The effect of exenatide compared to insulin glargine on cardiac function and metabolism in type 2 diabetic patients with congestive heart failure: a randomized-controlled trial

Patients with type 2 diabetes mellitus (T2DM) are at high risk of developing
congestive heart failure (CHF) due to the high presence of diabetic
cardiomyopathy (DCM) and ischemic heart disease. The concomitant occurrence of
T2DM and CHF is associated with excessive mortality rates. Recently, several
classes of blood-glucose lowering drugs have been related to an elevated risk
of CHF. Consequently, not only caution should be exercised when exposing
high-risk, but otherwise asymptomatic T2DM patients to these potentially
harmful agents, but more importantly, safely lowering of blood-glucose in T2DM
patients with concomitant CHF may be extremely challenging. Glucagon-like
peptide (GLP)-1 receptor agonists, a novel class of blood-glucose lowering
agents, have been reported to improve cardiac function in CHF patients with
T2DM. Whether GLP-1 receptor agonists act directly on the myocardium is
presently unknown, since the beneficial effects may be secondary to the
concomitant improvements in metabolic control. Exenatide is one of the
currently available GLP-1 receptor agonist that has durable effects on
metabolic control and simultaneously decreases body weight in patients with
T2DM.

In this study we will assess the effects of exenatide on cardiac metabolism and
function in patients with T2DM and CHF. We will address the following
hypothesis: exenatide improves global cardiac function in CHF patients with
T2DM, by favorable effects on cardiac metabolism leading to improvement of
cardiac efficiency.

Using a comparator-controlled, parallel-group study design, T2DM CHF patients
(NYHA class II-IV) who have not achieved a target HbA1c of <=6.5% with
metformin, will be treated with either exenatide (5 µg BID for 4 weeks,
subsequently increased to 10 µg BID for the remainder of the study) or insulin
glargine (initiated at 10 IU/day; titrated according to fasting blood glucose
concentrations based on general protocol-defined guidance) during a 26-week
period, to allow the evaluation of a direct GLP-1 receptor agonist mediated
effect. We expect that with the use of non-invasive imaging techniques,
including PET, MRI and echocardiography, myocardial function and oxidative
metabolism can be detailed and the effect of both treatment regimes be
evaluated. We will also compare the myocardial function and metabolism of these
patients with those of healthy BMI- and age-matched controls.

interventiongroup: exenatide 5 mcg BID first 4 weeks, subsequently increased to
10 µg BID for the remainder of the study

comparatorgroup: insulin glargine, initiated at 10 IU/day; titrated according
to fasting blood glucose concentrations based on general protocol-defined
guidance during a 26-week period

The healthy controls will not receive the studymedication

We are aware of the inconvenience that is imposed on the participants in this
study. After a screening visit, they have to visit the research facility 8
times. The visit duration ranges between approximately one hour to f4 and a
half hours. The risk associated with participation are the risks of venous
blood drawing, intravenous infusion and radioactivity (<10 mSv) during the PET
scanning, as described in full detail earlier. We will try to make this study
as bearable as possible for our patients. Appropriate measures will be taken to
minimize discomfort for the participants. All tests will be done by one
researcher.