(Laurie Barclay, MD, Sept. 9, 2002)

In diabetes mellitus, defects in insulin secretion, insulin action, or both cause hyperglycemia and other metabolic derangements affecting multiple organ systems. More than 17 million Americans have diabetes, with medical costs more than $45 billion annually, and an additional 800,000 Americans are newly diagnosed each year. Diabetes increases the risk of myocardial infarction or stroke two- to four-fold, and two-thirds of diabetics die from these cardiovascular complications. Overall, diabetes is the fifth leading cause of death by disease in the U.S.

More than 90% of diabetics in the U.S. have type 2 diabetes, a chronic disease associated with insulin deficiency and insulin resistance. As the obesity epidemic swells, so does the number of type 2 diabetics. Weight gain leads to metabolic syndrome, characterized by elevated lipids, abnormal glucose control, and insulin resistance. Although weight loss can sometimes reverse metabolic syndrome, overt diabetes typically follows, as insulin secretion is defective and insufficient to compensate for the insulin resistance.

Unlike type 1 diabetes, autoimmune destruction of ß-cells does not occur in type 2, but recent research suggests that inflammation may play some role in the poorly understood pathophysiology. Risk factors include obesity, advanced age, sedentary lifestyle, history of gestational diabetes, hypertension, dyslipidemia, and genetic predisposition.

The United Kingdom Prospective Diabetes Study (UKPDS), the largest and longest study to date of type 2 diabetes, showed that tighter glucose control reduced the overall rate of microvascular complications by 25%, and lowered the risk of retinopathy, nephropathy, and possibly neuropathy.

In early stages of type 2 diabetes, and in some cases throughout the course, diet, lifestyle changes and multiple medications including oral hypoglycemic agents can help avoid insulin treatment. However, there are 5.7 million type 2 diabetics in North America and Europe who require at least one daily insulin injection. Avoiding shots could greatly improve quality of life, so many new products are geared to alternate methods of insulin delivery, including oral pills, oral spray, pulmonary inhalants, and longer-acting injections.

CenterWatch has identified a pipeline of 44 drugs in development for type 2 diabetes, including different insulin formulations, lipid-lowering agents, hormone analogs, and hypoglycemics.

Furthest along the pipeline is Symlin (pramlintide), a synthetic analog of the human hormone amylin, for which Amylin Pharmaceuticals submitted a new drug application in December 2000 and received an approvable letter October 2001 pending additional clinical work. In 34 completed Phase 1 and Phase 2 studies of over 1,400 subjects, Symlin reduced post-prandial hyperglycemia and average 24-hour plasma glucose concentrations in type 2 diabetics who used insulin, without increasing hypoglycemia or other adverse events. Phase 3 studies involving over 3,500 subjects included two U.S. and one European/Canadian double-blind, placebo-controlled trials in type 2 diabetes. Approximately 70% of those receiving Symlin voluntarily continued it in the open-label extension.

The percentage of patients treated with Symlin who experienced an early reduction in HbA1c was about twice the percentage in the group of patients treated with insulin alone. Subjects who experienced an early glycemic response also lost weight and maintained weight loss during Symlin treatment, independent of HbA1c reduction. While maintaining tighter glycemic control, subjects receiving Symlin 120 micrograms twice daily for one year lost 3.1 pounds on average, compared with 1.5 pound mean weight gain in the controls.

Another hormone analog in Phase III development by Amylin Pharmaceuticals is AC2993 synthetic exendin-4, a 39-amino acid peptide which in clinical studies stimulated secretion of insulin when blood glucose was elevated, but not during periods of hypoglycemia, thereby reducing elevated post-prandial and fasting blood glucose. This drug needs to be injected only once monthly, thanks to Alkermes' Medisorb(R) injectable sustained release drug delivery technology. Of 109 patients inadequately controlled on oral hypoglycemics, with entry HbA1c levels between 9.1 and 9.4%, 15% of those treated with AC2993 for 28 days but only 4% of the placebo group achieved HbA1c levels below 7%.

