Exubera vs Lispro in a Lantus-based Regimen for Improved Glycemic Control in Type 2 Diabetes

• Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) at Each Visit [ Time Frame: Baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 ] [ Designated as safety issue: No ]
  Change in mean glycosylated hemoglobin A1c (HbA1c %) from Baseline to each visit through Week 24. Change = mean value at observation minus mean value at Baseline.
• Subjects That Attained Glycosylated Hemoglobin A1c (HbA1c) < 7.0%, < 6.5% and < 6.0% at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
  Number of subjects acheiving glycemic control: HbA1c target levels of <7.0%, <6.5%, and <6.0% at Week 24.
• Subjects That Attained Glycosylated Hemoglobin A1c (HbA1c) Target Levels of <7%, < 6.5%, and < 6.0% Without an Episode of Severe Hypoglycemia at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
  Number of subjects that attained HbA1c target levels of <7%, < 6.5%,and <6.0% at Week 24 without an episode of severe hypoglycemia.
• Change From Baseline in Fasting and 2-hour Postprandial Glucose as Determined by 8-point Self-monitored Blood Glucose Profiles [ Time Frame: Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 ] [ Designated as safety issue: No ]
  Mean change from Baseline in fasting and 2-hour postprandial glucose at each visit in 8-point self-monitored blood glucose (SMBG) profiles: includes values prior to each meal (breakfast, lunch and dinner), 2 hours after each meal, at bedtime, and at 2:00 ante meridiem (a.m.) Change=observation value minus Baseline value.
• Change From Baseline in Fasting and Postprandial Plasma Glucose as Determined by Standardized Meal Tolerance Tests at Week 12 [ Time Frame: Baseline, Week 12 ] [ Designated as safety issue: No ]
  Change from Baseine in fasting and postprandial plasma glucose as determined by standardized meal tolerance tests (MTT). Change = mean value at Week 12 minus mean value at Baseline. Time 0 results are for MTT (time 0) and non MTT (implied time 0) subjects.
• Change From Baseline in Fasting and Postprandial Plasma Glucose as Determined by Standardized Meal Tolerance Tests at Week 24 [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
  Change from Baseline in fasting and postprandial plasma glucose as determined by standardized meal tolerance tests (MTT). Change = mean value at Week 24 minus mean value at Baseline. Time 0 results are for MTT (time 0) and non MTT (implied time 0) subjects.
• Change From Baseline in Fasting and Postprandial Lipids as Determined by Standard Meal Tolerance Tests [ Time Frame: Baseline, Week 12, Week 24 ] [ Designated as safety issue: No ]
  Change from Baseline in fasting and postprandial lipids at Week 12 and Week 24 as determined by standard meal tolerance tests. Change = value at observation minus value at Baseline. Postprandial = 120 mins after meal.
• Number of Subjects With Change From Baseline in Fasting and Postprandial Markers of Cardiovascular (CV) Risk as Determined by Standardized Meal Tolerance Tests [ Time Frame: Week 12, Week 24 ] [ Designated as safety issue: No ]
  Cardiovascular risk markers included serum high-sensitivity C-reactive protein (hs-CRP)[mg/L], leptin (ng/mL), adiponectin (ug/mL), and spot urine microalbumin. Change = observation of mean fasting and postprandial markers of cardiovascular risk at Week 12 and Week 24 minus mean Baseline observation.
• Change From Baseline Weight at Each Visit [ Time Frame: Baseline, Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 ] [ Designated as safety issue: No ]
  Change = mean body weight at observation minus mean body weight at Baseline.
• Change From Baseline in Fasting Plasma Lipids [ Time Frame: Baseline, Week 12, Week 24 ] [ Designated as safety issue: No ]
  Change from baseline in fasting plasma lipids at Week 12 and Week 24. Change = observation mean minus Baseline mean.
• Change From Baseline in Insulin Glargine Dose at Each Visit (Office and/or Phone) [ Time Frame: Baseline, Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 ] [ Designated as safety issue: No ]
  Change from Baseline in insulin glargine at each visit. Change = mean at observation minus mean Baseline observation. Basal dose = injection of basal insulin (IU) (insulin glargine).
