Hospital Management of Hyperglycemia Study of Insulin Glargine Plus Insulin Lispro Versus Human Regular Insulin (HMH)

• Mean Plasma Glucose (MPG) Throughout Hospital Study Period [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
  Overall MPG is derived as the mean of plasma glucose (PG) readings from Day/Visit 1 to Day/Visit 10.
• Percentage of Capillary Plasma Glucose Measurements Within the Range of 71 to 179 mg/dL Throughout the Hospital Study Period [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
  Results are reported as the percentage of total number of capillary plasma glucose measurements within the range of 71 to 179 mg/dL for each treatment arm.

• Mean Plasma Glucose (MPG) throughout hospital study period [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
• Percentage of Capillary Plasma Glucose Measurements Within the Range of 71 to 179 mg/dL Throughout the Hospital Study Period [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]

• Mean Plasma Glucose (MPG) by Hospital Day [ Time Frame: Day 1 up to day 7 of hospital study period ] [ Designated as safety issue: No ]
  The intent was to report results up to Day 10; however, due to low enrollment, mean and standard deviations are only reported up to Day 7.
• Percentage of Plasma Glucose Measurements Within Range 71 to 179 mg/dL by Hospital Day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
  Due to low enrollment, this outcome measure was not analyzed.
• Percentage of Participants Achieving MPG Within Range 71 to 179 mg/dL and Within the Target of 100 to 179 mg/dL Throughout Hospital Study Period [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
  Due to low enrollment, this outcome measure was not analyzed.
• Percentage of Participants Achieving MPG Within Range 71 to 179 mg/dL and Within the Target of 100 to 179 mg/dL by Hospital Day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
  Due to low enrollment, this outcome measure was not analyzed.
• Mean Fasting Plasma Glucose (FPG) by Hospital Day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
  Due to low enrollment, this outcome measure was not analyzed.
• Mean FPG Throughout Hospital Study Period [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
  Due to low enrollment, this outcome measure was not analyzed.
• Percentage of Fasting Capillary PG Measurements Within the Range of 71 to 139 mg/dL and Within the Target of 100 to 139 mg/dL Throughout the Hospital Study Period [ Time Frame: Throughout the hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
  Due to low enrollment, this outcome measure was not analyzed.
• Percentage of Fasting Capillary PG Measurements Within the Range of 71 to 139 mg/dL and Within the Target of 100 to 139 mg/dL by Hospital Day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
  Due to low enrollment, this outcome measure was not analyzed.
• Percentage of Participants Achieving Mean FPG Range of 71 to 139 mg/dL and Target of 100 to 139 mg/dL Throughout the Hospital Study Period [ Time Frame: Throughout the hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
  Due to low enrollment, this outcome measure was not analyzed.
• Percentage of Participants Achieving Mean FPG Range of 71 to 139 mg/dL and Target of 100 to 139 mg/dL by Hospital Day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
  Due to low enrollment, this outcome measure was not analyzed.
• Percentage of Capillary PG Measurements >240 mg/dL Throughout the Hospital Study Period [ Time Frame: Throughout the hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
  Due to low enrollment, this outcome measure was not analyzed.
• Percentage of Capillary PG Measurements >240 mg/dL by Hospital Day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
  Due to low enrollment, this outcome measure was not analyzed.
• Total Daily Dose (TDD) of Insulin (Units) Throughout the Hospital Study Period [ Time Frame: Throughout the hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
  Due to low enrollment, this outcome measure was not analyzed.
• TDD of Insulin (Units/kg) Throughout the Hospital Study Period [ Time Frame: Throughout the hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
  Due to low enrollment, this outcome measure was not analyzed.
• TDD of Insulin (Units) by Hospital Day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
  Due to low enrollment, this outcome measure was not analyzed.
• TDD of Insulin (Units/kg) by Hospital Day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
  Due to low enrollment, this outcome measure was not analyzed.
• Length of Hospital Stay Post-randomization Throughout the Hospital Study Period [ Time Frame: Throughout the hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
  Due to low enrollment, this outcome measure was not analyzed.
• Number (Incidence) of Hypoglycemia and Severe Hypoglycemia Episodes, Throughout Hospital Study Period [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: Yes ]
  Hypoglycemia was defined as any time a recorded capillary PG level is ≤70 mg/dL, even if it is not associated with signs or symptoms, or treatment consistent with current guidelines (ADA 2005; ADA 2010). Severe hypoglycemia was defined as an episode associated with a recorded capillary (or venous) PG <40 mg/dL (Umpierrez et al. 2007; Moghissi et al. 2009; Umpierrez et al. 2009), even if it is not associated with need for assistance or neuroglycopenic symptoms (ADA 2005) or prompt recovery after oral carbohydrate, glucagon, or IV glucose.
• Number of Hypoglycemia and Severe Hypoglycemia Episodes Adjusted for 30 Days (Rate), Throughout Hospital Study Period [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
  Hypoglycemia was defined as any time a recorded capillary PG level is ≤70 mg/dL, even if it is not associated with signs or symptoms, or treatment consistent with current guidelines (ADA 2005; ADA 2010). Severe hypoglycemia was defined as an episode associated with a recorded capillary (or venous) PG <40 mg/dL, even if it is not associated with need for assistance or neuroglycopenic symptoms (ADA 2005) or prompt recovery after oral carbohydrate, glucagon, or IV glucose. Due to low enrollment, this outcome measure was not analyzed.
• Number (Incidence) of Hypoglycemia and Severe Hypoglycemia Episodes, by Hospital Day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
  Hypoglycemia was defined as any time a recorded capillary PG level is ≤70 mg/dL, even if it is not associated with signs or symptoms, or treatment consistent with current guidelines (ADA 2005; ADA 2010). Severe hypoglycemia was defined as an episode associated with a recorded capillary (or venous) PG <40 mg/dL, even if it is not associated with need for assistance or neuroglycopenic symptoms (ADA 2005) or prompt recovery after oral carbohydrate, glucagon, or IV glucose. Due to low enrollment, this outcome measure was not analyzed.
• Number of Hypoglycemia and Severe Hypoglycemia Episodes Adjusted for 30 Days (Rate), by Hospital Day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
  Hypoglycemia was defined as any time a recorded capillary PG level is ≤70 mg/dL, even if it is not associated with signs or symptoms, or treatment consistent with current guidelines (ADA 2005; ADA 2010). Severe hypoglycemia was defined as an episode associated with a recorded capillary (or venous) PG <40 mg/dL, even if it is not associated with need for assistance or neuroglycopenic symptoms (ADA 2005) or prompt recovery after oral carbohydrate, glucagon, or IV glucose. Due to low enrollment, this outcome measure was not analyzed.
• Number of Participants With Treatment-emergent Adverse Events Throughout Hospital Study Period [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: Yes ]
  Treatment-emergent adverse event - any untoward medical occurrence that either occurred or worsened at any time after treatment baseline and which did not necessarily have a causal relationship with this treatment. A summary of adverse events is located in the Reported Adverse Event Module.
• Percentage of Participants Requiring Intensive Care Unit Transfer [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
  Due to low enrollment, this outcome measure was not analyzed.
• Percentage of Participants With Deterioration of Renal Function Throughout the Hospital Study Period [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
  Deterioration of renal function was defined by an increase in serum creatinine by >0.5 milligrams per deciliter (mg/dL). Due to low enrollment, this outcome measure was not analyzed.
• Percentage of Participants With Documented Nosocomial Infections [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
  Due to low enrollment, this outcome measure was not analyzed.
• Number of Participants With Major Adverse Cardiovascular Events (MACE) [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
  MACE was defined as the composite of all-cause death, nonfatal myocardial infarction (MI), or nonfatal stroke. Due to low enrollment, this outcome measure was not analyzed.