To add a type 2 diabetes indication to its Xenical (orlistat) label, Roche has completed Phase III testing of this antiobesity drug, a lipase inhibitor that reduces dietary fat absorption. A randomized, placebo-controlled trial of 516 patients showed beneficial effects on blood pressure, lipid profile, and reduced need for additional diabetic medications. Despite significantly more gastrointestinal effects in the Xenical group, more patients withdrew from the placebo group, suggesting a perceived benefit. After one year of treatment, twice as many patients in the orlistat-treated group (39.0%) as in the control group (15.7%) lost 5% of baseline body weight, and 14.1% of orlistat-treated patients but only 3.9% of controls lost 10% of baseline body weight.

Regeneron Pharmaceuticals is in Phase III testing of Axokine, a genetically engineered version of the naturally occurring human protein known as ciliary neurotrophic factor. Like Xenical, Axokine targets obesity in type 2 diabetics, in the expectation that weight loss will have beneficial effects on glycemic control and insulin resistance.

Novel approaches to insulin delivery include inhalation, oral pills or spray, and long-acting injectables. In collaboration with Aventis and Inhale Therapeutic Systems, Pfizer is developing Exubera, a dry powder insulin inhalant. A three-month phase III multicenter study of 309 patients with type 2 diabetes failing oral hypoglycemics showed that Exubera, either alone or in combination with oral agents, offered significantly better glycemic control than did oral hypoglycemics alone, and it achieved target HbA1c in significantly more patients.

Aradigm has completed Phase II testing of the AERx Diabetes Management System, which produces a fine aerosol mist of insulin that is inhaled into the lungs for absorption into the bloodstream. In a randomized, open-label trial, the AERx system was safe and well tolerated, and intrasubject variability of pulmonary delivery was similar to that of subcutaneous insulin.

Oral insulin has failed previously because the molecule is too large for gastrointestinal absorption and is degraded before reaching the liver. To overcome these problems, Emisphere Technologies packages oral insulin in capsules with the Emisphere delivery agent, which facilitates absorption and release into systemic circulation. Maximum blood insulin concentrations within 15 to 25 minutes mimic pancreatic production and excretion, with corresponding maximum reductions in plasma glucose and C-peptide concentrations within one hour. In Phase II testing, Emisphere was well tolerated with no serious adverse events, although there were some hypoglycemic episodes.

Nobex Corporation, in conjunction with GlaxoSmithKline, is also in Phase II testing of their oral insulin pill Hexyl-Insulin Monoconjugate (HIM2), which uses polymer technology to resist enzymatic degradation of insulin and to promote its absorption into the bloodstream. Multiple doses of HIM2 over a three-day period offered glucose-lowering benefits comparable to injected insulin.

Another variation on the insulin theme is 1964, a fast-acting insulin analog in Phase III testing by Aventis. Its shorter duration of action than regular human insulin should allow treatment of hyperglycemia, flexible mealtime dosing and pump application.

Rather than modifying insulin, some drug companies are improving available oral hypoglycemics. Andrx is in Phase III testing of Metformin XT, a controlled-release formulation with safety profile, tolerability, and effects comparable to those of immediate-release Metformin on lipid profile, hemoglobin A1c, fasting plasma glucose, body weight, and body mass index. Bristol-Myers Squibb is conducting Phase III pediatric trials of Glucovance, which combines metformin and glyburide in a single pill and which is already approved in adults.

Dexlipotam (R+/- alpha-lipoic acid), an oral anti-hyperglycemic agent that improves peripheral glucose uptake and utilization, is thought to have a unique mechanism of action. It improves nerve function in diabetic rats, and it is currently in early phase II development by Aventis, in collaboration with Asta Medica.

Several companies are developing peroxisome proliferator-activated receptor (PPAR) agonists, including Bristol-Myers Squibb, which is in Phase II development of a dual alpha/gamma PPAR agonist. This compound, which may also prove to be useful in other metabolic disorders, appears to have the potential to simultaneously lower triglycerides and glucose levels while increasing insulin sensitivity. Beta-3-adrenergic receptor agonists, such as AJ-9677 in Phase II development by Dainippon Pharmaceutical and Takeda Chemical Industries, may also improve both lipid and glycemic metabolism by reducing insulin resistance and increasing energy consumption.

Other oral hypoglycemics, antiobesity agents, peptides, and growth factors target varying links in the complex relationship between glycemic control and lipid metabolism. Some of these products in the pipeline may ultimately work synergistically with each other, or with dietary and other lifestyle modifications that cannot be neglected for optimal control of type 2 diabetes and its complications. Novel approaches to insulin delivery should improve quality of life for the many type 2 diabetics who now require daily injections.