Adding Exenatide to Insulin Therapy for Patients With Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease
Condition: Nonalcoholic Fatty Liver Disease; Type 2 Diabetes Mellitus
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      The primary aim of the study is to determine the impact on hepatic steatosis of replacing
      premeal rapid-acting insulin for exenatide (Byetta) while maintaining bedtime long-acting
      detemir (Levemir) insulin in well-controlled patients with type 2 diabetes mellitus (T2DM)
      and nonalcoholic fatty liver disease (NAFLD).

      Secondary aims are to learn: 1) the efficacy and safety of such approach and whether it is an
      acceptable treatment strategy compared to intensified insulin therapy alone; 2) mechanisms of
      action (effects on insulin secretion and insulin action); 3) its impact on weight (can it
      prevent insulin-associated weight gain or cause weight loss) and rates of hypoglycemia; 4) if
      it may improve specific plasma biomarkers of disease activity in NAFLD and inflammatory
      markers common to both conditions - T2DM and NAFLD (hsCRP, ICAM, VCAM).
    

Detailed description: 
      Type 2 diabetes mellitus (T2DM) is a major public health problem in the United States with
      ~2/3 of Americans that are overweight or frankly obese. Less well recognized is that obesity
      and T2DM are fueling another "silent epidemic": non-alcoholic fatty liver disease (NAFLD). In
      NAFLD, hepatic fat accumulation ranges from simple steatosis to severe steatohepatitis
      (NASH), with necroinflammation and fibrosis that may progress to cirrhosis. Indeed, up to 40%
      of patients with NAFLD develop NASH and about ~15-20% of patients with NASH develop cirrhosis
      after 10 years. NASH is believed to be the most common cause of cryptogenic cirrhosis and
      ranking as the third leading indication for liver transplantation after alcohol and hepatitis
      C. The distinction between simple steatosis and NASH can only be done by means of a liver
      biopsy, but strategies that reduce fatty liver disease correlate with a reduction in
      steatohepatitis and fibrosis.

      It is estimated that ~1/3 of the general population of the United States have fatty liver
      disease as assessed by magnetic resonance imaging and spectroscopy (MRS), the gold-standard
      technique. It is also affecting the pediatric population, and while the natural history
      remains to be defined, most biopsies show some degree of fibrosis and cirrhosis has been
      reported in children as young as 10 years of age. Moreover, in the investigators experience
      using MRS for the past several years, ~80% of patients with T2DM have NAFLD. If the above is
      extrapolated to the overall population of the United States, there are ~15 million subjects
      with T2DM and NAFLD and more than 50 million overweight/obese individuals with NAFLD.

      As awareness of NAFLD/NASH increases, health care providers are now confronted with the
      unique challenge of achieving good metabolic control while treating fatty liver disease in
      the same subject. Inadequate glycemic control appears to worsen and accelerate progression of
      fatty liver disease. Paradoxically, most patients with T2DM do not reach established
      treatment goals. Moreover, it appears that the way metabolic control achieved is important in
      NAFLD: while metformin may be beneficial in NASH and pioglitazone is highly effective,
      control of hyperglycemia by insulin therapy alone has modest benefit on hepatic fat
      accumulation. In addition, long-term insulin therapy in T2DM is frequently associated with
      inadequate compliance, weight gain, frequent hypoglycemia and overall poor patient
      satisfaction. This is of great concern as ~35-40% of patients with T2DM are treated with
      insulin. Therefore, there is an unmet need to find better ways to treat patients that fail
      oral agent therapy, targeting both hyperglycemia and excessive liver fatty deposition.

      The investigators propose a strategy of adding exenatide to insulin therapy as a means to
      achieve better glycemic control while ameliorating hepatic steatosis (and improving hepatic
      insulin sensitivity), reduce body weight/total body fat (and visceral fat), decrease the risk
      of hypoglycemia by allowing a reduction in insulin doses (withdrawal of premeal insulin
      doses, reduction of basal long-acting insulin), and enhance insulin secretion and insulin
      action while improving the quality of life of patients with T2DM and NAFLD. As both T2DM and
      NAFLD will become more prevalent in the near future, this pilot study will likely set the
      stage for a large controlled multicenter trial with an approach that may be more effective
      than intensified insulin therapy alone.

      The central hypothesis is that insulin resistance and fat-overload play a key role in
      NAFLD/NASH, a condition believed to arise at the molecular level from the inability of the
      mitochondria to adapt to fat oversupply. Excessive fatty acid flux from exogenous (dietary)
      and endogenous (insulin resistant adipose tissue/increased lipolysis) sources drive hepatic
      lipogenesis. Exenatide would potentially be a good treatment fit against hepatic steatosis by
      decreasing excess dietary intake and substrate supply, reducing fat mass and plasma FFA and
      by lowering exogenous insulin needs and chronic hyperinsulinemia. Mitigating chronic
      hyperinsulinemia and hyperglycemia is important as they drive hepatic fat synthesis through
      sterol regulatory element-binding protein 1c (SREBP-1c) and carbohydrate regulatory
      element-binding protein (ChREBP) activity, respectively. Weight loss may also subdue systemic
      inflammation generated by dysfunctional adipose tissue, and at the local (hepatic) level,
      ameliorate fat-induced mitochondrial dysfunction (activation of Kupffer cells, local
      production of cytokines).

      While no systematic studies have been published yet, exenatide has been shown to reverse
      hepatic steatosis in an obese animal model of NAFLD and in a case report in a 59 year old
      poorly controlled T2DM patient in whom liver fat by MRS was reduced from 15.8% to 4.3%.
      Dietary intervention remains as the current standard of care for NAFLD, but studies in
      general have been small, uncontrolled and led to variable histological results. It is widely
      accepted that weight loss is difficult to achieve and even harder to maintain in the
      long-term. Moreover, weight loss is particularly difficult in patients with T2DM on insulin
      therapy. Pharmacological therapy at large has been ineffective in NAFLD/NASH, including
      trials using antioxidants and cytoprotective agents such as pentoxyfilline, vitamin E and
      ursodeoxycholic acid. A modest benefit has been reported in small studies with metformin, but
      only our study using pioglitazone has shown in a randomized, placebo-controlled trial, to be
      truly effective and safe in the treatment of patients with IGT or T2DM and NASH.

      Considering the impact that NAFLD has on patients with T2DM as a serious co-morbidity ranging
      from its metabolic impact on glycemia and dyslipidemia, to potentially causing end-stage
      liver disease and cardiovascular disease, it is rather surprising that no prior studies have
      focused on novel pharmacological approaches such as the one proposed for the treatment of
      patients with NAFLD and T2DM.
    

Intervention name(s): Exenatide
Intervention type(s): Drug
Intervention description(s): The participants with T2DM well-controlled on an intensified insulin regimen for the previous 6 months with the combination of a premeal insulin injection of the drug aspart (Novolog) three times a day and a bedtime insulin injection of the drug detemir (Levemir). The dosage of the insulin is determined by the need by the need of the participant. The Exenatide treatment will consist of an injection of the insulin twice daily and will replace the premeal insulin regiment of aspart.
Other intervention name(s): Byetta
Intervention MeSH terms: Exenatide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment