Effects of Liraglutide in Young Adults With Type 2 DIAbetes (LYDIA)
Effects of Liraglutide in Young Adults With Type 2 DIAbetes (LYDIA)
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).
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.
Inclusion Criteria:

 -  Capacity to provide informed consent before any trial-related activities

 -  Individuals aged 18 - 60 years inclusive

 -  Established T2DM

 -  BMI ≥ 30 kg/m2 (≥27 kg/m2 for South Asians or other BME populations)

 -  On mono or combination oral OAD therapy (sulphonylurea and/or metformin) for ≥ 3months

 -  No prescribed thiazolidinediones within the last 3 months

 -  An HbA1c value of greater than or equal to 6.5% and less than 10%

 Exclusion Criteria:

 -  < 18 years old

 -  Absolute contraindications to MRI

 -  Type 1 diabetes (identified through C-peptide analysis)

 -  Females of child bearing potential who are pregnant, breast-feeding or intend to
 become pregnant or are not using adequate contraceptive methods

 -  Suffer from terminal illness

 -  Have impaired renal function (eGFR < 30 ml/min/1.73m2) )

 -  Impaired liver function (ALAT≥2.5 times upper limit of normal)

 -  Known to be Hepatitis B antigen or Hepatitis C antibody positive

 -  Clinically significant active cardiovascular disease including history of myocardial
 infarction within the past 6 months and/or heart failure (NYHA class III and IV) at
 the discretion of the investigator

 -  Recurrent major hypoglycaemia as judged by the investigator

 -  Known or suspected allergy to the trial products

 -  Known or suspected thyroid disease

 -  Receipt of any investigational drug within four weeks prior to this trial

 -  Have severe and enduring mental health problems

 -  Are not primarily responsible for their own care

 -  Are receiving insulin therapy

 -  Have taken a thiazolidinedione within the last 3 months

 -  Any contraindication to Sitagliptin or Liraglutide

 -  Have severe irritable bowel disorder

 -  Have pancreatitis or a previous history of pancreatitis