• Baseline Prandial Insulin Dose (at Each Meal) at Each Visit [ Time Frame: Week 0, Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 ] [ Designated as safety issue: No ]
  Dose of inhaled insulin prior to each meal at each visit.
• Number of Subjects With Hypoglycemic Events [ Time Frame: Month 1, Month 2, Month 3, Month 4, Month 5, Month 6 ] [ Designated as safety issue: Yes ]
  Severe event = subject unable to treat self, at least 1 neurological symptom (memory loss, confusion, uncontrollable/irrational behavior, difficulty awakening, suspected seizure, loss of consciousness), and blood glucose <= 49 milligrams per deciliter (mg/dL) or not measured but clinical manifestations reversed by oral carbohydrates or glucose. Non-severe events = events that were mild-moderate.
• Number of Total Hypoglycemic Events [ Time Frame: Month 1, Month 2, Month 3, Month 4, Month 5, Month 6 ] [ Designated as safety issue: Yes ]
  Total number and severity of hypoglycemic events. Severe events = subject unable to treat self, at least 1 neurological symptom (memory loss, confusion, uncontrollable or irrational behavior, difficulty awakening, suspected seizure, loss of consciousness), and blood glucose <= 49 milligrams per deciliter (mg/dL) or not measured but clinical manifestations reversed by oral carbohydrates or glucose. Non-severe events = events that were mild or moderate.
• Treatment Exposure for Hypoglycemic Subjects at Each Interval of the Study: Number of Subject Months of Treatment [ Time Frame: Month 1, Month 2, Month 3, Month 4, Month 5, Month 6 ] [ Designated as safety issue: Yes ]
  Subject months of treatment = number of days from start of treatment to last day of active treatment + 1 day lag (total number of subjects treated * days treated), including off-drug time)/30.44. Severity: severe = subject unable to treat self, had at least 1 neurological symptom (memory loss, confusion, uncontrollable/irrational behavior, difficulty awakening, suspected seizure, loss of consciousness), and blood glucose <= 49 milligrams/deciliter; or not measured but clinical manifestations were reversed by oral carbohydrates or glucose. Non-severe events = events that were mild or moderate.
• Crude Hypoglycemic Event Rate [ Time Frame: Month 1, Month 2, Month 3, Month 4, Month 5, Month 6 ] [ Designated as safety issue: Yes ]
  Crude event rate = (number of events)/(subject months); severe hypoglycemic events: crude event rate = (number of events)/(100 subject months). Severe = subject unable to treat self, at least 1 neurological symptom (memory loss, confusion, uncontrollable or irrational behavior, difficulty awakening, suspected seizure, loss of consciousness), and blood glucose <= 49 milligrams per deciliter (mg/dL) or unmeasured but clinical manifestestation reversed by oral carbohydrates or glucose. Non-severe events = mild-moderate.
• Change From Baseline in Patient Treatment Satisfaction (as Assessed by Patient Satisfaction With Insulin Treatment [PSIT] Questionnaire) [ Time Frame: Week 4, Week 24 ] [ Designated as safety issue: No ]
  Patient Satisfaction with insulin treatment Questionnaire (PSIT): 15-item self administered questionnaire that measures global satisfaction and two domains (subscales): convenience/ease of use and social comfort in people with type 1 and type 2 diabetes. 5-point Likert scale ranging from 1 (strongly agree) to 5 (strongly disagree). The scoring of responses to each item is analyzed so that a higher item score indicates more satisfaction. Change = mean Patient Satisfaction of Insulin Treatment (PSIT) score at observation minus mean score at Baseline.
• Change in Patient Treatment Satisfaction (as Assessed by Patient Satisfaction With Insulin Treatment [PSIT] Questionnaire) From Week 4 to Week 24 [ Time Frame: Week 4, Week 24 ] [ Designated as safety issue: No ]

  Patient Satisfaction with insulin treatment Questionnaire (PSIT): 15-item self administered questionnaire that measures global satisfaction and two domains (subscales): convenience/ease of use and social comfort in people with type 1 and type 2 diabetes. 5-point Likert scale ranging from 1 (strongly agree) to 5 (strongly disagree). The scoring of responses to each item is analyzed so that a higher item score indicates more satisfaction.

