Impact of race/ethnicity on the efficacy and safety of commonly used insulin regimens: a post hoc analysis of clinical trials in type 2 diabetes mellitus.

OBJECTIVE: To explore the impact of race/ethnicity on the efficacy and safety of commonly used insulin regimens in patients with type 2 diabetes mellitus. METHODS: In this post hoc analysis, pooled data from 11 multinational clinical trials involving 1455 patients with type 2 diabetes were used to compare specific insulin treatments in Latino/Hispanic, Asian, African-descent, and Caucasian patients. Insulin treatments included once daily insulin glargine or neutral protamine Hagedorn (BASAL), insulin lispro mix 75/25 twice daily (LMBID), or insulin lispro mix 50/50 three times daily (LMTID). RESULTS: Race/ethnicity was associated with significant outcome differences for each of the insulin regimens. BASAL therapy was associated with greater improvement in several measures of glycemic control among Latino/Hispanic patients compared with Caucasian patients (lower end point hemoglobin A1c, greater reduction in hemoglobin A1c from baseline, and a larger proportion of patients achieving hemoglobin A1c level <7%). In contrast, LMBID therapy was associated with higher end point hemoglobin A1c and a smaller decrease in hemoglobin A1c from baseline in Latino/Hispanic and Asian patients than in Caucasian patients. Furthermore, fewer Asian patients attained a hemoglobin A1c level <7% than did Caucasians patients. For LMTID therapy, hemoglobin A1c outcomes were comparable across patient groups. Fasting blood glucose and glycemic excursions varied among racial/ethnic groups for the 3 insulin regimens. Weight change was comparable among racial/ethnic groups in each insulin regimen. During treatment with LMTID, Asian patients experienced higher incidence and rate of severe hypoglycemia than Caucasian patients. CONCLUSIONS: Latino/Hispanic, Asian, and African-descent patients with type 2 diabetes show different metabolic responses to insulin therapy, dependent in part on insulin type and regimen intensity.

Two-year efficacy and safety of AIR inhaled insulin in patients with type 1 diabetes: An open-label randomized controlled trial.

BACKGROUND: Patients with type 1 diabetes require intensive insulin therapy for optimal glycemic control. AIR((R)) inhaled insulin (system from Eli Lilly and Company, Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) may be an efficacious and safe alternative to subcutaneously injected (SC) mealtime insulin. METHODS: This was a Phase 3, 2-year, randomized, open-label, active-comparator, parallel-group study in 385 patients with type 1 diabetes who were randomly assigned to receive AIR insulin or SC insulin (regular human insulin or insulin lispro) at mealtimes. Both groups received insulin glargine once daily. Efficacy measures included mean change in hemoglobin A1C (A1C) from baseline to end point, eight-point self-monitored blood glucose profiles, and insulin dosage. Safety assessments included hypoglycemic events, pulmonary function tests, adverse events, and insulin antibody levels. RESULTS: In both treatment groups, only 20% of subjects reached the target of A1C <7.0%. A significant A1C difference of 0.44% was seen favoring SC insulin, with no difference between the groups in insulin doses or hypoglycemic events at end point. Patients in both treatment groups experienced progressive decreases in lung function, but larger (reversible) decrements in diffusing capacity of the lung for carbon monoxide (DL(CO)) were associated with AIR insulin treatment. Greater weight gain was seen with SC insulin treatment. CONCLUSIONS: The AIR inhaled insulin program was terminated by the sponsor prior to availability of any Phase 3 data for reasons unrelated to safety or efficacy. Despite early termination, this trial provides evidence that AIR insulin was less efficacious in lowering A1C and was associated with a greater decrease in DL(CO) and increased incidence of cough than SC insulin in patients with type 1 diabetes.

AIR inhaled insulin versus subcutaneous insulin: pharmacokinetics, glucodynamics, and pulmonary function in asthma.

