Effect of Liraglutide on Cardiovascular Endpoints in Diabetes Mellitus Type 2 Patients
Condition: Diabetes Mellitus Type 2; Metabolic Syndrome; Cardiovascular Disease; Diastolic Dysfunction; Fatty Liver
MeSH terms: Fatty Liver; Cardiovascular Diseases; Diabetes Mellitus; Metabolic Syndrome; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      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. The investigators hypothesize that treatment of DM2 patients with
      Liraglutide is associated with improvement of cardiovascular function and a reduction of
      triglyceride accumulation in end-organs.
    

Detailed description: 
      1. INTRODUCTION AND RATIONALE

           Type 2 diabetes mellitus is an endemic disease associated with obesity and a sedentary
           lifestyle. In the year 2025 the prevalence of DM2 patients worldwide is expected to be
           334 million. In the year 2000 there were an estimated 2,9 million diabetes-related
           deaths worldwide. Especially cardiovascular disease contributes for a great deal to the
           high mortality rates. Diabetes patients have a two-fold excess risk for a wide range of
           vascular diseases, independently of other risk factors, making cardiovascular disease
           the leading cause of death of diabetes patients. Therefore, treatment of DM2 is focused
           on the prevention of cardiovascular disease and other diabetes related complications
           such as retinopathy, neuropathy and nephropathy. Unfortunately, despite lifestyle
           advises, glucose lowering therapy and co-treatment of other risk factors such as
           hypertension and dyslipidemia, complication rates remain high. Classical glucose
           lowering treatment strategies such as sulfonylurea derivatives and insulin ultimately
           can not control the disease, partly because they participate in the vicious cycle of
           increasing body weight and insulin resistance. A hopeful new therapeutic agent is the
           Glucagon Like Peptide -1 analogue Liraglutide. Next to its glucose lowering effect, it
           reduces body weight resulting in increased insulin sensitivity. The group of GLP-1
           analogues are therefore widely prescribed nowadays. However, the effect on the
           cardiovascular system has not been investigated yet. Since cardiovascular disease is the
           major threat for the DM2 patient, the effect of this new drug on the cardiovascular
           system is a very important issue. Interestingly, a cardio-protective effect from
           Liraglutide can be expected on the basis of both the associated weight loss and because
           of a direct protective effect on the heart. The investigators hypothesize that treatment
           with Liraglutide improves cardiac function in DM2 patients. The pathogenesis of
           cardiovascular disease in DM2 is rather complex and multifactorial. Ultimately most
           patients develop myocardial infarction and / or heart failure. Often DM2 patients
           already have subclinical signs of cardiac dysfunction before DM2 is recognized, the main
           early sign being diastolic dysfunction. Diastolic dysfunction is a strong predictor of
           mortality. The subclinical characteristics of cardiac dysfunction are highly associated
           with a condition called the metabolic syndrome. The metabolic syndrome consists of the
           existence of three out of five of the following risk factors: 1. elevated waist
           circumference; 2. elevated triglycerides; 3. reduced HDL-C; 4. elevated blood pressure;
           5. elevated fasting blood glucose including diabetic-range elevated blood glucose level.
           With these criteria most patients with diabetes meet the criteria for the metabolic
           syndrome. A key element in the pathogenesis of the metabolic syndrome might be ectopic
           fat deposition; the earliest sign of the syndrome being visceral adiposity. Next to
           visceral adiposity, there is significant deposition of ectopic fat stores in the liver,
           heart, skeletal muscle and kidney. Triglyceride accumulation in the cardiomyocyte is
           called myocardial steatosis. Studies performed by our group have proven that caloric
           restriction results in a reduction in myocardial steatosis and improvement of diastolic
           function. Hence, myocardial steatosis and associated cardiac dysfunction seem to be
           reversible as is the case for hepatic steatosis. The putative mechanism of steatosis
           resulting in cardiac dysfunction is thought to be explained by a phenomenon called
           lipotoxicity. Altered substrate metabolism and insulin resistance of cardiomyocytes may
           also play an important role in the pathogenesis of cardiac dysfunction in obesity and
           DM2. Systemic and cardiac insulin resistance was proven to be associated with increased
           production of toxic lipids such as diacylglycerol and ceramide. The ultimate treatment
           for obesity and diabetes related cardiac disease seems to be weight loss. However,
           lifestyle intervention programs have repeatedly been unsuccessful to have a sustained
           long term effect. Liraglutide is characterized as a long-acting, human GLP-1 analogue as