  Change = difference in mean Patient Satisfaction with Insulin Treatment (PSIT) score from Week 4 to Week 24.

• Change From Baseline in 24-hour Mean Glucose Values Measured by Continuous Glucose Monitoring System (CGMS) [ Time Frame: Baseline, Week 12, Week 24 ] [ Designated as safety issue: No ]
  Mean of 24-hour Continuous Glucose Monitoring (CGMS) glucose values. Change from Baseline = mean at observation minus mean Baseline value.
• Change From Baseline in Standard Deviation of 24-hour Glucose Values Measured by Continuous Glucose Monitoring System (CGMS) [ Time Frame: Baseline, Week 12, Week 24 ] [ Designated as safety issue: No ]
  Mean change in standard deviation of all blood glucose values within 24-hour period. Change = mean at observation minus mean at Baseline.

• Secondary endpoints include, but are not limited to:
• oChange in A1C from baseline at each visit
• oPercent of subjects that attain an A1C < 7.0%, < 6.5% and < 6.0% at Week 24
• oPercent of subjects that attain A1C targets of <7%, < 6.5%, < 6.0% at Week 24
• without an episode of severe hypoglycemia
• oChange from baseline in fasting and 2-hour postprandial glucose at each visit
• as determined by 8-point self-monitored blood glucose profiles
• oChange from baseline in fasting and postprandial plasma glucose, lipids, and
• markers of CV risk as determined by standardized meal tolerance tests performed
• at Week 12 and Week 24
• oChange from baseline in weight at each visit
• oChange from baseline in fasting plasma lipids at Weeks 12 and 24
• oChange from baseline in insulin glargine dose at each visit
• (office and/or phone)
• oChange in baseline prandial insulin dose (at each meal) at each visit
• oThe prevalence and severity of hypoglycemia
• oChange from baseline in patient treatment satisfaction (as assessed
• by Patient Satisfaction of Insulin Treatment [PSIT] Questionnaire) at
• Week 4 and 24
• oChange in patient treatment satisfaction (as assessed by PSIT Questionnaire)
• from Week 4 to Week 24
• oChange from baseline in 24-hour mean glucose values, and glycemic variability
• measured by CGMS

The current trial will examine the efficacy and safety of Exubera administered as a mealtime insulin compared to lispro, when added to an existing regimen of basal insulin glargine + or = Oral Agents (OAs). Dose titrations will be provided which should allow a large proportion of subjects to reach target glycosylated hemoglobin (A1C) levels.

• Drug: Insulin Lispro
  Weight based initiation dose, and individually adjusted doses, per subject's blood glucose, over the six months study, in addition to insulin glargine and oral agents.
• Drug: Exubera
  Weight based initiation dose, and individually adjusted doses, per subject's blood glucose, over the six months study, in addition to insulin glargine and oral agents.

• Active Comparator: Insulin Lispro
  Weight based initiation dose, and individually adjusted doses, per subject's blood glucose, over the six months study, in addition to insulin glargine and oral agents.
  Intervention: Drug: Insulin Lispro
• Experimental: Exubera
  Weight based initiation dose, and individually adjusted doses, per subject's blood glucose, over the six months study, in addition to insulin glargine and oral agents.
  Intervention: Drug: Exubera

Inclusion Criteria:

• Adults with type 2 diabetes using Lantus® (insulin glargine) as their basal insulin, not at glycemic goal.

Exclusion Criteria:

• lung disease
• current smoking or discontinued smoking within past 6 months