OBJECTIVE: This study evaluated pharmacokinetic and glucodynamic responses to AIR inhaled insulin relative to subcutaneous insulin lispro, safety, pulmonary function, and effects of salbutamol coadministration. RESEARCH DESIGN AND METHODS: Healthy, mildly asthmatic, and moderately asthmatic subjects (n = 13/group, aged 19-58 years, nonsmoking, and nondiabetic) completed this phase I, open-label, randomized, crossover euglycemic clamp study. Subjects received 12 units equivalent AIR insulin or 12 units subcutaneous insulin lispro or salbutamol plus AIR insulin (moderate asthma group only) before the clamp. RESULTS: AIR insulin exposure was reduced 34 and 41% (both P < 0.01) in asthmatic subjects (area under the curve(0-t'), 24.0 and 21.1 nmol x min x l(-1) in mild and moderate asthma subjects, respectively) compared with healthy subjects (35.2 nmol x min x l(-1)), respectively. Glucodynamic (G) effects were similar in healthy and mildly asthmatic subjects (G(tot) = 38.7 and 23.4 g, respectively; P = 0.16) and were reduced in moderately asthmatic subjects (G(tot) = 10.7 g). Salbutamol pretreatment (moderately asthmatic subjects) improved bioavailability. AIR insulin had no discernable effect on pulmonary function. AIR insulin adverse events (cough, headache, and dizziness) were mild to moderate in intensity and have been previously reported or are typical of studies involving glucose clamp procedures. CONCLUSIONS: This study suggests that pulmonary disease severity and asthma treatment status influence the metabolic effect of AIR insulin in individuals with asthma but do not affect AIR insulin pulmonary safety or tolerability. In view of the potential interactions between diabetes treatment and pulmonary status, it is prudent to await the results of ongoing clinical trials in diabetic patients with comorbid lung disease before considering the use of inhaled insulin in such patients.

Effects of exenatide versus insulin analogues on weight change in subjects with type 2 diabetes: a pooled post-hoc analysis.

BACKGROUND AND OBJECTIVE: In two previously reported multi-center, randomized, open-label, comparator (insulin) controlled trials in patients with type 2 diabetes sub-optimally controlled with metformin and a sulfonylurea, treatment with exenatide and insulin analogue therapy produced similar reductions in glycosylated hemoglobin A(1c) (A1C). However, treatment with exenatide was associated with a reduction in body weight while insulin analogue therapy was associated with weight gain. This analysis further characterizes the relative impact of commonly employed insulin analogues versus exenatide on weight change over a 6-month period. RESEARCH DESIGN AND METHODS: In this pooled post-hoc analysis of two trials, 1047 subjects with diabetes were compared regarding the relative impact of an adjunctive treatment - an insulin analogue (glargine or biphasic insulin aspart) or exenatide (5 mug twice daily for 4 weeks, 10 mug thereafter) - on body weight. RESULTS: While exenatide treatment provided similarly effective glycemic control compared with insulin analogue therapy, it was also associated with weight reduction in the majority of subjects (73.3%, averaging 3 kg decrease by endpoint), with approximately 22% achieving > or =5% weight loss, and 3.2% of subjects achieving > or =10% weight loss. In contrast, by the end of the study most insulin-treated subjects (75.9%) had gained weight (mean 3 kg). Only 2% of insulin-treated subjects achieved > or =5% weight loss, and 0.2% of subjects achieved > or =10% weight loss. CONCLUSIONS: These findings support the use of exenatide as a treatment option in insulin-naïve subjects with type 2 diabetes and who are overweight and sub-optimally controlled by metformin and sulfonylurea. However, these results should be interpreted with caution given the exploratory nature of this post-hoc analysis.

Inhaled insulin delivery--where are we now?

Since 1925, when the concept of treating diabetes with inhaled insulin (INH) was originally published, a number of clinical challenges have been resolved through technological advancements. Efforts by pharmaceutical partnerships or individual companies have resulted in the development of both injection-free devices and novel insulin formulations. Four different INH systems are now in phase 3 of clinical development, and several other INH systems are in earlier stages of clinical study. Clinical data consistently demonstrate that INH therapy is comparable to subcutaneous (SC) therapy in improving glycaemic control in patients with either type 1 or type 2 diabetes, generally without greater risk of overall hypoglycaemia. INH is generally well tolerated and appears to be safe. Adverse-event profiles for INH therapies are similar to SC insulin therapy, with the majority of events being reported as being mild to moderate. Long-term safety studies are ongoing, with emphasis on evaluating the impact of INH therapy on pulmonary function and immune responses. Although small, reversible decreases in pulmonary diffusion capacity (DL(co)) and FEV1 have been reported in response to INH, pulmonary function and structure do not appear to be affected in any clinically significant way. While insulin antibodies are increased in INH therapy, these antibodies have not been correlated with haemoglobin A1c (HbA1c), insulin dosage, hypoglycaemia, pulmonary function or adverse events. Nevertheless, properly controlled, long-term studies will best answer any remaining concerns. From the patient's perspective, INH therapy is preferred by the majority of patients over conventional SC insulin therapy. Studies have shown that patients prefer INH therapy, because it provides greater lifestyle flexibility and social acceptability while at the same time avoiding the pain associated with injection. Thus, after more than 80 years during which the injection route has been the only means of administering insulin, patients and physicians may soon avail themselves of another valuable tool in management of diabetes.