The future of diabetes care: the impact of inhaled insulin on glycemic control.

The emerging epidemic of diabetes in the United States has been well documented. It is estimated that 7% of the US population, or nearly 21 million individuals, now have diabetes. Perhaps as many as 54 million more Americans have prediabetes. (1) The potential consequences of diabetes are severe. In the United States, diabetes is the number one cause of adult blindness, end-stage kidney disease, and nontraumatic amputations and is associated with a two-to fourfold increase in the risk of cardiovascular disease (CVD). Glycemic control is the cornerstone of treatment for diabetes. Studies have clearly demonstrated that improved glycemic control reduces the risk for microvascular and neuropathic complications, and there is increasing evidence for a beneficial effect on cardiovascular risk. (2) Unfortunately, for many patients, glycemic control is difficult to attain and/or maintain. Novel formulations of insulin are new options for patients with diabetes. The first inhaled insulin, for example, is now Food and Drug Administration-approved and provides a means of delivering insulin without the need for injections. This tutorial reviews the overall approach to diabetes care and examines the latest data regarding the utility of inhaled insulin.

The Prevalence and Burden of Diabetes

Increases in the prevalence of diabetes have occurred throughout the United States and across demographic groups. Most states now have a prevalence of diabetes of 6% or greater; in 1994, only two states had prevalence rates that high. (3) This change appears related to a similar trend in the prevalence of obesity (defined as a body mass index of [greater than or equal to]30 kg/[m.sup.2]). Most states in this country now have a prevalence of obesity of at least 20%, with several states exceeding 25%; in 1994, no state had a prevalence of obesity as high as 20%. (4) Approximately 10% of adult men and 8.8% of adult women have diabetes, and nearly 21% of people aged 60 years or older--the fastest growing segment of the US population--have diabetes. Annually, 1.5 million new cases are diagnosed. Type 2 diabetes accounts for more than 90% of all cases. (1)

Diabetes is associated with tremendous morbidity. The American Association of Clinical Endocrinologists (AACE) estimates that approximately 60% of people with type 2 diabetes have at least one of the serious health problems associated with the disease, including CVD kidney disease, blindness, or peripheral neuropathy. (5) Every 24 hours in the United States, there are an estimated 810 deaths, 230 amputations, 120 new cases of kidney failure, and 55 new cases of blindness due to or among people with diabetes. (6) A recent analysis from the Framingham Heart Study reported that people with diabetes had a 2.5-fold increased risk for CVD and approximately a 2-fold increased risk of death due to CVD. Furthermore, both men and women more than 50 years of age with diabetes lived an average of 8 years less than their nondiabetic counterparts. (7)

Treating Diabetes: Preventing Complications by Treating to Target

The American Diabetes Association (ADA) guidelines for the treatment of diabetes (8) recommend an overall target for hemoglobin [A.sub.1c] (A1C) of less than 7.0%, with the goal for an individual patient as close to the non-diabetic range (<6.0%) as possible without significant hypoglycemia (Table 1). A goal--6.5% or less--is recommended by the AACE and American College of Endocrinology (ACE). (9)

The diabetes treatment guidelines are based in large part on studies that demonstrated a clear association between better glycemic control and reduced risk of complications. Both the Diabetes Control and Complications Trial (DCCT) involving patients with type 1 diabetes and the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that more intensive therapy that lowered A1C was associated with a marked reduction in the risk of microvascular and neuropathic diabetes complications. There was also a reduction of macrovascular risk associated with improved glycemia in both trials, but this did not achieve statistical significance. However, Nathan et al (10) reported long-term follow-up from the DCCT in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. In this trial, subjects with type 1 diabetes were randomized to receive conventional treatment (one or two injections of insulin per day) or intensive treatment (three or more daily injections of insulin, or an insulin pump) for a mean of 6.5 years. Intensive treatment resulted in lower Al C values and a reduction in microvascular complications. Most subjects (93%) were subsequently followed after the study when they had returned to the care of their usual healthcare professional for an average of 11 additional years. After a mean of 17 years of total follow-up, those in the DCCT intensive treatment group had a 42% reduction in the risk for any cardiovascular event (P=0.02) and a 57% reduction in the risk for death from CVD (P=0.02) compared to those in the DCCT conventional treatment group. There are two major messages from this study: treating glycemia will reduce the risk for heart attack and stroke and, in addition, the sooner one begins to optimally treat diabetes, the better because there appears to be a metabolic memory of good and bad control that persists for many years afterwards.

