New diabetic drug class shows promise

The development of a novel class of drugs that treats type II diabetic patients is good news for sufferers that have had to put up with treatments and therapies with unpleasant side effects.

GLP-1, a hormone produced in the intestine, induces insulin secretion in a glucose dependent manner, controls gastric emptying and inhibits food intake as well as glucagon and somatostatin secretion. The natural GLP-1 molecule rapidly degrades in the blood and, therefore, needs to be stabilised to be clinically useful. Clinical studies in type 2 diabetes patients have confirmed the therapeutic potential of GLP-1 analogues.

The phase I study was to demonstrate the safety of the candidate TH0318 and consisted of 36 healthy male volunteers, aged 18 to 45, divided into 6 groups. TH0318 was administered by subcutaneous injection and the dose level was raised in sequential groups.

Overall, the safety profile of the treated population was similar to placebo tests and, at all doses, there were no cases of nausea, which is a common side effect of GLP-1 therapy. Dose-related pharmacokinetics was noted across the entire dose range. At the higher doses tested, pharmacodynamic effects (decreased blood glucose levels) were also noted.

"TH0318 is only one compound in our portfolio of GLP-1 analogues that lends itself to several interesting alternatives in terms of dosing intervals and delivery systems,"​ said Yves Rosconi, president and chief executive officer of theratechnologies.​

Currently there are six classes of approved oral agents, each of which works through a different mechanism. An estimated 5.9 million patients are taking oral therapy in the United States. Eventually, many of those patients require insulin therapy. Oral agents are also used with insulin therapy. It is estimated that currently, over 3.5 million patients in the United States are on insulin therapy.

Type 2 diabetes mellitus generally occurs after age 40 and is the most common form of diabetes. Patients suffer from insulin resistance or insufficient production of insulin, a hormone that allows glucose (sugar) to enter cells and be converted into energy. Diabetes often leads to severe complications, including heart disease, stroke, blindness, kidney disease, nerve damage, and ultimately premature death.

Diabetes, which has many treatments but no definitive cure, is approaching epidemic status, increasing at three times the rate of the population growth in North America. There are an estimated 18 million people in the United States suffering from diabetes and another 41 million have pre-diabetic conditions that put them at risk. The aging population, sedentary life styles, and obesity are contributing to the rapid expansion of the diabetic population.

Sulfonylureas are the oldest class, and they work by increasing insulin secretion. These agents work only when there is sufficient insulin producing B-cells in the pancreas. Commonly used sulfonylureas include short acting agent, Tolbutamide, intermediate acting agents, Gilpizide and Glicazide, and long acting agents, Chlorpropamide, Glyburide and Climepiride.

The Meglitinides act like the sulfonylureas in that they stimulate insulin secretion. However, they bind to different receptors and are generally more rapidly absorbed and cleared. There are only two commercially available meglitinides: NovoNordisk's Repaglinide (Prandin) and Novartis' Nateglinide (Starlix).

The Biguanide class features one main compound, Metformin, sold by Bristol-Myers Squibb, and is now available in generic form by a range of suppliers. Metformin increases insulin activity but does not impact pancreatic beta cells. A central activity of Metformin is to lower glucose production in the liver by potentiating insulin activity.

The class of (alpha)-glucosidase inhibitors has acarbose as the main agent in this category. The (alpha)-glucosidase inhibitors work by breaking down oligosccharides into monosaccharides in the small intestine, thereby lowering post-meal (prandial) glucose and delaying glucose absorption.

Thiazolidinediones are the newest class of diabetic drugs and are broadly thought of as insulin potentiating agents or insulin sensitisers. This class of agents includes GlaxoSmithKline's rosiglitazone (Avandia) and Takeda's piglitazone (Actos). The thiazolidinediones work through a receptor called the PPARy receptor, which regulates transcription factors for genes involved in insulin action and lipid metabolism.

These agents are thought to enhance insulin's ability to cause glucose uptake in muscle tissue. The thiazolidinediones have also demonstrated postive effects on plasma lipids, including raising HDL and lowering LDL cholesterol.

The first approved thiazolidinedione was Warner Lambert's Rezulin, which was removed from the market due to high liver toxicity. However liver toxicity is believed to be attributable only to Rezulin, and is not thought to be a class effect. Side effects that are more common to the class include weight gain, fluid retention and mild general swelling.