of future heart failure. Thus, SGLT2 inhibitors could potentially be useful in obese patients. However, whether the SGLT2 inhibitors benefit obese patients without type 2 diabetes or overt heart failure is unknown and no randomized clinical trials are to our knowledge underway (www.clinicaltrials.gov).
Studies focusing on the mechanistic effects of Empagliflozin are warranted. In terms of the drug's observed cardioprotective properties, LV mass is of particular interest, as it has been shown in several studies to be an important and independent predictor of death and cardiovascular events including heart failure. Importantly the magnitude of reduction in LV mass after therapeutic intervention is associated with cardiovascular risk reduction and improvement in outcome. Furthermore, peak oxygen consumption (VO2) is an interesting parameter to examine, as it is the reference standard for assessment of maximal exercise capacity and associated with a reduced mortality risk in patients with heart failure. In heart failure patients peak VO2 correlates with important clinical and patient-related variables like functional class, 6-minute walking test, and quality of life scores.
When looking into Empagliflozin's proposed metabolic effects, changes in epicardial adipose tissue (EAT) volume are interesting to examine, as recent evidence suggest that EAT may play an important role in the development and progression of cardiovascular disease. Similarly, changes in estimated extracellular volume (eECV) as a measure of fluid volume response may play an important role in Empagliflozin's renal effects.
Empagliflozin is an orally available competitive inhibitor of SGLT2, a transport protein, exclusively expressed in the proximal renal tubules, and exhibits antihyperglycemic activity. Upon oral administration, Empagliflozin selectively and potently inhibits SGLT2 in the kidneys, thereby suppressing the reabsorption of glucose in the proximal tubule. Inhibition of SGLT2 increases urinary glucose excretion by the kidneys, resulting in a reduction of plasma glucose levels in an insulin-independent manner. SGLT2 mediates approximately 90% of renal glucose reabsorption from tubular fluid.
Standard treatment is one tablet of Empagliflozin 10 mg once a day. Common, known side effects to treatment with empagliflozin are urinary tract infections and genital infections. Hypoglycemia has only been observed with concomitant use of a sulphonyl urea or insulin. An uncommon, known side effect is hypovolemia. A rare side effect is ketoacidosis.
Data of the present trial program will elucidate whether heart failure can be prevented in elderly and obese patients at increased risk of developing heart failure. The two parts of the trial program are designed to capture a possible beneficial effect of SGLT2 inhibition on: 1) functional capacity and patient's activity level, as well as changes in LV morphology (EMPIRE II cardiac), 2) metabolic risk profile and fluid volume (EMPIRE II metabolic). The PhD student at Odense University Hospital will focus on EMPIRE II cardiac. The mechanistic effects of Empagliflozin will be further evaluated in sub-studies investigating the effects on daily activity level, myocardial structure and function, pericardial fat, lipid metabolism, metabolic risk profile, and volume homeostasis, i.e. blood pressure, plasma volume and kidney function.
Collaborating researchers and departments
Steno Diabetes Center Odense, Odense University Hospital
- Kurt Højlund, M.D., PhD., DmSc
Department of Endocrinology, Odense University Hospital
Department of Nuclear Medicin, Odense University Hospital
Department of Radiology, Odense University Hospital
Department of Cardiology, Herlev University Hospital
- Morten Schou, M.D., PhD., DmSc