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

Sponsor

RWTH Aachen University (Other)

Overall Status

Completed

CT.gov ID

NCT03132181

Collaborator

Boehringer Ingelheim (Industry)

Enrollment

Location

Arms

Actual Duration (Months)

1.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus Type 2 (T2DM)	Drug: Empagliflozin Other: Placebo	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Apr 24, 2017

Actual Primary Completion Date :

Jan 23, 2019

Actual Study Completion Date :

Jan 23, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Empagliofizin Patients will receive empagliflozin 10 mg qd for a period of 3 months.	Drug: Empagliflozin Patient will be treaded according to standard care but additionally take one tablet Empagliflozin per day Other Names: Jardiance
Placebo Comparator: Placebo Patients of the placebo arm will receive placebo tablets qd for a period of 3 months.	Other: Placebo Patient will be treaded according to standard care but additionally take one tablet placebo per day

Arm

Intervention/Treatment

Experimental: Empagliofizin

Patients will receive empagliflozin 10 mg qd for a period of 3 months.

Drug: Empagliflozin

Patient will be treaded according to standard care but additionally take one tablet Empagliflozin per day

Other Names:

Jardiance

Placebo Comparator: Placebo

Patients of the placebo arm will receive placebo tablets qd for a period of 3 months.

Other: Placebo

Patient will be treaded according to standard care but additionally take one tablet placebo per day

Outcome Measures

Primary Outcome Measures

Mode of action [3 months]
vascular resistance (dyn*s/cm^5)
Mode of action [3 months]
cardiac output (l/min)

Secondary Outcome Measures

Hemodynamics [3 months]
Stroke volume (ml/beat)
Hemodynamics [3 months]
stroke volume variation (%)
Energie expenditure [3 months]
resting energy expenditure (calories/24h)
Cardio cascular [3 months]
blood pressure (mmHg)
Urine [3 months]
24 h sodium excretion (mmol/day)
Body weight [3 months]
body weight (kg)
Cardio vascular [3 months]
heart rate (bpm)
Blood [3 months]
NT-proBNP (ng/l)
Blood [3 months]
cystatin C(mg/dl)
Blood [3 months]
serum levels of Glucose (mg/dl)
Blood [3 months]
HbA1c (%)
Metabolism [3 months]
total-ketone bodies (mmol/l)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Type 2 diabetes
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)
Age ≥ 18 years
Participants of child-bearing age should use adequate contraception
Written informed consent prior to study participation

Exclusion Criteria:

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