Metabolic disorders, such as hyperlipidemia, diabetes, high cholesterol, arteriosclerosis, hypertension and obesity, and the related diseases present a significant burden to public health. For instance, obesity, clinically defined as a body mass index of over 30 kg/m2, is estimated to affect 35.7% of the U.S. adult population. In the U.S., obesity is estimated to cause roughly 110,000-365,000 deaths per year. Obesity can result in hyperlipidemia, characterized by an excess of lipids, including cholesterol, cholesterol esters, phospholipids, and triglycerides, in the bloodstream. Additionally, obesity can result in diabetes and other related diseases. Diabetes is a metabolic disorder characterized by high blood glucose levels or low glucose tolerance, and is estimated to affect 8% of the U.S. population. Obesity is also associated with vascular disease, cancer, renal disease, infectious diseases, external causes, intentional self-harm, nervous system disorders, and chronic pulmonary disease (N Engl J Med 2011; 364:829-841). Metabolic syndrome, in which subjects present with central obesity and at least two other metabolic disorders (such as high triglycerides, high blood pressure, or diabetes), is estimated to affect 25% of the U.S. population.
Hepatic steatosis, also sometimes referred to as fatty liver disease, is a condition generally characterized by an abnormal retention of lipids in cells of the liver. Hepatic steatosis affects millions of people worldwide. The prevalence of fatty liver disease has been estimated to range from 10-24% in various countries around the globe. Fatty liver disease can be classified into several categories. For example, non-alcoholic fatty liver disease (NAFLD) generally refers to a spectrum of hepatic lipid disorders characterized by hepatic steatosis with no known secondary cause. NAFLD can be subcategorized into (a) non-alcoholic fatty liver (NAFL), defined as the presence of steatosis in the absence of histological evidence of hepatocellular injury, and (b) non-alcoholic steatohepatitis (NASH), hepatic steatosis accompanied by hepatocyte injury and inflammation. NASH may occur with or without fibrosis, but may progress to fibrosis and cirrhosis. NAFLD is generally associated with energy metabolism pathologies, including obesity, dyslipidemia, diabetes and metabolic syndrome. The prevalence of NAFLD in the general population is estimated at 20%, with prevalence of NASH estimated to be 3-5%. Among patients with obesity (or diabetes) and patients with dyslipidemias, the prevalence rate of NAFLD is estimated 70% and 50%, respectively.
Nicotinic acid, a form of vitamin B3 (niacin), has been used to treat hyperlipidemia which is one of the symptoms of obesity and other conditions. When taken in high doses (1-4 g/day typically; maximum clinical dose is 6 g/day), nicotinic acid can treat hyperlipidemia, as it can lower total lipid, LDL, cholesterol, triglycerides, and lipoprotein, or raise HDL lipoprotein in the bloodstream. It can also reduce atherosclerotic plaque progression and coronary heart disease morbidity and mortality.
Diabetes, also sometimes associate with obesity, can be treated with anti-diabetic agents such as metformin. Metformin, along with phenformin and buformin, is a form of biguanide, which is a guanide. When ingested (1000-2550 mg/day), metformin can treat diabetes by increasing insulin sensitivity, increasing glucose uptake in the gut, increasing glucose utilization, and lowering blood glucose level. Metformin does not increase the amount of insulin produced by the body and thus generally does not cause hypoglycemia, as many other diabetes medications can do.
Many efforts have been attempted to develop treatments for metabolic disorders such as hyperlipidemia and diabetes. However, both nicotinic acid and metformin can have significant side-effect and hence can be generally poorly tolerated. For instance, one significant side-effect of nicotinic acid involves severe cutaneous vasodilation and flushing responses. Such well-documented side-effects have limited the prescription of nicotinic acid. (Carlson L A. Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review. J Int Med 2005; 258:94-114). Current anti-diabetic agents such as metformin can be associated with other adverse effects. Amongst them are common adverse gastrointestinal effects that cause discomfort and limit effective dosing, as well as the rare but serious adverse event of lactic acidosis. While side effects are somewhat attenuated in sustained (SR) and extended (ER) release preparations, the side effects persist sufficiently to limit the usage of these otherwise effective drugs.