• MPG by hospital day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
• Plasma Glucose measurements within range 71 to 179 mg/dL by hospital day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
• Percentage of patients achieving MPG within range 71 to 179 mg/dL and within the target of 100 to 179 mg/dL throughout hospital study period [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
• Percentage of patients achieving MPG within range 71 to 179 mg/dL and within the target of 100 to 179 mg/dL by hospital day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
• Mean FPG by hospital day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
• Mean FPG throughout hospital study period [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
• Percentage of fasting capillary PG measurements within the range of 71 to 139 mg/dL and within the target of 100 to 139 mg/dL throughout the hospital study period [ Time Frame: Throughout the hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
• Percentage of fasting capillary PG measurements within the range of 71 to 139 mg/dL and within the target of 100 to 139 mg/dL by hospital day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
• Percentage of patients achieving mean FPG range of 71 to 139 mg/dL and target of 100 to 139 mg/dL throughout the hospital study period [ Time Frame: Throughout the hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
• Percentage of patients achieving mean FPG range of 71 to 139 mg/dL and target of 100 to 139 mg/dL by hospital day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
• Percentage of capillary PG measurements >240 mg/dL throughout the hospital study period [ Time Frame: Throughout the hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
• Percentage of capillary PG measurements >240 mg/dL by hospital day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
• Total Daily Dose (TDD) of insulin (units) throughout the hospital study period [ Time Frame: Throughout the hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
• TDD of insulin (units/kg) throughout the hospital study period [ Time Frame: Throughout the hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
• TDD of insulin (units) by hospital day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
• TDD of insulin (units/kg) by hospital day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: No ]
• Length of hospital stay post-randomization throughout the hospital study period [ Time Frame: Throughout the hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
• Incidence of hypoglycemia and severe hypoglycemia episodes, throughout hospital study period [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: Yes ]
• Rate of hypoglycemia and severe hypoglycemia episodes, throughout hospital study period [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: Yes ]
• Incidence of hypoglycemia and severe hypoglycemia episodes, by hospital day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: Yes ]
• Rate of hypoglycemia and severe hypoglycemia episodes, by hospital day [ Time Frame: Day 1 up to day 10 of hospital study period ] [ Designated as safety issue: Yes ]
• Treatment-emergent adverse events throughout hospital study period [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: Yes ]
• Percentage of patients requiring intensive care unit transfer [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
• Percentage of patients with deterioration of renal function throughout the hospital study period [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
• Percentage of patients with documented nosocomial infections [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: No ]
• Major adverse cardiovascular events (MACE) [ Time Frame: Throughout hospital study period (1 to 10 days post-randomization) ] [ Designated as safety issue: Yes ]