           it shows 97% homology with the amino acid sequence of human GLP-1. The phase 3a program
           for Liraglutide encompasses five clinical trials in which Liraglutide treatment was
           studied in each stage of the treatment cascade for type 2 diabetes mellitus. In five
           studies, Liraglutide was compared directly to standard treatment. The phase 3a clinical
           development program, included 3,978 exposed patients with DM2, investigated the efficacy
           and tolerability of Liraglutide 1.2 or 1.8 mg daily (n = 2735) as monotherapy and in
           combination with various oral antidiabetic drugs. The phase 3a studies showed HBA1C
           reductions of 1-1.5% and fasting plasma glucose reductions of 0,83 - 2,39 mmol/L. In
           addition, weight reduction was consistent: Liraglutide 1.8 mg as monotherapy was
           accompanied by a mean weight loss of 2.5 kg over a 52-week period. A substudy of two
           phase 3a trials showed that the weight loss caused by Liraglutide, is predominantly
           caused by a reduction in fat mass; the visceral fat compartment was reduced by 16% from
           baseline during 26 weeks of Liraglutide 1,2 mg daily. Recent experimental data suggest
           GLP-1 and its analogues to have direct effects on the heart. In studies on rat heart,
           the size of an infarct was diminished by more than 50% by an infusion of GLP-1. Post
           conditioning efficacy of GLP-1 was also demonstrated in an ex vivo rat heart. Exendin-4
           was shown to diminish infarct size by approximately 56% and 39%, respectively, in rat
           global and pig focal models of heart ischemia. The GLP-1 receptor (GLP-1R) is present in
           the cardiomyocytes as well as in the endothelium and smooth muscle cells of myocardial
           vasculature. The cell death effector mechanisms targeted by the GLP-1R appear to be
           mitochondrial permeability transition and apoptosis. Animal studies have suggested
           myocardial contractility improvement after GLP-1 administration. For instance, dogs with
           dilated cardiomyopathy treated with GLP-1 for 48 h showed strong improvements in
           myocardial contractility and cardiac output. GLP-1 infusion was associated with
           increased myocardial glucose uptake, suggesting ameliorated insulin sensitivity of the
           cardiomyocytes. In a few small clinical studies, GLP-1 was infused to patients after PCI
           for approximately 72 h and to patients selected for elective coronary artery bypass
           grafting from 12 h before to 48 h after the surgery. The latter group showed an improved
           metabolic profile but no hemodynamic change. In contrast, a left ventricular ejection
           fraction (LVEF) increase from 29% to 39% was found in the former study, as well as in a
           study of 12 diabetic, overweight heart failure patients (New York Heart Association
           class III/IV, LVEF ≤ 40%), given GLP-1 infusion for 5 weeks: at the end of the
           treatment, these patients showed an increased LVEF, cardiac output, and improved scores
           in a life quality questionnaire. A number of laboratory studies have suggested a
           vasorelaxant effect of GLP-1. No pressor effect has been found associated with GLP-1
           treatment in studies on diabetic patients. In fact, a decrease of both systolic and
           diastolic blood pressure values was noted in DM2 patients after an 82-week exenatide
           trial [33], in a manner correlated to weight loss. Recent experiments (unpublished data)
           have shown that the GLP-1 analogue exendin - 4 can protect against atherosclerosis and
           non-alcoholic steatohepatitis (NASH) in APOE 3 - Leiden.CETP mice on a western diet
           probably due to decreased hepatic CETP expression as well as reduced monocyte
           recruitment from the circulation to the vessel wall. In addition, hepatic steatosis was
           improved by a GLP-1 receptor agonist in mice. So far, no dedicated clinical studies have
           been performed to systematically study the effects of GLP-1 analogues on cardiovascular
           function. Given the consistency of the results from animal experiments and clinical
           observations, this area appears ripe for clinical studies. Beneficial effects on
           cardiovascular endpoints will be crucial to consolidate the therapeutic profile of
           Liraglutide. Although large scale studies on cardiovascular endpoints are underway, an
           attractive option is to perform small scale, short-term studies with advanced
           cardiovascular imaging techniques. Thereby gaining insight in what way GLP-1 therapy
           affects the cardiovascular system. Advanced cardiovascular magnetic resonance imaging
           and spectroscopy (MRI/S) enables to assess effects of interventions, in relatively small
           groups of patients in a limited period of time. As these cardiovascular parameters are
           strong and clinically relevant predictors of cardiovascular events, measurements of
           these parameters with MRI/S are worthwhile. Our research group has developed advanced
           cardiovascular MRI and MRS techniques and algorithms and gained extended experience in
           the field of DM2 related cardiac function and lipid metabolism.

