Type 2 diabetes mellitus (T2DM) is characterized by high blood glucose (hyperglycemia) as well as abnormal carbohydrate, fat, and protein metabolism.  Insulin produced by the pancreas is insufficient to maintain normal levels of blood glucose due to demands placed on the pancreas by the metabolic abnormalities as well as relative insensitivity of the body to the action of insulin in T2DM (insulin resistance).  Longstanding poorly controlled blood glucose can lead to small blood vessel damage caused by high blood sugar, which can result in complications such as blindness, kidney failure, and lower extremity amputations. In fact, diabetes is the leading cause of blindness, kidney failure and non-traumatic amputations in the US. T2DM is also strongly associated with macrovascular events such as heart attacks and strokes and increases the heart mortality by 2 to 4 fold ^[1]. Diabetes is the sixth leading cause of death in the US, although this number is considered to underestimate the actual number because diabetes is often a secondary cause of death ^[2].

Because of these outcomes, T2DM is one of the largest and most concerning health epidemics in the developed and developing world. Diabetes currently affects 246 million people worldwide and is expected to affect 380 million by 2025 ^[3]. In the US, 6% of the population (18 million people) have T2DM and an estimated 21% of Americans over the age of 60 have the disease. The number of T2DM cases is growing at 7% annually, and this trend is expected to continue due to aging of the population. The number of pre-diabetics, those with abnormally high blood glucose levels but not yet meeting criteria for a diagnosis of diabetes, is estimated to be 41M. In 2007, is has been estimated that $174B was spent on diabetes or 10% of the total healthcare spend in the US ^[1].

There are two primary etiological features associated with T2DM: insulin resistance (IR) and diminished insulin production through pancreatic beta cell decline and failure. The natural history of T2DM starts with pre-diabetes, the period leading up to the diagnosis of T2DM, and is characterized by insulin resistance, which precedes the high blood sugars of diabetes. The years of exposure to this burden of IR and its associated metabolic dysregulation explain why so many people already have diabetic complications at the time of diagnosis of hyperglycemia. It has been estimated that patients have had the disease for an average of five years at the time of diagnosis. Thus, diabetes delay or prevention is emerging as an important therapeutic strategy to minimize potential disease complications. 

The treatment of T2DM is focused on control of high blood glucose, with diet (often with a goal of weight loss), physical activity, and pharmacotherapy.  An objective of therapy is to reduce the risk of small and large vessel disease through controlling blood glucose, blood pressure, and lipids.   

There are three primary oral therapeutic approaches for treating T2DM: controlling glucose output of the liver (inhibition of gluconeogenesis), increasing insulin production within the pancreas, or treating IR through improving the use of glucose or insulin in tissues. Existing therapies are sometimes associated with side effects or tolerability issues in addition to their positive effects in controlling blood sugar level.   

Metformin is typically used as first line therapy for glucose control and acts by inhibition of gluconeogenesis and is associated with GI side effects. Insulin secretagogues such as the sulfonylurea class of drugs increase insulin levels and are typically used as second or third-line therapy and are associated with weight gain and with hypoglycemia. Insulin sensitizers (such as the TZDs Actos® and Avandia®) are commonly used as second or third-line therapy to treat underlying IR and are associated with fluid retention, weight gain, and have black box label warnings for congestive heart failure (CHF).  DPP-4 inhibitors represent a relatively new mechanism of action (inhibition of degradation of gut peptides GLP-1 and GIP) and thus far seem to have a favorable safety profile.  For this reason, they have been well received despite modest efficacy. 

Given the progressive nature of T2DM, very large patient numbers and the fact that existing therapies have product profile gaps with safety and/or efficacy, improved therapies are needed to help patients control their blood sugar, avoid the significant health consequences, and ideally impact the disease progression.   

In particular, treating insulin resistance through PPARγ activation offers the opportunity to significantly impact the course of pre-diabetes and T2DM. However, the side-effects of the current TZD agents have limited this powerful therapeutic approach.  INT131, a non-TZD selective PPARγ modulator (SPPARM) , offers the promise to provide the powerful insulin sensitizing activity of a PPARγ activator without the side effects.  

^[1] American Diabetes Association

^[2] Center for Disease Control

^[3] International Diabetes Federation