Empagliflozin as a Modulator of Systemic Vascular Resistance and Cardiac Output in Patients With Type 2 Diabetes
Condition: Diabetes Mellitus Type 2 (T2DM)
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 2

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.
    

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.
    

Intervention name(s): Empagliflozin; Placebo
Intervention type(s): Drug; Other
Intervention description(s): Patient will be treaded according to standard care but additionally take one tablet Empagliflozin per day; Patient will be treaded according to standard care but additionally take one tablet placebo per day
Other intervention name(s): Jardiance
Intervention MeSH terms: Empagliflozin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Empagliflozin; Diabetes; Systemic vascular resistance; Cardiac output; Blood pressure