Endocrine, nutritional and metabolic disorders affect many individuals in this country at some level. The National Center for Health Statistics reports that endocrine diseases, obesity; hyperlipidemia and diabetes affect 26%, 19% and 3% of the general population, respectively. Furthermore, the prevalence of overweight individuals in this country is increasing. Sixty-one percent of US adults are overweight or obese and 13% of children are overweight. Given that large body mass contributes significantly to an increased risk for cardiovascular disease, diabetes, hypertension and hyperlipidemia, the nutritional health of Americans is of great concern.

It is estimated that $44 billion each year is spent on obesity management. The morbidity from obesity is significant; obese individuals have to contend with respiratory difficulties, musculoskeletal problems, skin problems, infertility, gall bladder disease and depression. Diabetes is the seventh biggest cause of death among Americans and the leading cause of new blindness, kidney failure and lower extremity amputations. While these statistics present a grim picture, there is a positive note in the landscape of endocrine disorders; the prevalence of hypercholesterolemia is decreasing in this country. In the early 1960s, the prevalence of high cholesterol (defined as a value above 200 mg/dl) was noted in almost 32% of the adult population in this country, but that had fallen to 18.9% in 1998-1994. Mean cholesterol values decreased from 220 mg/dl to 203 mg/dl during the past three decades. Some statistics that are relevant to endocrine, nutritional and metabolic disorders in this U.S. are as follows:

Condition	Prevalence	Cost
Obesity	16-54 years	$44 billion/year
Diabetes	Adults	$98 billion/year
Hyperlipidemia	Adults	N/A
Thyroid disorders	Adults	N/A
Cystic fibrosis	Adults	$50,000/person/year
Hemochromatosis	Adults	N/A

There are currently about 15-20 drugs in clinical trials for obesity and about 55 drugs for diabetes. Control of blood glucose levels is a key objective in treating diabetic patients and type 2 diabetics (90% of diabetics) who are often prescribed a combination of agents to increase insulin secretion and decrease insulin resistance. Areas of research for new oral anti-diabetic agents in the preclinical and clinical arenas are ongoing.

Drugs that block glycogen phosphorylase, as this enzyme contributes to a high production of glucose by the liver. Currently, the only approved drug that decreases hepatic glucose production is Metformin. A glycogen phosphorylase inhibitor that is in phase I clinical trials is Novo Nordisk's NN 4201.

Insulinotropic factors that stimulate the secretion of insulin in response to a raised blood glucose level include the glucagon-like polypeptide (GLP-1). Infusion of this hormone can normalize glucose levels in subjects with type 2 diabetes. Drugs that inhibit the cleaving enzyme dipeptidyl peptidase IV (DPP-IV) or DDP-IV resistant GLP-1 analogues may prove helpful in the management of diabetic subjects. Currently, there are at least three drugs in clinical trials that may function to control blood sugar through a GLP-1-related process.

Beta-3 receptor agonists are in clinical trials for the management of diabetes and obesity. The incidence of a naturally occurring variant of the human beta-3-adrenergic receptor was shown to be related to the development of non-insulin-dependent diabetes mellitus in Western obese persons. This receptor is a clear target for the pharmaceutical industry; there are at least three clinical trials evaluating the efficacy of novel agonists in the management of diabetes.

Peroxisone proliferator-activated Receptor (PPAR) agonists (for example, thiazolidinediones) continue to be studied to modify insulin sensitivity in diabetics and obese patients. Thiazolidinedione drugs are effective in about 50% of type 2 diabetic patients with higher efficacy in obese patients who have high insulin levels. There are at least four ongoing trials involving PPAR agonists.

Glycosylation end-product formation inhibitors promise to be particularly useful in the prevention of the complications of diabetes. In particular, Pimagedine (Alteon's lead candidate) has completed a phase II/III trial in diabetic subjects with overt nephropathy. In the trial, pimagedine therapy resulted in a statistically significant reduction in urinary protein excretion. In addition, pimagedine reduced triglyceride levels and the progression of retinopathy. If confirmed, these results show significant promise in reducing morbidity from two complications of diabetes: end-stage renal disease and blindness.
Oral and inhaled insulin preparations will help subjects avoid the difficulties associated with subcutaneous insulin injections. There are currently at least four trials evaluating the feasibility of nasally and orally administered insulin formulations.

For the treatment of obesity, many of the same medications being investigated for diabetes management are also being evaluated for weight loss. PPRA-agonists and beta-3 receptor agonists are in trials for obesity. In addition, appetite suppressants (P57 by Pfizer), hormone analogues/agonists, dopamine-2-receptor agonists, and naturally occurring hormones (for example, leptin and ciliary neurotrophic factor) are also being evaluated in clinical trials for weight loss.

Finally, for the treatment of metabolic disorders, recent approvals have been Zoledronate (Zometa; Novartis) for the management of hypercalcemia related to malignancy and Nitisinone (Orfadin) for the treatment of tyrosinemia. Agalsidase alpha (Replagal by Transkaryotic Therapies) has been approved in Europe for the treatment of Fabry Disease and is under review by the FDA.