        2. RECRUITMENT AND SCREENING PROCEDURE OF STUDY POPULATION

           Patients will be recruited from the outpatient clinics of the Leiden University Medical
           Center, general practitioners, local hospitals and by advertisement. Patients own
           physicists will be asked to point eligible patients to the opportunity of study
           participation. If interested, patients will be informed by the principal investigator.
           Patients will be given oral and written explanation about the study. After a
           consideration time of two weeks, patients are asked to give written acknowledgement of
           informed consent to participate. Then a medical screening will take place. Screening
           will be performed after an overnight fast of at least 12 hours. The screening will
           consist of a medical history, physical examination consisting of measurement of height,
           body weight, heart rate, blood pressure and examination of thorax and abdomen.
           Furthermore laboratory tests and rest-ECG will be performed. If the patient is eligible-
           and willing to participate in the study, and has signed the informed consent, the
           patient will be included. Informed consent must be obtained before any trial related
           activities take place. After inclusion in the study protocol, the patient's treating
           physician and general practitioner will be notified. Although the patients are free to
           leave the study at any time, it will be attempted to recruit patients who are likely to
           continue the study to completion.

        3. SAMPLE SIZE CALCULATION

           Because of the absence of data on the effects of GLP-1 in DM2 patients without heart
           failure, it is hard to calculate the sample size needed to detect differences between
           myocardial function at 26 weeks between active treatment and controls. Clinically
           relevant differences and standard deviations of two studies were chosen to generate data
           for the sample size calculation. The data we used to incorporate the precision of MRI
           assessment of cardiac function was generated by a study performed by our group with
           pioglitazone vs metformin on cardiac function parameters. To estimate the effect of
           GLP-1 therapy on cardiac function, we only have data of a pilot study with eight DM2
           patients with heart failure. Calculations for diastolic function parameters were based
           on the "early deceleration peak" and for systolic function on the basis of "ejection
           fraction". With a power of 90% and alfa = 0.05, groups varying from 9 to 17 patients
           will be needed. In a comparable trial the drop-out rate was 10%. Taken into
           consideration that the population studied will have a significant better systolic
           function than the heart failure patients studied by Sokos et al, differences may be
           smaller. In conclusion, investigators estimate to be able to detect a clinically
           relevant, significant result with 90% power and alfa = 0.05 with 25 patients in each
           group.

        4. USE OF CO-INTERVENTION

           Patients should continue to use the oral glucose lowering medicament metformin during
           the study. For glycaemic control after initiation of the study drug, the current
           clinical guideline will be followed. Excluded concomitant therapy: thiazolidinediones,
           other GLP-1 analogues or DPP-IV inhibitors, fibrates, prednisone, cytostatic and
           antiretroviral therapy.

