Magnetic Resonance Assessment of Victoza Efficacy in the Regression of Cardiovascular Dysfunction In Type 2 Diabetes Mellitus

Study 1:
The most important cause of mortality amongst DM2 patients is cardiovascular
disease. An early finding of cardiovascular disease in DM2 and obesity is
diastolic dysfunction. Diastolic dysfunction is an independent predictor of
mortality and has been shown to improve in patients on a low calorie diet. The
improvement of diastolic function was associated with a reduction in
triglyceride accumulation in the heart and liver. A relatively new widely
prescribed therapeutic agent for DM2 patients is Liraglutide (Victoza®).
Liraglutide is a Glucagon Like Peptide - 1 homologue that improves glucose
homeostasis and reduces blood pressure and body weight. Next to the induction
of weight loss, which is potentially beneficial for cardiac function, GLP-1
therapy might have a direct advantageous effect on the cardiovascular system.
However, the effect of Liraglutide on cardiovascular function has not been
investigated yet. We hypothesize that treatment of DM2 patients with
Liraglutide is associated with improvement of cardiovascular function and a
reduction of triglyceride accumulation in end-organs.

Study 2:
Among South Asians, there is an increased susceptibility to DM2 and a markedly
enhanced risk of cardiovascular disease in comparison to the Western European
population. The disadvantageous metabolic phenotype as seen in South Asians
includes a relatively large total fat mass, with predominately visceral (VAT)
relative to subcutaneous adipose tissue (SAT) and lower brown adipose tissue
(BAT) volume and activity, accompanied by increased lipid levels (*thin fat
phenotype*). Interestingly, the key elements in the mechanism of action of the
GLP-1 analogue Liraglutide correspond to these differences in metabolic profile
between South Asians and Western Europeans.

Considering the aforementioned metabolic differences, the effects of
Liraglutide as found in DM2 patients of Western European descent cannot be
extrapolated to the South Asian DM2 patients. There has already been evidence
that the glucose lowering effects of Liraglutide are stronger among South
Asians, as compared to Western-Europeans. Moreover, BMI values associated with
increased risk of DM2 and cardiovascular disease are known to be lower for
South Asians as compared to Western Europeans. Up till now, the criteria for
financial reimbursement of Liraglutide, as employed by the health insurance
companies, have been based on BMI values applicable to the Western European
population. However, regarding cardiovascular protection, Liraglutide-induced
weight reduction may already be beneficial at lower BMI for South Asian DM2
patients. Also, considering the elevated cardiovascular event rate, there is an
additional need to assess the cardioprotective potential of Liraglutide among
South Asians.

In the care of DM2, ethnicity-specific guidelines have already been
implemented. For example, in primary care, ethnicity-specific cut-off values
for age have been defined, at which DM2 screening is considered to be
indicated. This study may support further development of personalized care,
addressing ethnicity-specific complications risks.

With the increasing therapeutic options to target DM2, this study evaluates the
cardiovascular effects of Liraglutide in South Asian patients specifically at
risk for cardiovascular DM2-related complications.

Study 1:
1) To test the hypothesis that Liraglutide improves cardiovascular function in
DM2 patients and whether the improvement is associated with redistribution of
ectopic fat stores. 2) To test the hypothesis that Liraglutide activates BAT in
DM2 patients. 23) To investigate the metabolic and cardiovascular effects
related to DM2.

Study 2:
1) To test the hypothesis that Liraglutide results in more improvement of
cardiovascular function in DM2 patients of South Asian descent compared to
Western European and whether the improvement is associated with a higher
redistribution of ectopic fat stores. 2) To test the hypothesis that
Liraglutide activates BAT in DM2 patients of South Asian descent, in higher
degree as compared to DM2 patients of Western European descent. 3) To
investigate the metabolic and cardiovascular effects related to DM2 among South
Asians.

Study 1 and 2:
A 26 weeks double blind, placebo controlled, randomized clinical trial,
extended by an observational study at baseline including healthy controls.

Study 1 and 2:
The intervention group of 25 patients injects Liraglutide (Victoza®) once daily
subcutaneously, the control group of 25 patients injects Liraglutide-Placebo
subcutaneously once daily.
The thirty healthy controls are compared with the fifty DM2 patients at
baseline and receive no intervention.

Study 1 and 2:

Risks:
Patients eligible for study inclusion have an indication for additive glucose
lowering therapy, amongst which is the study medication. The risk of the use of
study medication is therefore considered to be acceptable. However, Liraglutide
is not recommended for use by current clinical guidelines because of a lack of
studies on the efficacy on clinical endpoints as morbidity and mortality.
Liraglutide is commonly expected to be favorable on these parameters by
physicians proven by the large amount of prescriptions; the associated weight
loss is a very important aspect of the popularity of the drug. Therefore,
clinical experience with Liraglutide has grown in the years since introduction
in 2010. Liraglutide is well tolerated with the most important clinical side
effect being mild and usually transient nausea. Furthermore hypoglycemic
episodes can occur, most often seen during co-treatment with SU-derivatives.
Patients will be instructed how to recognize a hypoglycemic episode and how to
act when hypoglycemia is proven or suspected. Apart from study medication,
patients will be treated according to current clinical guidelines. This implies
that patients in the control group will be treated exactly according to
clinical guidelines, apart from the study procedures. The risk of the study
procedures is limited: there is a minimal risk of anaphylactic reaction (<
1:100.000 cases) upon administration of the MRI contrast medium.

Burden:
The burden of the study protocol consists of a total time expenditure of
thirteen hours in 26 weeks, a standard physical examination at screening, to
study days and five doctor's visits for history taking, measurement of weight,
pulse and blood pressure and interpretation of laboratory examinations to guide
treatment and study medication dosage. In total eight blood samples will be
taken with a volume of 300 ml. Furthermore patients are instructed to perform
fasting blood glucose monitoring once a week. The study medication consists of
a subcutaneous injection once daily which is well tolerated in general. Two MRI
scans will be performed with a maximal scan duration of four hours. The MRI
scan has the risk of the determination of an incidental finding. Three/four
times indirect calorimetry will be performed with a total duration of two
hours. Last, patients are asked not to actively change their diet and level of
physical activity during the study period.

Justification:
Above mentioned risks and burden are acceptable in our opinion given the fact
that the knowledge provided by the study can be of benefit for the study
participants themselves. We think that the treatment of DM2 patients can be
optimized with the insight in the cardiovascular effects of Liraglutide since
cardiovascular disease is the most important contributor to mortality in this
group of patients.