JanUmet Before Insulin Lantus In Eastern Population Evaluation Program (JUBILEE) In Type 2 Diabetic Patients
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      To evaluate the efficacy and safety of a new treatment regimen of metformin plus sitagliptin
      (Janumet) followed by a long-acting basal insulin (Lantus) treatment compared to the usual
      treatment regimen of metformin followed by sulfonylurea and intermediate-acting basal insulin
      in Type 2 Diabetes Mellitus patients.
    

Detailed description: 
      Type 2 diabetes mellitus (T2DM) accounts for more than 90% of all diabetes. The worldwide
      prevalence of T2DM is increasing.

      Microvascular and macrovascular complications are well known to cause significant morbidities
      and shorten life expectancy in diabetic patients. T2DM is the leading cause of adult-onset
      blindness, renal failure, limbs amputation, ischaemic heart disease and stroke in the
      industrialized world. Progressive pancreatic beta-cell failure together with insulin
      resistance underlie the pathogenesis of T2DM.

      Glycaemic control is essential and fundamental to the management of diabetes. Randomized
      control trials have confirmed the long term benefits of achieving glycaemic control early in
      the course of disease on future clinical outcomes. Long term follow up of The Diabetes
      Control and Complications Trial Research Group (DCCT) and U.K. Prospective Diabetes Study
      (UKPDS) cohorts showed that improving glycaemic control reduces the incidences of both
      microvascular and macrovascular complications.

      It is generally agreed that HbA1c <7% is a reasonable goal in adults to reduce risk of
      diabetes complications. Subgroup analyses of DCCT and UKPDS and results of Action in Diabetes
      and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE)
      trial suggest a small but incremental benefit in microvascular outcomes with HbA1c values
      closer to normal. In the subgroup analysis of the ACCORD study, subjects without history of
      cardiovascular disease and attained HbA1c goal of 6.5% had lower risk of cardiovascular
      endpoints than those with HbA1c goal of 7%. Therefore, selected individual patients including
      those with short duration of diabetes, long life expectancy and no significant cardiovascular
      disease, may benefit from a more stringent HbA1c goal of <6.5%, a value close to normal
      individual.

      According to the American Diabetes Association (ADA) and the European Association for the
      Study of Diabetes, lifestyle modification plus Metformin is a well-validated step 1 therapy
      for patients with T2DM. Sulfonylurea or insulin treatment formed the step 2 therapy in those
      who fail to achieve optimal glycaemic control after step 1 treatment. Sulfonylurea is an
      insulin secretagogue. It acts in a glucose-independent fashion by increasing the insulin
      concentration irrespective of the ambient glucose concentration. Despite its efficacy, it is
      associated with increased risk of hypoglycaemia and weight gain.

      Incretins are gut-derived hormones that include Glucagon-like peptide-1 (GLP-1) and
      Glucose-dependent insulinotropic peptide (GIP). Incretins are released into the circulation
      after a meal. Both GLP-1 and GIP stimulate endogenous insulin secretion in a
      glucose-dependent fashion. They also inhibit glucagon secretion, delay gastric emptying and
      induce satiety. The combined effect of incretins in augmenting insulin secretion and
      suppressing glucagon reduces post-prandial glucose excursion. In animal models, GLP-1 has
      also been shown to preserve pancreatic beta-cell mass by increased proliferation and
      decreased apoptosis. In T2DM patients, the attenuated post-prandial GLP-1 secretion may
      partially explain the increased post-prandial rise in glucose concentration.

      However, incretins have very short half-lives of a few minutes. They are rapidly inactivated
      by the enzyme dipeptidyl peptidase IV (DPP-4) in the circulation. Inhibitors of the enzyme
      DPP-4 can augment active incretin levels by delaying the clearance of the active incretins,
      hence augmenting the incretin action with resultant improvement in glycaemic control in T2DM
      patients.

      In later stage of T2DM, progressive pancreatic beta-cell failure frequently results in
      deterioration in glycaemic control despite oral drug treatment, necessitating supplementary
      insulin therapy. New generations of once-daily, long-acting basal insulin may have better
      safety profile in terms of less hypoglycaemic events compared with traditional
      intermediate-acting basal insulin. Supplementary basal insulin, when titrated appropriately,
      will almost always improve fasting blood glucose levels and HbA1c control.

      Sitagliptin is an orally active, potent and highly selective DPP-4 inhibitor which was
      approved by the U.S. Food and Drug Administration (FDA) in October 2006 as a new class of
      oral drug treatment for T2DM. Sitagliptin is marketed as Januvia by Merck & Co. In April
      2007, the FDA approved an oral combination of sitagliptin and metformin marketed as Janumet
      with preparations of 50/500mg and 50/1000mg dosage per tablet. Sitagliptin has been proved to
      be effective in treating T2DM with minimal risk of hypoglycaemia together with additional
      benefits on reducing glucagon, slowing gastric emptying and inducing satiety.

      Insulin glargine, marketed by Sanofi Aventis under the name Lantus, is a long-acting basal
      insulin analogue. It has the advantage of a long action duration of 18 to 26 hours and a
      peakless profile, which resembles basal insulin secretion of non-diabetic pancreatic
      beta-cells.

      In T2DM patients, we proposed that a new treatment regimen consists of a combination of
      DPP-IV inhibitor plus metformin followed by long-acting basal insulin may be more effective
      in achieving good and sustained glycaemic control with less hypoglycaemic drawbacks compared
      with the traditional regimen of metformin followed by sulfonylurea and finally
      intermediate-acting insulin. This proposed new treatment regimen forms the basis of this
      study.

      The objective of this multicentre, randomized, open-label prospective study is to evaluate
      the efficacy and safety of a new treatment regimen of metformin plus sitagliptin (Janumet)
      followed by a long-acting basal insulin (Lantus) treatment compared to the usual treatment
      regimen of metformin follow by sulfonylurea and intermediate-acting basal insulin in T2DM
      patients.
    

Intervention name(s): Janumet, Lantus; metformin, gliclazide, protaphane
Intervention type(s): Drug; Drug
Intervention description(s): In this multicentre, randomized, open-label prospective study. Recruited patients will be randomized to one of the two treatment groups. Treatment efficacy and safety in terms of HbA1c control and hypoglycemic events will be evaluated.
Treatment groups:
Group 1 - Metformin followed by Sulfonylurea (Gliclazide) and supplementary intermediate-acting insulin (Protaphane) injection.
Group 2 - Janumet followed by Lantus insulin injection.; In this multicentre, randomized, open-label prospective study. Recruited patients will be randomized to one of the two treatment groups. Treatment efficacy and safety in terms of HbA1c control and hypoglycemic events will be evaluated.
Treatment groups:
Group 1 - Metformin followed by Sulfonylurea (Gliclazide) and supplementary intermediate-acting insulin (Protaphane) injection.
Group 2 - Janumet followed by Lantus insulin injection.
Intervention MeSH terms: Metformin; Gliclazide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: type 2 diabetes mellitus; JUBILEE Study; Janumet; Lantus