Empagliflozin as a Modulator of Systemic Vascular Resistance and Cardiac Output in Patients With Type 2 Diabetes

SGLT2 inhibitors are a novel class of glucose lowering drugs that act in the kidney by inhibiting SGLT2-mediated glucose reabsorption in the proximal tubule. The resulting increase in urinary glucose excretion leads to a reduction in plasma glucose levels. This is accompanied by reduction of total body weight due to urinary energy loss. In addition, glucose dependent osmotic diuresis contributes to blood pressure lowering effects of SGLT2 inhibition.

Aim of the trial is to assess hemodynamic changes by empagliflozin, identify new empagliflozin dependent metabolic regulators and evaluate empagliflozin dependent effects on cardiac function.

Strikingly, empagliflozin was recently found to reduce cardiovascular mortality in addition to heart failure in the EMPA-REG OUTCOME trail. This multi-center, randomized, placebo controlled study enrolled 7020 patients with type 2 diabetes at high cardiovascular risk. Patients were randomized to placebo or one of 2 doses of empagliflozin (10 or 25 mg/d) on the background of state-of-the-art glucose-lowering therapy with good control of associated CV risk factors at trial entry. At the end of the study, empagliflozin led to a slightly lower HbA1c of 0.3 - 0.4 % in comparison to placebo with higher addition of other anti-hyperglycemic medications found in the placebo group. Moreover, empagliflozin compared with placebo led to a significant reduction in blood pressure and body weight, similar to what has been reported in earlier studies. For the primary outcome empagliflozin significantly reduced the risk of cardiovascular death, myocardial infarction and stroke compared with placebo with a hazard ratio of 0.86 (95% CI 0.74-0.99; p=0.038). This reduction was mainly driven by a highly significant 38% reduction in cardiovascular death (HR 0.62; 95% CI 0.49-0.77), with a very early separation of the curves evident as early as 2 months into the trial. There was a non-significant 13% reduction of non-fatal myocardial infarction (p=0.30) and a non-significant 24% increased risk for non-fatal stroke (p=0.16). In addition, in a secondary/exploratory analysis, empagliflozin led to a significant reduction of hospitalization for heart failure with a 35% risk reduction (HR 0.65; 95% CI 0.50-0.85; p\<0.002), with separation of the curves evident almost immediately during trial observation, suggesting a very early effect of the SGLT2-inhibitor. Finally, empagliflozin reduced overall mortality by 32% (HR 0.68; 95% CI 0.57-0.82; p\<0.0001), a highly significant effect translating into a number-needed-to-treat (NNT) of 39 over 3 years to prevent one death.

These large unexpected, beneficial effects of empagliflozin on all-cause death, CV death and HF hospitalization have raised important questions, as to the mechanism underpinning these favorable CV actions, which cannot be explained by glucose control nor a reduction of atherosclerotic events.

The rapid separation of survival and HF-event curves suggest an instant mode of empagliflozin action - which we here hypothesize to be driven by immediate changes of hemodynamic parameters. This might be followed by more delayed metabolic effects contributing to the beneficial risk profile.

The investigators speculate empagliflozin dependent hemodynamic changes to be responsible for the early and longer term blood pressure lowering effects. This might initially be driven a rapidly occurring empagliflozin dependent natriuresis.

This hypothesis is based on:

* The glucosuric effects of SGLT2 inhibitors leading - at least temporarily- to an increase in sodium excretion as well as a reduction in plasma volume due to glucose osmotic diuretic effects and natriuresis
* SGLT2 inhibition has been suggested to directly affect the tubulo-glomerular feedback mechanism in the kidney. The increased delivery of solute (sodium and chloride) to the macula densa in the setting of SGLT2 inhibition may reduce hyperglycemia-induced glomerular hyperfiltration via tubulo-glomerular feedback invoking adenosine-dependent pathways, with direct effects on afferent glomerular arteriolar tone that may diminish hyperfiltration acutely and consistently during treatment. Moreover, these hemodynamic effects may possibly lead to aldosterone withdrawal (thus mimicking to some degree the efficacy of mineralocorticoid antagonism) as well as contributing to inhibition of sympathetic activation.
* Several trials have shown that SGLT2-inhibitors lead to a reduction in systolic blood pressure in a range of 3-5 mmHg and about 2-3 mmHg in diastolic blood pressure. In addition, SGLT2-inhibitors reduce pulse pressure, mean arterial pressure and the product of heart rate-X-systolic blood pressure (a.k.a. "double product") vs. placebo suggesting an effect on different markers and mediators of arterial stiffness. Interestingly, these BP effects occurred without a compensatory increase in heart rate, suggesting a lack of compensatory sympathetic activation. Various mechanisms may contribute to the reduction in BP including weight loss, diuretic effects (osmotic diuresis and natriuresis), sodium depletion but also potential direct and indirect effects on arteriolar relaxation and oxidative stress. In a clinical trial from 2015, Chilton et al. supposes positive effects on blood pressure, arterial stiffness and vascular resistance. So far there is no data about systemic vascular resistance and cardiac output in patients with type 2 diabetes with empagliflozin treatment or other SGLT2 inhibitors.
* Consequently, it remains currently unclear whether osmotic diuresis can be accounted for the longer term blood pressure lowering effects of empagliflozin, which remains stable also after new blood glucose equilibrium is reached.

Eligibility Criteria:
Inclusion Criteria:

1. Type 2 diabetes
2. Serum levels of HbA1c ≥ 6.5 %, despite treatment with diet and glucose lowering agents, which should include metformin (unless intolerance or contraindication to metformin exists)
3. Age ≥ 18 years
4. Participants of child-bearing age should use adequate contraception
5. Written informed consent prior to study participation

Exclusion Criteria:

1. Type 1 diabetes
2. Systolic blood pressure ≥ 160 mmHg, diastolic blood pressure ≥ 90 mmHg
3. Age ≥ 75 years
4. Pregnancy or lactating females
5. Urinary tract infections or significant formation of residual urine in medical history
6. Renal impairment (GFR \< 30 ml/min/1.73 m2)
7. Liver disease (serum levels of AST, ALT or AP more than three times the upper limit of normal)
8. Uncontrolled thyroid disease
9. Endocrinopathies like Graves' disease, acromegaly, Cushing's disease
10. Hypertensive retinopathy or encephalopathy
11. Acute coronary syndrome, stroke or transient ischemic attack in last 6 weeks prior to randomization
12. The subject is mentally or legally incapacitated
13. The subject received an investigational drug within 30 days prior to inclusion into this study
14. Patients with newly diagnosed diabetes, who have not been subjected to diet and glucose lowering drug treatment.
15. Patients with particular risk for ketoacidosis (alcohol abuse, pancreatitis, pancreatic insulin deficiency from any cause, caloric restriction etc.) or ketoacidosis in the past
16. Frequent hypoglycaemic events (in the opinion of the investigator)
17. Patients in whom study participation is not deemed appropriate under consideration of clinical wellbeing by the principal investigator
18. Intolerance to Empagliflozin and excipients in Empagliflozin or rather placebo
19. Hypotension in the past (systolic blood pressure \< 90 mmHg) in patients receiving treatment with blood lowering drugs
20. Signs of exsiccosis
21. Previous treatment with Empagliflozin in the past
22. Critically ill patients (in the opinion of the investigator)