Diabetes Mellitus Type 2 (T2DM) Clinical Trial
Official title:
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.
;
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Terminated |
NCT01888796 -
Diastolic Dysfunction in Patients With Type 2 Diabetes Mellitus
|
Phase 3 | |
| Terminated |
NCT02077309 -
Effect of Linagliptin on Vascular Inflammation in Patients With Type 2 Diabetes Mellitus
|
Phase 3 |