           Permitted concomitant medication: any other medication required, including SU
           derivatives, insulin, antihypertensive agents and incidental analgesic and antibiotic
           therapy. Glycaemic management during study the will be performed as described in
           appendix 1. To avoid the potential risk of hypoglycaemia, a rigorous monitoring and
           therapy adjustment schedule will be applied, which will prevent risk of hypoglycemia to
           a great extent. In addition, patients will be instructed how to recognize and manage a
           hypo or hyperglycaemic episode. Appropriate individualized adjustments will be made in
           the unlikely case of a hypo or hyperglycaemic episode. Routine self-measurement of blood
           glucose by the study participants will be performed once a week. In addition, patients
           with insulin will be instructed to perform routine self-measurement of blood glucose
           more frequently when study medication and / or insulin dosage is titrated (see appendix
           1).

           Furthermore patients are asked not to change their diet or level of physical activity
           during the study period and adequate contraception is obligatory for study
           participation.

        5. RANDOMIZATION, BLINDING AND TREATMENT ALLOCATION

           After the medical screening and mutual agreement of participation in the study, patients
           will be randomized by block randomization, stratified 1:1 for gender and insulin use. A
           randomization schedule will be prepared by the research pharmacist who is employee at
           the Department of Clinical Pharmacy. Coded and sealed envelopes for each participant
           will be kept at the department of Radiology. In case of safety issues, the sealed
           envelopes are readily available to the principal investigator and project leader. In
           case of a serious adverse event - or a medical emergency requiring knowledge of the
           study medication - the randomization code will be broken. In order to ensure that in
           medical emergencies, the study participation of the patient is apparent, each patient
           will receive a patient file in the electronic patient registry. In this personal file,
           the study number of the patient including the procedure for deblinding and notification
           of the investigators will be mentioned. When the whole study is completed the
           randomization list will be provided to the principle investigator by the pharmacist.

        6. STUDY PROCEDURES

           Withdrawal of individual subjects: Patients can leave the study at any time for any
           reason if they wish to do so without any consequences. The responsible investigator can
           also withdraw a subject if continuing participation is in his opinion deleterious for
           the subject's well being. Patients can also be withdrawn in case of protocol violations
           and non-compliance. When a subject withdraws from the study, a medical examination will
           be performed. In case of withdrawal because of a severe or serious adverse event,
           appropriate laboratory tests or other special examinations will be performed. Finally
           patients can be withdrawn from study participation if an incidental finding at the MRI
           examination - for example a malignancy - influences the ratio of justification versus
           risks / benefits.

           Specific criteria for withdrawal: not applicable

           Replacement of individual subjects after withdrawal: Patients will not be replaced after
           withdrawal.

           Follow-up of subjects withdrawn from treatment: Follow-up of patients after withdrawal
           will be done by the treating physicist (general practitioner in most cases). Immediately
           after study withdrawal, the treating physicist will be updated on the patient's
           condition and laboratory results and whether the patient was in the control group or
           intervention group.

           Premature termination of the study: In case of the incidence of three serious adverse
           events, the study will be terminated prematurely and an independent committee will be
           asked to investigate the safety of the trial. Furthermore, the investigators will
           prematurely terminate the study when the number of subjects withdrawn from the study
           exceeds the number used for sample size calculation, i.e. 16 individuals in total.

        7. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS and SUSPECTED UNEXPECTED SERIOUS ADVERSE
           REACTIONS

      Adverse events (AEs):

      Adverse events are defined as any undesirable experience occurring to a subject during a
      clinical trial, whether or not considered related to the used medication or the infused
      drugs. All adverse events reported spontaneously by the subject or observed by the
      investigator or his/her staff will be recorded on the adverse event data collection form. The
      intensity of these adverse events will be graded by the investigator as follows:

        -  Mild: Discomfort noted but no disruption of normal daily activity

        -  Moderate: Discomfort sufficient to reduce or affect normal daily activity

        -  Severe: Inability to work or perform daily activity All adverse events will be actively
           queried by asking the question: "Have you had any complaints since the last time we
           talked/met?" at all visits. All adverse events will be followed until they have abated,
           or until a stable situation has been reached. Depending on the event, follow up may
           require additional tests or medical procedures as indicated.

