The Effect of Insulin Antibodies on the Metabolic Action of Inhaled and Subcutaneous Insulin

Abstract

OBJECTIVE -To assess the impact of the development of high-or low-affinity insulin antibodies (IABs) on postprandial glucose tolerance, duration of insulin action, and clinical safety in patients with type 1 diabetes receiving inhaled insulin (Exubera). RESEARCH DESIGN AND METHODS-This study consisted of a prospective, randomized, open-label, parallel-group trial in which 47 patients with type 1 diabetes received NPH insulin twice daily plus either premeal inhaled insulin (INH group; n ϭ 24) or premeal subcutaneous regular insulin (SC group; n ϭ 23) for 24 weeks. Meal challenge and euglycemic clamp studies were performed on consecutive days at baseline, week 12, and week 24. Adverse events were monitored.RESULTS -For the INH and SC groups, mean (ϮSD) IAB levels were 3.5 Ϯ 3.9 and 2.6 Ϯ 4.1 U/ml at baseline, respectively, compared with 101.4 Ϯ 140.4 and 4.3 Ϯ 9.4 U/ml at week 24. At week 24, the changes from baseline were similar for the INH and SC groups for maximal plasma glucose concentration (C max ) (adjusted ratio for treatment group difference 0. B efore the introduction of highly purified porcine and recombinant human insulins into clinical practice, the use of less purified animal-derived insulin in patients with diabetes was associated with a near 100% prevalence of detectable insulin antibodies (IABs) (1). Although mean antibody levels are now lower in patients treated with subcutaneous human insulin, ϳ50% of such patients have measurable IABs (2). Since the initial description of IABs in the 1950s, the effect of antibody development, from low levels at baseline to levels commonly observed during clinical therapy, on key glycemic parameters has not been tested in a prospectively designed randomized controlled study.Multiple cross-sectional studies over the years have investigated whether IABs can cause alterations in insulin pharmacokinetics or pharmacodynamics. Although some studies have shown associations between IABs and delayed rises in free insulin concentrations (3,4) or prolonged half-life of free insulin (3,5) after insulin dosing, the clinical impact of these observations remains unclear (6). Using a standardized meal challenge test, one study showed a relationship between high-affinity IAB binding and impaired postprandial glucose tolerance (7), although such a relationship has not been consistently reported (8,9). Significantly, although some studies have reported a deleterious effect of IABs on long-term glycemic control (10 -12), most have not (8,(13)(14)(15)(16)(17)(18). Notably, the syndrome of immunologic insulin resistance has been reported in patients with high levels of maximum insulin binding (5).Furthermore, reports of prolongation of insulin half-life have not been associated with an increased incidence of clinical hypoglycemia (14), although rare cases of unusual hypoglycemic syndromes associated with insulin therapyrelated antibodies have been described (19 -21). In addition, hypoglycemia thought to be due primarily to high levels of low-affinity binding has been described in th...

Two-Year Safety and Efficacy of Inhaled Human Insulin (Exubera) in Adult Patients With Type 1 Diabetes

“…In addition, there were no clinical manifestations of the increased antibodies observed in this study. This result is supported by previous studies that have shown that antibody formation in response to EXU does not appear to have any clinical relevance, as there are no correlations between antibody formation and glycemic control, insulin dose, the small changes observed in FEV 1 or DL CO , hypoglycemic episodes, or allergies (14,25,26). The design of the present study did not permit a detailed analysis of the onset and time course of the development of the antibody response in relation to the changes in lung function.…”

Intersession Variability in Single-Breath Diffusing Capacity in Diabetics without Overt Lung Disease

“…In the initial drug safety trials, lung function was measured in community pulmonary function laboratories (hereafter referred to as ''routine testing''). In later trials, a comprehensive program of centralized quality control monitoring was instituted (referred to as ''highly standardized testing'') (23)(24)(25)(26)(27). Individuals enrolled in the comparator groups did not receive inhaled therapies during the study protocol.…”

Inhaled insulin: gone with the wind?

“…Inhaled insulin, as it emerged, promotes more antibody formation than injected insulin, especially in those with type 1 diabetes. As in other situations in which the question has arisen, there was no correlation between insulin antibody levels and glycaemic control or rates of hypoglycaemia [15], but the observation contributes to our unease as we enter this hitherto unexplored territory. To underline the same point, we come to the third concern: insulin has trophic effects and is potentially carcinogenic.…”