Effects of Liraglutide in Young Adults With Type 2 DIAbetes (LYDIA)
Condition: Type 2 Diabetes Mellitus; Cardiovascular Disease
MeSH terms: Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 3

Summary: 
      There are recent advances in therapies for the treatment of Type 2 Diabetes Mellitus (T2DM)
      which include the GLP1 analogues and the DPP IV inhibitors. Both of these therapies target
      the incretin system using different methods to elevate/maintain circulating levels of GLP1 to
      subsequently achieve improved blood sugar control. Interestingly, GLP1 analogues have been
      reported not only to improve blood sugar control but to additionally induce weight-loss and
      emerging experimental evidence has shown it may have beneficial effects on the heart's
      structure and function. Due to the profile of this condition being a lot worse and younger
      patients having greater CVD risk, a therapy offering multiple positive effects, in particular
      the potential cardiometabolic effects, make this line of therapy attractive in this patient
      population.

      The aim of this research is to investigate the cardiometabolic effects of Liraglutide (GLP1
      analogue) compared to that of its clinically relevant comparator Sitagliptin (DPP IV
      inhibitor).
    

Detailed description: 
      T2DM in the young

      T2DM has traditionally been associated with older age, with type 1 diabetes (T1DM) being the
      dominant form in younger populations. This traditional profile has dramatically altered over
      the last couple of decades; the sharp rise in levels of obesity and sedentary lifestyles
      witnessed in younger age groups in developed countries has resulted in up to a 10 fold
      increase in the prevalence of T2DM in younger adults and youth [7]. Whereas T2DM was once a
      rarity in those under 40 years, we have recently shown that T2DM now represents up to 20% of
      all registered diabetes cases across centres in Leicester and Sheffield in this age group
      [8]. More worryingly, sub-analysis of the Leicester arm of the international ADDITION study
      [9], a large population-based screening study that included a small cohort under 40 years of
      age (n = 445), and an on-going NPRI-MRC study in younger high risk adults, suggest the
      prevalence of undiagnosed T2DM in those under 40 years is between 2 to 4% depending on the
      diagnostic criteria used and over 5% in those with a family history or obesity (unreported
      observations). The focus of health care policy and research has lagged behind this
      substantive shift in the profile of T2DM towards younger populations. For example, the NHS
      health checks programme is targeted at those over 40 years of age while previous
      self-management, lifestyle and pharmaceutical interventions which have been used to inform
      NICE guidance have been conducted in groups aged between 50 and 70 years.

      Clinical Burden of T2DM in the young

      The onset of T2DM in younger adults and youth represents an extreme phenotype that magnifies
      the disease profile observed in older adults. For example, those diagnosed with T2DM under 40
      years are more likely to be classified with Class II or Class III obesity (≥35 kg/m2), have a
      multigenerational family history of T2DM, lead a sedentary lifestyle and be of minority
      ethnic origin [7]. Of particular concern is that the onset of T2DM in younger adults is
      associated with dramatic elevations in the risk of cardiovascular disease, particularly
      coronary heart disease. For example, the risk of any macrovascular complication in younger
      adults with T2DM compared to controls has been shown to be twice as high compared to other
      T2DM patients (HR 7.9 vs. 3.8, respectively)[10]. Myocardial infarction (MI) was found to be
      the most common macrovascular outcome; the hazard of developing an MI in younger adults with
      T2DM was 14-fold higher than in control subjects [10]. In contrast, older adults with T2DM
      had less than four times the risk of developing an MI compared with control subjects. Others
      have reported that the mortality rate in young people with T2DM was as high as 9% over a 9
      year period [11]. Younger people with T2DM therefore have higher complication rates than
      their peers with Type 1 diabetes, despite a shorter duration of diabetes, highlighting the
      aggressive nature of the disease.

      Our group has recently completed a Medical Research Council (MRC) funded study aimed at
      elucidating the biochemical and cardiac abnormalities associated with T2DM in younger adults
      (18 to 40 years). The study recruited 20 young adults (18 to 40 years) with diagnosed T2DM
      and 20 age-matched metabolically healthy obese and lean controls (paper under preparation).
      Cardiac structure and function were assessed by state-of-the-art tagged cardiac MRI imaging.
      The most striking finding from this study was evidence of greater diastolic dysfunction in
      T2DM compared to both the obese and lean controls. Specifically, peak end diastolic strain
      rate, a highly sensitive measure of left ventricular (LV) diastolic function, had an average
      value of 1.27 s-1 in the T2DM cohort (the lower limit of normal ranges has been defined as
      1.3 s-1) which was 20% lower than the obese controls and 30% lower than the lean controls.
      This finding is consistent with a larger study that used echocardiography to assess cardiac
      function and structure in over 150 adolescents and younger adults with T2DM compared to obese
      and lean controls; this study reported that diastolic dysfunction was reduced from lean to
      obese and from obese to T2DM. These studies therefore suggest that pre-clinical diastolic
      dysfunction is already manifest in younger adults with T2DM, despite their relatively young
      age and short duration of type 2 diabetes. This finding is highly clinically relevant and
      suggests that the high risk of cardiovascular disease observed in T2DM is predominantly
      characterised by diastolic dysfunction predisposing these patients to heart failure, in
      advance of overt systolic compromise [12,13]. For example, 50% of all cases of chronic heart
      failure have preserved ejection fraction [12,13]. Therefore therapeutic strategies that
      target both glycaemic control and diastolic cardiac function would be highly desirable in
      younger adults with T2DM.