The purpose of this study is to compare the use of insulin glargine plus insulin lispro to human regular insulin for treatment of hyperglycemia in the hospital setting in patients without known prior history of diabetes.

This study involves a comparison of 2 methods for administering subcutaneous insulin therapy to non-critically ill adult patients with hyperglycemia and without known history of diabetes who are admitted to non-intensive care unit (ICU) general medical hospital services. Basal-bolus therapy, considered the gold standard for glucose control in patients with known diabetes, will be compared with sliding scale insulin, a commonly used method of glucose control (prevailing standard practice) in hospitalized patients. In this study, basal-bolus therapy will consist of once-daily glargine plus lispro 3 to 4 times daily adjusted to achieve pre-meal capillary plasma glucose <140 milligrams per deciliter (mg/dL) and bedtime capillary plasma glucose <180 mg/dL for patients who are eating [predose plasma glucose <140 mg/dL for patients with nil per os (NPO) orders]; sliding scale insulin will be administered using human regular insulin 4 times daily as needed adjusted to achieve predose capillary plasma glucose target <140 mg/dL in patients who are eating or have NPO orders.

• Drug: Human regular insulin
  Administered subcutaneously, four times daily, according to sliding scale insulin algorithm throughout hospital study period (1 to 10 days post-randomization)
  Other Names:

  • Humulin R
  • LY041001
• Drug: Insulin lispro
  Administered subcutaneously, 3 to 4 times daily, according to plasma glucose levels throughout hospital study period (1 to 10 days post-randomization)
  Other Names:

  • Humalog
  • LY275585
• Drug: Insulin glargine
  Administered subcutaneously, once daily, according to plasma glucose levels throughout hospital study period (1 to 10 days post-randomization)
  Other Name: Lantus

• Active Comparator: Sliding scale regular insulin
  Intervention: Drug: Human regular insulin
• Experimental: Basal-bolus therapy
  Interventions:

  • Drug: Insulin lispro
  • Drug: Insulin glargine

• Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 2005 May;28(5):1245-9. Review. No abstract available.
• Moghissi ES, Korytkowski MT, DiNardo M, Einhorn D, Hellman R, Hirsch IB, Inzucchi SE, Ismail-Beigi F, Kirkman MS, Umpierrez GE; American Association of Clinical Endocrinologists; American Diabetes Association. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Endocr Pract. 2009 May-Jun;15(4):353-69.
• Umpierrez GE, Smiley D, Zisman A, Prieto LM, Palacio A, Ceron M, Puig A, Mejia R. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). Diabetes Care. 2007 Sep;30(9):2181-6. Epub 2007 May 18.
• Umpierrez GE, Hor T, Smiley D, Temponi A, Umpierrez D, Ceron M, Munoz C, Newton C, Peng L, Baldwin D. Comparison of inpatient insulin regimens with detemir plus aspart versus neutral protamine hagedorn plus regular in medical patients with type 2 diabetes. J Clin Endocrinol Metab. 2009 Feb;94(2):564-9. Epub 2008 Nov 18.

Major Inclusion Criteria:

• No known history of diabetes
• Admission or pre-entry plasma glucose (PG) level between 140 and 400 mg/dL
• Non-critically ill and admitted to acute care medical services
• Have a body mass index greater than or equal to 18.5 kg/m^2 and less than or equal to 45 kilograms per square meter (kg/m^2)

Major Exclusion Criteria:

• Received any insulin/analog therapy for longer than 108 hours prior to study entry or intermediate- or long-acting insulin/analogs (neutral protamine Hagedorn, detemir, or glargine) in the 24 hours prior to randomization or any intravenous insulin therapy prior to randomization
• Laboratory evidence of diabetic ketoacidosis for patients with pre-randomization PG greater than 250 mg/dL
• Have taken any oral or injectable antihyperglycemic medications other than insulin within 3 months prior to study entry
• Have acute critical illness or are expected to require admission to an ICU or equivalent or be treated with glucocorticoid therapy during the hospital study period
• Expected hospitalization less than 24 hours post-randomization