There are some indications that diabetes care overall has improved in recent decades. Saaddine et al (11) reviewed data from the National Health and Nutrition Examination Survey (NHANES) and the Behavioral Risk Factor Surveillance System and reported on changes in glycemic control and other factors among people with diabetes from 1988 to 2002. During this time period, the proportion of people with A1C levels of 6.0% to 8.0% increased from 34.2% to 47.0%, whereas the proportion with A1C levels greater than 9.0% decreased from 24.5% to 20.6%. Nevertheless, nearly 60% of individuals in the study continued to have A1C levels of 7.0% or greater. In 2005, the AACE reported a database review of more than 157,000 people with type 2 diabetes in 39 states. (5) Two thirds of these individuals had A1C levels in excess of the AACE/ACE goal of 6.5% or less.

Barriers to Care: Why Patients Don't Achieve Glycemic Goals

There are a number of reasons why patients fail to reach glycemic goals recommended by the ADA and the AACE/ACE. They include:

* Suboptimal adherence of some patients to lifestyle modifications and pharmacologic treatments

* Failure of some clinicians to consistently adopt a treat-to-target approach

* Lack of optimal healthcare delivery systems in a significant number of clinical settings

* Reimbursement issues

* Unmet needs with conventional therapies.

Patient Adherence

The Council for Advancement of Diabetes Research and Education conducted a survey of 4,000 general internal medicine physicians, of whom 23% (n=910) responded. The survey assessed physicians' impressions of barriers to diabetes care. The most frequently reported barriers to effective care included patient nonadherence to non-pharmacologic and pharmacologic care, lack of interest and/or motivation on the part of the patient, and lack of physicians' time to spend with patients. (12)

Studies of patients' adherence to diabetes care programs support these perceptions. A recently published survey evaluated levels of physical activity of more than 23,000 adults in the United States. (13) Overall, 39% of adults with diabetes were physically active compared to 58% of adults without diabetes, despite the fact that 73% of those with diabetes had been advised by a healthcare professional to exercise more compared to 31% of those without diabetes. (14) Adherence to pharmacologic treatment is also suboptimal in patients with diabetes. Cramer (15) performed a literature review to evaluate adherence rates with diabetes medications. The author found that adherence to oral antidiabetic therapy ranged from 36% to 93% in patients remaining on treatment for 6 to 24 months; adherence to insulin therapy among patients with type 2 diabetes was 62% to 64%. A variety of resources exist to help patients improve adherence to pharmacologic and nonpharmacologic therapies (Table 2).

Clinician Approach to Therapy

Another reason that patients may fall short of glycemic goals is that sometimes clinicians fail to adopt a treat-to-target approach. The progressive nature of type 2 diabetes dictates the need for continued modifications to therapy. However, data suggest that therapy is often not modified soon enough. Brown et al, (16) using retrospective data, estimated A1C values and the length of time before modifications were made to therapy for patients with type 2 diabetes. Patients receiving metformin or sulfonylurea monotherapy had initial A1C values of 7.6% to 8.2%, respectively. The best A1C values achieved by these patients while on monotherapy remained above treatment goals: 7.1% to 7.7%. Still, no modifications were made to the therapy for an average of 27 to 35 months, at which time A1C levels had reached 8.8% to 9.1%, respectively. The average length of time from diagnosis to initiation of combination therapy was 5 years; by the time insulin was initiated, the average patient had spent 5 years with A1C levels greater than 8.0%, and 10 years above the ADA goal of 7.0% (Figure 1).

Initiating Insulin