      GLP-1 THERAPY

      Traditional therapies in the management of T2DM have focused on enhancing the secretion,
      action and availability of insulin. However, whilst these approaches have been successful in
      managing blood glucose levels, they have had only modest benefit in reducing rates of
      myocardial infarction and are associated with a number of deleterious side effects, including
      hypoglycaemia, bone fractures, congestive heart failure, weight gain, and, in some analyses,
      increased mortality [14]. Therefore the development of new therapies simultaneously targeting
      hyperglycaemia and cardiovascular disease is a major priority. Two recently approved classes
      of incretin based therapies, glucagon like peptide -1 (GLP-1) analogues and dipeptidyl
      peptidase-4 (DPP-4) inhibitors, have shown promise in these areas. Both classes exert their
      actions through potentiation of incretin receptor signalling, particularly GLP-1.

      In vivo GLP-1 is predominately secreted from the L-cells of the distal jejunum, ileum and
      colon. Low basal levels are secreted in the fasting state, however, levels rapidly and
      transiently increase in response to the ingestion of food; secretagogues include the major
      macronutrients, particularly glucose. Endogenous GLP-1 has a short half-life of only 1 - 2
      minutes following rapid degradation by the enzyme DPP-4 [15].

      GLP-1 receptors are widespread throughout the body including in the pancreas, stomach lining,
      intestine, brain and heart. The widespread distribution of GLP-1 receptors supports a
      diversity of pleiotropic effects. Other than the direct effect on appetite regulation, the
      most widely investigated action of GLP-1 has been around the homeostasis of glucose levels.
      GLP-1 is known to stimulate insulin secretion in a glucose dependant manor (thus limiting
      risk of hypoglycaemia), as well as promoting glucose stimulated insulin gene transcription
      and biosynthesis [14]. It may also have trophic effects on pancreatic beta-cells. Given these
      glucose dependant effects, GLP-1 therapies have been developed as treatment strategies in the
      management of T2DM. Due to the short half-life of native GLP-1, therapies have revolved
      around inhibiting the action of DPP-4 and thus augmenting naturally occurring levels of the
      incretin hormones, or through the intravenous administration of GLP-1 analogues which are
      resistant to the action of DPP-4. In contrast to DPP-4 inhibitors, GLP-1 analogues can be
      administered at supra-physiological levels and thus lead to more profound receptor activation
      and biological effects. This is particularly true in relation to weight-loss, where GLP-1
      analogues have been shown to directly induce substantial weight loss with greater effect seen
      with higher levels of obesity. In contrast, DPP-4 inhibitors appear weight neutral.

      Both DPP-4 inhibitors, such as Sitagliptin Vildagliptin and Linagliptin and GLP-1 such as
      Liraglutide and Exenatide are licensed for use in the management of T2DM within the United
      Kingdom.

      Liraglutide is the most recently approved GLP-1 analogue therapy and has the greatest promise
      in terms of glycaemic efficacy and weight loss. The Liraglutide Effect and Action in Diabetes
      (LEAD) studies have demonstrated that when used in combination with one or more OADs, doses
      of 1.2 or 1.8 mg of Liraglutide daily significantly reduce HbA1c (mean HbA1c decrease:
      1.0-1.5%) [16-22]. Clinically important decreases in fasting plasma glucose (FPG) and
      postprandial plasma glucose (PPG) levels have also been well documented following Liraglutide
      treatment (mean FPG decrease: -1.6 to 2.2 mmol/l and 1.55 to 2.4 mmol/l with 1.2 and 1.8 mg
      Liraglutide, respectively [16-23]; mean PPG decrease: 2.3-2.6 and 1.81-2.7 mmol/l with 1.2
      and 1.8 mg Liraglutide, respectively [16-19]). Liraglutide has also proven to have superior
      effects on glycaemic control compared to other licensed GLP-1 analogues and DPP-4 inhibitors
      [20,21].

