Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

67th Annual Scientific Sessions of the American Diabetes Association

Chicago, Illinois / June 22-26, 2007

Although data are clear that tight glycemic control is associated with reductions in the incidence of microvascular complications in patients with either type 1 or 2 diabetes, adherence to a regimen of multiple daily injections of insulin is challenging. Indeed, nearly two-thirds of patients with diabetes fail to achieve treatment goals for control of blood sugar.

Inhaled insulin as part of a basal/bolus insulin strategy represents an alternative to standard injection regimens in patients who are unwilling or unable to use preprandial injections and/or in whom oral agents are failing. At present, inhaled insulin is available for prandial coverage only and patients still require subcutaneous injections of long-acting insulins for basal coverage.

Glycemic Control Remains Poor

According to Dr. Lawrence Blonde, Ochsner Diabetes Clinical Research Unit, New Orleans, Louisiana, over the past decade, the proportion of diabetic patients with poor glycemic control has remained unchanged and fewer than half attain a hemoglobin (Hb) A1c level of 6.0% to 8.0%.

Suboptimal patient adherence to lifestyle changes and pharmacologic treatments and a failure of clinicians to adopt a “treat-to-target” approach are two reasons for a lack of HbA1c goal attainment, he noted. A systematic review of adherence to medications for diabetes found that patients take only 67% to 85% of doses of oral antidiabetic agents and that insulin adherence among patients with type 2 diabetes was only 62% to 64%.

“Many physicians fail to advance therapy or add insulin in a timely manner,” Dr. Blonde told delegates. “Standard approaches to therapy result in prolonged exposure to elevated glucose.” For example, in patients with type 2 diabetes, new or additional treatments are typically not started for nine months after monotherapy is tried but has failed to achieve HbA1c goal. Furthermore, the average patient has HbA1c >8.0% for five years and HbA1c >7.0% for 10 years before insulin is initiated.

“There’s also a lack of appreciation that type 2 diabetes is a progressive disease,” with progressive loss of beta cell function, mentioned Dr. William T. Cefalu, Division of Nutrition and Chronic Diseases, Louisiana State University, Baton Rouge.

Data from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Intervention and Complications (EDIC) indicate that early glycemic control with intensive insulin therapy can significantly reduce the risk of microvascular and macrovascular complications for as long as 17 years, which suggests that metabolic memory to the early control may be taking place, remarked Dr. Blonde.

In patients with type 2 diabetes, insulin should be considered (or intensified if already being used) if lifestyle changes, metformin, and a second medication do not result in goal glycemia. Although a third oral medication is an alternative, it is not as effective as adding or intensifying insulin in lowering glycemia.

Candidates for Insulin Therapy

Initial therapy with insulin is appropriate in type 2 diabetes when patients have severely uncontrolled diabetes, defined as a fasting plasma glucose (FPG) >250 mg/dL (>13.9 mmoL/L), random glucose levels consistently above 300 mg/dL (16.6 mmol/L), HbA1c>10% or the presence of ketonuria with polyuria, polydipsia and weight loss.

The advantage of insulin is that it can be titrated rapidly and is the most effective of the available options for lowering blood glucose levels. Unlike other glucose-lowering medications, “there is no maximum dose of insulin beyond which a therapeutic effect will not occur,” noted Dr. Cefalu. “You can titrate it until you get where you need to be.”

Although basal insulin is traditionally the first type used, prandial insulin can be used to initiate insulin therapy. The importance of postprandial glucose is emerging, as its contribution to HbA1c increases as HbA1c improves.

“Prandial insulin may be a good option when oral agents fail,” indicated Dr. Vivian Fonseca, Section of Endocrinology and Metabolism, Tulane University, New Orleans. “Postprandial glucose contributes a lot to A1c when the HbA1c gets close to goal.” Postprandial glucose contributes as much as 70% to overall glycemia when the HbA1c is <7.3%.

Furthermore, postprandial glucose is associated with the development of microvascular and macrovascular complications. It is a more accurate predictor of myocardial infarction than FPG and it correlates better with HbA1c than does FPG, he explained.

Barriers to Advancing to Insulin

“Most patients will eventually need insulin, but implementation of insulin is often delayed,” commented Dr. Blonde.

Insulin use has not increased despite poor glucose control in patients with type 2 diabetes. In the US, only about 27% of type 2 patients are treated with insulin, a percentage that has remained unchanged since the late 1980s.

Alternative methods of delivering insulin can overcome barriers to insulin use. Fear of injection is one such barrier; another is the fear of demands of insulin therapy, especially basal/bolus regimens that require multiple injections.

Inhalation of insulin may facilitate earlier insulin use and better glycemic control. Among patients on dual oral therapy who remained uncontrolled (HbA1c of 8% to 11%), substituting inhaled insulin resulted in a 1.4% decline in HbA1c and adding inhaled insulin to the oral agents resulted in a 1.9% decline (Rosenstock et al. Ann Intern Med 2005; 143:549-58).

Comparable Glycemic Control

“The pulmonary bed is amenable to peptide uptake,” confirmed Dr. Cefalu. “Inhaled insulins have an uptake similar to that of fast-acting insulins. Ideally, they will give good prandial coverage so you can replace the prandial insulin with inhaled insulin. Inhaled insulin will not replace basal insulin; it will either be used first or on top of basal.”

As demonstrated by Hollander et al. (Diabetes Care 2004;27:2356-62), the change in HbA1c with inhaled insulin produced glycemic control comparable to that seen with conventional insulin therapy in patients with type 2 diabetes, with a slightly lower incidence of hypoglycemia with inhaled insulin, noted Dr. Cefalu.

Mealtime inhaled insulin plus oral agents was superior to oral therapy alone or inhaled insulin alone in getting type 2 patients to their target HbA1c. Rosenstock et al (Ann Intern Med 2005) showed that 32% of patients uncontrolled on combinations of oral agents could achieve HbA1c <7.0% by adding inhaled insulin, whereas only 1% could achieve this target by adding more oral agents. In this same study, 86% of patients on inhaled insulin plus oral agents achieved HbA1c <8.0%. Other data show that inhaled insulin results in a greater decline in FPG than subcutaneous insulin (Skyler et al. Diabetes Care 2007; 30:579-85).

Efficacy in controlling glycemia is maintained with inhaled insulin. In patients with type 1 diabetes, the mean observed HbA1c was comparable between inhaled and subcutaneous insulin at two years of follow-up. In addition, the rates of hypoglycemia are comparable between inhaled and subcutaneous formulations, remarked Dr. Cefalu, and there is less weight gain with inhaled insulin.

Adequate Lung Function Required

The effect of inhaled insulin on pulmonary function has been studied and found to be minimal. In a three-year follow-up of patients taking inhaled insulin, a slight drop in forced expiratory volume in 1 second (FEV1) was observed early in the regimen. “The slight drop in FEV1 is not progressive,” remarked Dr. Cefalu. “We’ve also shown that it’s completely reversible when you take the patient off inhaled insulin.” He recommended that physicians schedule FEV1 testing before starting inhaled insulin to ensure that pulmonary function is adequate.

Inhaled insulin is contraindicated in patients with chronic lung disease and in active smokers (in whom insulin absorption is increased). Those who quit smoking should wait for approximately six months before using inhaled insulin, Dr. Cefalu advised.