Stephen H. Schneider, MD, professor of medicine, UMDNJ- Robert Wood Johnson Medical School

Diabetes mellitus has become one of the major public health problems of our society. In the U.S., more than 15 million people have diabetes, and that number is expected to climb rapidly over the next decade. In other areas of the world the prevalence of diabetes is growing even more quickly. In addition to its direct morbidity, diabetes is the leading cause of blindness, renal failure, non-traumatic amputation, and premature coronary artery disease. Diabetes is broadly divided into two major categories. Type 1 diabetes accounts for fewer then 5% of cases. It tends to occur in younger patients or children and is associated with autoimmune destruction of the pancreas and absolute insulin deficiency. Type 2 diabetes, which accounts for more than 90% of cases, is the result of a dual defect. Patients have significant insulin insensitivity from an early age but, over time, a progressive loss of beta cell function also occurs. By the time patients present with hyperglycemia, more then 50% of their capacity to produce insulin is gone. Virtually all cases of diabetes are associated with either absolute or relative and progressively worsening insulin deficiency. Thus, most patients will eventually require insulin replacement therapy to obtain adequate control of carbohydrate metabolism.

In recent years, large studies have confirmed that the complications of diabetes are related in large part to the elevation of blood glucose and can be prevented by tight glucose control. Such control can be particularly difficult to obtain after meals. Current treatment regimens require multiple injections of insulin to achieve normalization of blood glucose. Usually, long acting basal insulin is given and, in addition, an injection of short acting insulin is taken prior to each meal or snack. Recent advances in genetically engineered insulin have resulted in the development of insulin analogs with much more physiologic and convenient pharmacokinetic profiles. Nevertheless, many patients and physicians remain hesitant to initiate and sustain aggressive insulin therapies that require self-injection of insulin four to six times a day.

As a result, many attempts have been made over the years to develop a means of delivering insulin by alternative, more palatable mechanisms. One attractive approach to insulin delivery has been to utilize the human lung. The lung presents a large, very vascular surface area that is capable of absorbing peptides efficiently into the circulation. Pfizer and Aventis have been engaged in a joint venture to develop inhaled human insulin as a therapeutic option. Over the past few years, we and other investigators here and in Europe have been working with industry to understand the efficacy, side effects and practicality of this approach in patients with type 1 and type 2 diabetes mellitus.

A dry powder insulin delivery system to administer insulin via inhalation has been developed. The system generates particles of the size necessary to penetrate to the alveoli where absorption occurs. The relative bioavailability of insulin administered in this way is about 10-15% that of subcutaneous insulin. One mg of inhaled insulin is approximately the equivalent of two to three units of subcutaneous insulin. The insulin is absorbed slightly more rapidly than currently available rapid acting insulin analogs and has a slightly shorter time course of action. These kinetics actually make inhaled insulin a better physiologic replacement with meals than subcutaneous insulin injection. Inhaled insulin can be taken shortly before a meal with an excellent therapeutic effect. Studies to better define the kinetics of inhaled insulin in various situations are currently underway. For example, we are now initiating studies to examine the effects of moderate exercise on pulmonary absorption of inhaled insulin.

While the short duration of inhaled insulin makes it ideal for meal-related administration, it means that long-acting basal insulin must be administered as part of the regimen in patients with absolute insulin deficiency. Fortunately, this can usually be accomplished with a single injection of a long-acting analog, reducing the number of required injections from four to six to one injection per day. Many patients with type 2 diabetes have adequate beta cell function to provide basal, but not prandial, insulin requirements. We are currently studying the efficacy of using inhaled insulin with meals in combination with oral hypoglycemic agents in such patients to achieve good glucose control without the need for injectable insulin. Interestingly, this approach has produced significant improvements in fasting, as well as post-meal, glucose levels, possibly as a result of a reduction in so called “glucose toxicity” on beta cell function. Thus far, results of regimens using inhaled insulin have been very promising, with therapeutic efficacies similar to those of subcutaneous regimens persisting for multiple years and with greater patient acceptance.

Two major concerns regarding inhaled insulin are the subjects of ongoing investigation. Studies are demonstrating development of low titers of anti-insulin antibodies in patients using the inhaled product. These levels are higher than those seen with subcutaneous therapy, but are still quite modest and thus far have not been associated with any side effects or a detectable negative impact on effectiveness. The major concern with administration of insulin in the lung is the potential for damage to the pulmonary system over time. In fact, many of our patients develop a mild cough that tends to decrease over time. We and others monitor pulmonary function intensively in our subjects. Thus far, only small, clinically non-significant, and reversible changes in pulmonary function have been noted in studies lasting more than a year.

The advent of inhaled insulin therapy would represent a major therapeutic breakthrough in the treatment of diabetes mellitus, allowing tight glucose control in large numbers of patients not currently willing or able to take multiple insulin injections. This should translate into important public health benefits by reducing the complications of diabetes. The success of inhaled insulin therapy may pave the way for administration by this alternative route of other therapeutic peptides that now require injection. We hope that studies such as ours will help define the safety and optimal therapeutic regimens for using inhaled insulin and improve the quality of the lives of our patients.

Stephen H. Schneider, MD, is a professor of medicine at RWJMS. He received his BA from Boston University and his MD from Boston University School of Medicine. Dr. Schneider completed his residency at Boston University Hospital and a fellowship in endocrinology at Boston City Hospital. He is on the board of the American Diabetes Association-Council on Exercise as well as its Exercise Advisory Panel. Dr. Schneider was named among the “Best Docs in New Jersey” in NJ Monthly magazine as well as among the “Best Doctors in America” by Best Doctors, Inc. His research interests include: diabetes and exercise, atherosclerosis and exercise physiology and obesity. §