JanUmet Before Insulin Lantus In Eastern Population Evaluation Program (JUBILEE) In Type 2 Diabetic Patients

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.