      The chronicity of the event will be classified by the investigator on a three-item scale as
      defined below:

        -  Single occasion: Single event with limited duration

        -  Intermittent: Several episodes of an event, each of limited duration

        -  Persistent: Event that remains indefinitely For each adverse event, the relationship to
           the used medication or infused drug (definite, probable, possible, unknown, definitively
           not) as judged by the investigator, will be recorded, as well as any actions undertaken
           in relation to the adverse event, will be recorded. The occurrence of an adverse event
           that is fatal, life-threatening, disabling or requires in-patient hospitalization, or
           causes congenital anomaly, will be described according to CHMP guidelines as (suspected)
           "serious" adverse events and will be notified in writing to the Medical Ethics
           Committee.

      Furthermore, the investigators will copy Novo Nordisk when expediting SARs and SUSARs to
      competent authorities and will report all SARs related to Novo Nordisk product to Novo
      Nordisk. The submission to Novo Nordisk must however be within day 15 from the investigator
      getting knowledge about a valid case no matter local timelines for reporting to the
      authorities. All pregnancies in trial patients occurring during use of a Novo Nordisk product
      must be reported to Novo Nordisk.

      Serious Adverse Events (SAEs):

      A serious adverse event is any untoward medical occurrence or effect that at any dose:

        -  results in death;

        -  is life threatening (at the time of the event);

        -  requires hospitalization or prolongation of existing inpatients' hospitalization;

        -  results in persistent or significant disability or incapacity;

        -  is a congenital anomaly or birth defect;

        -  Any other important medical event that may not result in death, be life threatening, or
           require hospitalization, may be considered a serious adverse experience when, based upon
           appropriate medical judgement, the event may jeopardize the subject or may require an
           intervention to prevent one of the outcomes listed above.

      The sponsor will report the SAEs to the accredited METC that approved the protocol, within 15
      days after the sponsor has first knowledge of the serious adverse reactions.

      SAEs that result in death or are life threatening should be reported expedited. The expedited
      reporting will occur not later than 7 days after the responsible investigator has first
      knowledge of the adverse reaction. This is for a preliminary report with another 8 days for
      completion of the report.

      Suspected Unexpected Serious Adverse Reactions (SUSARs):

      Unexpected adverse reactions are SUSARs if the following three conditions are met:

        1. the event must be serious

        2. there must be a certain degree of probability that the event is a harmful and an
           undesirable reaction to the medicinal product under investigation, regardless of the
           administered dose;

        3. the adverse reaction must be unexpected, that is to say, the nature and severity of the
           adverse reaction are not in agreement with the product information as recorded in:

             -  Summary of Product Characteristics (SPC) for an authorized medicinal product;

             -  Investigator's Brochure for an unauthorized medicinal product. The sponsor will
                report expedited all SUSARs to the competent authorities in other Member States,
                according to the requirements of the Member States.

      The expedited reporting will occur not later than 15 days after the sponsor has first
      knowledge of the adverse reactions. For fatal or life threatening cases the term will be
      maximal 7 days for a preliminary report with another 8 days for completion of the report.

      SAEs need to be reported till end of study within the Netherlands, as defined in the protocol

      8. STATISTICAL ANALYSIS

      Primary and secondary study parameters:

      The study endpoints will be analyzed according to intention-to-treat principles. All endpoint
      parameters are continuous variables. Data will be calculated as mean SD, median (percentile
      range) according to nature and distribution of the variable. Within group changes from
      baseline will be tested with independent paired t-test or Wilcoxon signed-rank test. Between
      group differences will be compared after 26 weeks between Liraglutide and control. The
      endpoints will be analyzed using a linear regression model, with gender, age, BMI and HBA1C
      as covariates. For the covariates age, BMI and HbA1c in the primary analysis the baseline
      value will be used. The data set for the primary analysis will include data from all subjects
      with at least one post-baseline measurement. Analysis will be performed with SPSS. A 2-sided
      significance level of p < 0.05 will be applied.