      In addition to improved glycaemic control, Liraglutide is also effective at inducing weight
      loss and reducing blood pressure. Mean body weight reductions of at least 1 kg were apparent
      with both doses of Liraglutide (-1.0 to -2.9 kg with 1.2 mg; -1.8 to -3.4 kg with 1.8 mg)
      [17-21]. Greater decreases in body weight were exhibited by patients with a higher adiposity
      [23]. Furthermore, when used in daily doses of 2.4 mg or more, Liraglutide has been shown to
      have a greater effect on body weight than Orlistat [24]. Mean reductions in systolic blood
      pressure of up to 6 mmHg have also been reported [22]

      GLP-1 ANALOGUE THERAPY BLOOD PRESSURE AND HEART RATE

      Observed systolic blood pressure reduction of up to 6 mmHg with Liraglutide would be expected
      to result in a 15 to 25% reduction in cardiovascular event rate independent of any glucose
      lowering effect [25]. It is hypothesized a GLP-1 receptor independent nitric oxide mediated
      vasodilatory pathway is responsible for this, and other potentially beneficial cardiovascular
      effects on endothelial function, renal sodium excretion and PAI-1 (Plasminogen Activator
      Inhibitor). GLP-1 receptor activation may also induce sympathetic autonomic activity which
      stimulates myocyte glucose uptake as well as provoking a positive chronotropic and inotropic
      response. Although recent reviews suggest these pleiotropic actions have no detrimental
      effect on cardiovascular events, the clinical significance of a modest elevation in resting
      heart rate with this treatment is currently unclear [26,27]. Liraglutide is now licensed for
      use in Europe, Canada, Japan, Mexico and the USA.

      GLP-1 ANALOGUE THERAPY AND CARDIAC FUNCTION

      Clearly, substantial clinical benefits accrue from the glucose and weight lowering properties
      of GLP-1 analogue therapy. However, emerging experimental evidence suggests that GLP-1
      therapy has specific cardioprotective effects that are independent of whole body glucose
      metabolism. In particular, along with improvements in endothelial function, GLP-1 treatment
      has been shown to have direct effects on cardiac function and structure. For example, rat and
      canine models of heart failure/cardiomyopathy have demonstrated that GLP-1 administration is
      associated with improved cardiac output, decreased left ventricular end-diastolic volume and
      reduced myocyte apoptosis [for recent reviews see 28,29]. Furthermore, mice lacking the GLP-1
      receptor were reported to have LV diastolic dysfunction, greater LV wall thickening and
      impaired LV contractile function [30]. Although limited, human studies have confirmed a link
      between GLP-1 treatment and cardiac function and structure. For example, after 5 weeks of
      GLP-1 therapy, 12 patients with chronic heart failure improved their LV function as well as
      their exercise capacity [31]. Similarly, 72 hours of GLP-1 infusion was associated with
      improved LV ejection fraction in survivors of acute myocardial infarction [32] and Exenatide
      administered during percutaneous coronary intervention reduced reperfusion injury and infarct
      size [33]. Although promising, these studies are limited by their small samples and the
      non-randomised methodology. However several randomised trials have recently been published.
      In one study 20 patients were randomised to GLP-1 or saline infusion after percutaneous
      coronary intervention; GLP-1 was found to ameliorate LV dysfunction [34]. Another randomised
      cross-over study demonstrated that GLP-1 therapy improved LV function in 14 patients with
      coronary artery disease [35].

      Whilst the above findings are highly promising, data is lacking around the efficacy of GLP-1
      therapy at improving cardiac function in high risk populations without overt cardiovascular
      disease. This limitation is particularly relevant to young individuals with T2DM who are
      likely to have extreme levels of obesity and present with sub-clinical diastolic dysfunction.
      Therefore research is needed to investigate to what extent GLP-1 therapy can ameliorate the
      early stages of cardiac dysfunction.

      The objective of this study is to determine if Liraglutide, a GLP-1 analogue, leads to
      improved LV diastolic function in younger adults with T2DM compared to the clinical relevant
      active comparator Sitagliptin, a DPP-4 inhibitor.
    

Intervention name(s): Liraglutide; Sitagliptin
Intervention type(s): Drug; Drug
Intervention description(s): Liraglutide (Victoza®, Novo Nordisk) is a stable analogue of the natural hormone glucagon-like peptide-1 (GLP-1). Liraglutide is licensed for use within the United Kingdom and recommended by NICE in combination with metformin, and/or sulphonylurea and/or thiazolidinedione if the following conditions are satisfied.
BMI ≥ 35 kg/m2 in those of European descent (with appropriate adjustment for other ethnic groups) and specific psychological or medical problems associated with high body weight, or
BMI < 35 kg/m2, and therapy with insulin would have significant occupational implications or weight loss would benefit other significant obesity-related comorbidities.; Sitagliptin (Januvia®, Merck & Co) is an enzyme-inhibiting drug used to inhibit the natural enzyme dipeptidyl peptidase-4 (DPP-4). It is an oral antihyperglycaemic agent used in the treatment of T2DM. Sitagliptin is licensed to be used either alone or in combination with other oral antihyperglycemic agents (such as metformin or a sulphonylurea) and is recommended by NICE as a second line therapy.
Other intervention name(s): Victoza; Januvia
Intervention MeSH terms: Sitagliptin Phosphate; Liraglutide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Type 2 Diabetes Mellitus (T2DM); Young Adults; Cardiovascular Disease (CVD); GLP1 Analogue; DPP IV Inhibitor; Obesity; Cardiometabolic Effects; Cardiac MRI