Disease Type II Diabetes
Diabetes is a very serious disease. It is characterized by the inability of the body to self-regulate proper blood glucose levels, which is the most basic fuel for the cells comprising the human body. The body requires relatively constant levels of blood glucose, which can be difficult to maintain, especially with relatively large meals spread out over the course of the day. A function of the liver is to store glucose produced from meals and release it into the blood stream to maintain adequate blood glucose levels. In order to know how much glucose to secrete, and when to do so, the liver must have a sense of relative blood glucose levels at all times. With diabetic patients, the blood glucose regulation process goes awry in one way or another. Insulin is the hormone which is produced by the pancreas to regulate blood glucose levels. Diabetes is characterized by frequent states of abnormally high blood glucose levels (hyperglycemia). Hyperglycemia is caused either when the pancreas fails to produce sufficient levels of insulin or when the body fails to respond adequately to the insulin produced by the body. Persistent hyperglycemia can have profound long-term ramifications for the patient. Over time, hyperglycemia can damage the eyes, kidneys and nerves.
According to the Canadian Diabetes Association, (the CDA), as of 2005, more than 2 million people in Canada, representing over 6% of the population, suffered from diabetes. On a larger scale, the World Health Organization estimated that in the year 2000, there were approximately 23 million people in North America and 177 million people globally who had diabetes. As the population ages in developed countries, lifestyle and dietary habits increasingly place many more people at risk. If these trends continue, the number of people with diabetes is expected to double by 2025, according to CDA data. It is also estimated that as many as 44% of people with diabetes are currently undiagnosed, according to the Third National Health and Nutrition Examination Survey conducted in the United States from 1988-1994. The CDA cites an American study which concludes that diabetes and its related complications cost the Canadian healthcare system an estimated $13.2 billion every year. These costs are expected to rise to $15.6 billion and $19.2 billion for the years 2010 and 2020, respectively. However, the cost of diabetes is beyond the financial burden of the disease. The CDA lists the “personal costs” of diabetes to include a reduced quality of life and the increased likelihood of complications such as heart disease, stroke, kidney disease, blindness, amputation and erectile dysfunction. They further state that (i) diabetes is a contributing factor in the deaths of approximately 41,500 Canadians each year, (ii) that Canadian adults with diabetes are twice as likely to die prematurely, compared to persons without diabetes, and (iii) that life expectancy for people with T2DM may be shortened by 5 to 10 years.
There are two major forms of diabetes, Type 1 and Type 2. Type 1 Diabetes is an autoimmune disease characterized by an inability of the pancreas to produce insulin, so insulin must be delivered into the body for survival. Type 2 diabetes (T2DM) is characterized by insulin resistance. The pancreas continues to produce insulin, but the body is unable to remove glucose from the blood in its presence. The pancreas initially produces more insulin to compensate for the insulin resistance leading to hyperinsulinemia (a condition present in people with T2DM or insulin resistance where excess levels of insulin circulate in the blood). Eventually, if not properly controlled through lifestyle and/or drug intervention, the pancreas becomes exhausted and is unable to produce insulin. When this happens, persistent hyperglycemia results; insulin must be administered into the body for survival, and health risks are increased. According to the Canadian Diabetes Association, T2DM is the significantly more prevalent form of the disease, accounting for 90% of the people diagnosed with diabetes. Current standard of care treatments include metformin and the class of drugs known as thiazolidinediones (“TZDs”), which improve insulin sensitization. With these treatments, the mechanism of action is not fully understood, and there can be unwanted side-effects, particularly with the use of TZDs. In addition, it appears that a sufficiently large portion of the diabetic population eventually fails to control their diabetes with these drugs, and thus there is an ongoing need to develop new, safe drugs to compliment those currently available. In type 2 diabetes either the body does not produce enough insulin or the cells ignore the insulin. Insulin resistance means that cells in the body do not respond appropriately when insulin is present. Insulin is necessary for the body to be able to use sugar, as insulin takes the sugar from the blood into the cells.
Obesity
In recent years, obesity has become a major health problem for many post-industrial societies, so much so that in 2004, the United States Health and Human Services declared obesity to be a disease. The World Health Organization (WHO) projects that globally in 2005, 1.6 billion adults were overweight with at least 400 million adults obese. By 2015, approximately 2.3 billion adults will be overweight and 700 million will be obese. Obesity poses a major health risk because it greatly increases the risk of co-morbidities such as diabetes, cardiovascular diseases, arthritis, and cancer. Recognizing the potential for a new blockbuster market, major pharmaceutical companies have increasingly focused on obesity and its causes and, in the process, seeking to identify many potential targets and pathways that could be exploited to create novel therapies. Studies on the molecular mechanisms involved in obesity are revealing a complex set of pathways, feedback loops, hormones, and metabolites that integrate multiple physiological systems in the brain, gastrointestinal system, endocrine system, and metabolic systems. The challenge for obesity drug discovery is that drugs must compete against powerful physiological and behavioural factors that have been selected by evolution to favour feeding and energy storage. In consideration of this important market opportunity there are several potential business implications.
The prevalence of obesity has increased dramatically in the last ten years, prompting the Centers for Disease Control and Prevention to describe obesity as an epidemic. Obesity increases predisposition to various diseases, including diabetes, cardiovascular diseases, and cancer. In 2004, the United States Health and Human Services declared obesity to be a disease, creating important changes to Medicare and health care reimbursement policy for obesity-related therapies.
Obesity has increasingly become the focus of major pharmaceutical companies as they recognize the potential for a new blockbuster market. Companies are forming high-value alliances, including target and lead identification deals, with biotech companies for obesity drug discovery.
Research into the causes of obesity has identified many potential targets and pathways that could be exploited to create novel therapies. New investigational obesity drugs and drug targets can be generally categorized into those that regulate appetite, lipid metabolism, and adipocytes or their signals. Obesity research is still in its infancy, and researchers are likely to identify many new potential targets and therapeutic approaches. Because obesity therapy is a preventive therapy for otherwise outwardly healthy people, patients and regulatory agencies will not tolerate unacceptable medium-to-long-term side effects.
Companies must develop therapies with side effects that are not worse than the obesity-related co-morbidities the drugs are trying to prevent. Another challenge for long-term obesity therapy is simply to overcome the evolutionary selection of multiple physiological and metabolic responses that favour appetite and fat storage. Role of SGLT Inhibitors in Treatment of Type 2 Diabetes and Obesity
Glucose (sugar) is transported across the cells in the human body by a family of energy-dependent Sodium-Dependent Glucose Transporters (SGLTs). The kidneys filter approximately 180 gm. of glucose per day from the blood which is then mostly reabsorbed back into the blood. SGLT Specific Inhibitors inhibit the glucose reabsorption process, such that excess glucose is excreted in the urine, rather than reabsorbed into the bloodstream. That is to say, they have a hypoglycemic effect.
Chemically, most of the known SGLT inhibitors are derived from the prototype phlorizin and structurally are glycosides. Isolated from nature, phlorizin has been identified as having a hypoglycemic effect by inhibiting excessive glucose re-absorption in the kidney and accelerating glucose excretion. However, when administered orally phloridzin derivatives are hydrolyzed by the action of the glycosidase present in the small intestine, thus resulting in low absorption efficiency. Currently, there are no “stable mimetics” for SGLT glycosides which preserve their electronic architecture and behaviour, but eliminate or decrease hydrolization. In the stabilized SGLT inhibitors already developed, when the stabilization is efficient, it leads to drastic changes in the architecture of the sugar and then to its selectivity. When the sugar’s architecture is largely unchanged there is only a slight improvement in the efficacy. |