      9 REGULATION STATEMENT

      The study will be conducted according to the principles of the "Declaration of Helsinki" (as
      amended in Tokyo, Venice and Hong Kong, Somerset West and Edinburgh) and in accordance with
      the Guideline for Good Clinical Practice (CPMP/ICH/135/95 - 17th July 1996).

      10. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION

      Handling and storage of data and documents:

      Study participants are provided a study name of the letter "MV" followed by the number of
      enrollment (1-50). The study name is coupled to a randomly chosen seven - digit study number.
      The study number will be used to register the participant in the Electronic Patient Registry
      of the LUMC. This file will be used as the general patient record, as well as collection of
      routine laboratory measurements needed for clinical and study treatment. The MRI images will
      be filed under this registry so that anonymity will be safeguarded. The subject
      identification code list will be stored by the principal investigator and will only be
      accessible by the principal investigator and project leader. The data extracted from the
      study file in the Electronic Patient Registry and from the MRI images will be saved in an
      SPSS file. From this file the true identity of the study participants can not be discovered.
      The data will be stored for fifteen years. The blood samples will be frozen and stored
      anonymously using the above mentioned study name and study number. For ad hoc laboratory
      tests of inflammatory, endocrine and other biomarkers, blood samples will be kept for a
      maximum period of three years. The blood samples are solely accessible by the investigator
      team.

      In order to ensure that in medical emergencies, the study participation of the patient is
      apparent, each patient will receive a patient file in the electronic patient registry. In
      this personal file, the investigator will mention the study number of the patient including
      the procedure for de-blinding and notification of the investigators. In this file, the signed
      Informed Consent form of the patient will be stored.

      Public disclosure and publication policy: The data analysis will be performed by the
      investigators. Novo Nordisk has no role in data analysis and / or publication of the results
      of the trial in peer reviewed papers. The results of the study will be submitted to peer
      reviewed papers, also in case the hypothesis has not been proven.
    

Intervention name(s): Liraglutide; Liraglutide - Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Preparation and labelling of Investigational Medicinal Product:
Liraglutide will be packed and labeled by Novo Nordisk A/S and provided in non-subject specific boxes. Labeling will be in accordance with Annex 13, local law and trial requirements. The examples of labels are not readily available, but will be supplied when received from Novo Nordisk.
Drug accountability:
Drug accountability will be cared for by the Department of Clinical Pharmacy of the LUMC. The trial product will be dispensed to each subject as required according to treatment group by the clinical pharmacist. No trial product will be dispensed to any person not enrolled in the trial.; Preparation and labelling of Investigational Medicinal Product:
Liraglutide - Placebo will be packed and labeled by Novo Nordisk A/S and provided in non-subject specific boxes. Labeling will be in accordance with Annex 13, local law and trial requirements. The examples of labels are not readily available, but will be supplied when received from Novo Nordisk.
Drug accountability:
Drug accountability will be cared for by the Department of Clinical Pharmacy of the LUMC. The trial product will be dispensed to each subject as required according to treatment group by the clinical pharmacist. No trial product will be dispensed to any person not enrolled in the trial.
Other intervention name(s): Trade name: Victoza; EV Product Code: SUB25238; Name of the Marketing Authorisation Holder: Novo Nordisk; Marketing Authorisation number: EU/1/09/529/001; ATC code: A10BX07; CAS number 204656-20-2; Placebo
Intervention MeSH terms: Liraglutide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Diabetes mellitus type 2; Glucagon-Like Peptide 1; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Steatosis