Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes (IONM)

• ClinicalTrials.gov Identifier: NCT00191282
• Recruitment Status: Completed
• First Posted: September 19, 2005
• Results First Posted: August 4, 2009
• Last Update Posted: January 20, 2011
• Sponsor: Eli Lilly and Company
• Information provided by: Eli Lilly and Company

Tracking Information

• First Submitted Date: September 12, 2005
• First Posted Date: September 19, 2005
• Results First Submitted Date: October 17, 2008
• Results First Posted Date: August 4, 2009
• Last Update Posted Date: January 20, 2011
• Study Start Date: October 2002
• Actual Primary Completion Date: October 2007 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 19, 2009)

Number of Participants Who Experienced a Primary Combined Outcome [ Time Frame: Randomization (Day 0) until first occurrence of primary combined outcome (18 month initial treatment period, extended treatment follow-up period up to 5.5 years) ]

The combined study outcomes consisted of cardiovascular (CV) death, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for acute coronary syndromes (HACS), and coronary revascularization procedures planned after randomization.

Original Primary Outcome Measures (submitted: September 12, 2005)

• To demonstrate a difference between the two treatment strategies on the time until the occurrence of the first event from the combined study outcomes in patients with type 2 diabetes and acute MI.
• The combined study outcomes will consist of CV death, nonfatal MI, nonfatal stroke, hospitalization for acute coronary syndromes, and coronary revascularization procedures planned after randomization.

Current Secondary Outcome Measures (submitted: January 18, 2011)

• Number of Participants Who Experienced Death From Any Cause or Any One of the Primary Outcomes [ Time Frame: Randomization (Day 0) until death from any cause or one of the primary outcomes (18 month initial treatment period, extended treatment follow-up period up to 5.5 years) ]
  Primary outcomes in this study consisted of: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for acute coronary syndromes (HACS), and coronary revascularization procedure planned after randomization.
• Number of Participants Who Experienced Any One of the Primary Outcomes Adjusted for Indicators of Metabolic Control [ Time Frame: Randomization (Day 0) until occurrence of primary outcome (18 month initial treatment period, extended treatment follow-up period up to 5.5 years) ]
  Indicators of metabolic control included glycosylated hemoglobin (HbA1c) and fasting blood glucose concentrations.
• Number of Participants Who Experienced Primary Outcomes Adjusted for Metabolic Control and Major Cardiovascular (CV) Risk Factors [ Time Frame: Randomization (Day 0) until occurrence of primary outcome (18 month initial treatment period, extended treatment follow-up period up to 5.5 years) ]
  Primary outcomes adjusted for major cardiovascular (CV) risk factors (blood pressure, cholesterol [total, high density lipoprotein (HDL), and low density lipoprotein (LDL)], triglycerides, smoking, albuminuria, age, gender, and body mass index (BMI).
• Number of Participants Who Experienced Death From Any Cause [ Time Frame: Randomization (Day 0) until death from any cause (18 month initial treatment period, extended treatment follow-up period up to 5.5 years) ]
• Number of Participants Who Experienced Cardiovascular (CV) Death [ Time Frame: Randomization (Day 0) until cardiovascular death (18 month initial treatment period, extended treatment follow-up period up to 5.5 years) ]
• Number of Participants Who Experienced Myocardial Infarction (MI) [ Time Frame: Randomization (Day 0) until myocardial infarction (18 month initial treatment period, extended treatment follow-up period up to 5.5 years) ]
  Occurrence of myocardial infarction (MI) (fatal, nonfatal, any).
• Number of Participants Who Experienced Stroke [ Time Frame: Randomization (Day 0) until stroke (18 month initial treatment period, extended treatment follow-up period up to 5.5 years) ]
  Occurrence of stroke (fatal, nonfatal, any).
• Number of Participants Who Experienced Hospitalization for Acute Coronary Syndromes (HACS) [ Time Frame: Randomization (Day 0) until HACS (18 month initial treatment period, extended treatment follow-up period up to 5.5 years) ]
• Number of Participants Who Experienced Coronary Revascularization Procedures [ Time Frame: Randomization (Day 0) until coronary revascularization procedures (18 month initial treatment period, extended treatment follow-up period up to 5.5 years) ]
  Occurrence of all coronary revascularization procedures (angioplasty or coronary artery by-pass surgery) planned after randomization.
• Number of Participants Who Experienced Amputation for Peripheral Vascular Disease Planned After Randomization [ Time Frame: Randomization (Day 0) until amputation (18 month initial treatment period, extended treatment follow-up period up to 5.5 years) ]
• Number of Participants Who Experienced Congestive Heart Failure [ Time Frame: Randomization (Day 0) until congestive heart failure (18 month initial treatment period, extended treatment follow-up period up to 5.5 years) ]
  Occurrence of congestive heart failure (newly diagnosed after Visit 2).
• Number of Participants Who Experienced Revascularization Procedure for Peripheral Vascular Disease Planned After Randomization [ Time Frame: Randomization (Day 0) until revascularization procedure (18 month initial treatment period, extended treatment follow-up period up to 5.5 years) ]
• Number of Participants Who Experienced Coronary Angiography Planned After Randomization [ Time Frame: Randomization (Day 0) until coronary angiography (18 month initial treatment period, extended treatment follow-up period up to 5.5 years) ]
• Number of Participants With Self-Reported Hypoglycemia During Month 1 [ Time Frame: Visit 3 (Month 1) ]
  Hypoglycemia was defined as any time a patient feels, or another person observes, that the patient is experiencing a sign/symptom which he/she would associate with hypoglycemia (for example, tremors, headache, sweating, disorientation, weakness, etc) or a blood glucose measurement less than 3.5 mmol/L (63 mg/dL).
• Number of Episodes of Self-Reported Hypoglycemia Reported by Participants With Self-Reported Hypoglycemia During Month 1 [ Time Frame: Visit 3 (Month 1) ]
  Hypoglycemia was defined as any time a patient feels, or another person observes, that the patient is experiencing a sign/symptom which he/she would associate with hypoglycemia (for example, tremors, headache, sweating, disorientation, weakness, etc) or a blood glucose measurement less than 3.5 mmol/L (63 mg/dL).
• Number of Participants With Self-Reported Hypoglycemia During Month 3 [ Time Frame: Visit 4 (Month 3) ]
  Hypoglycemia was defined as any time a patient feels, or another person observes, that the patient is experiencing a sign/symptom which he/she would associate with hypoglycemia (for example, tremors, headache, sweating, disorientation, weakness, etc) or a blood glucose measurement less than 3.5 mmol/L (63 mg/dL).
• Number of Episodes of Self-Reported Hypoglycemia Reported by Participants With Self-Reported Hypoglycemia During Month 3 [ Time Frame: Visit 4 (Month 3) ]
  Hypoglycemia was defined as any time a patient feels, or another person observes, that the patient is experiencing a sign/symptom which he/she would associate with hypoglycemia (for example, tremors, headache, sweating, disorientation, weakness, etc) or a blood glucose measurement less than 3.5 mmol/L (63 mg/dL).
• Number of Participants With Self-Reported Hypoglycemia During Month 6 [ Time Frame: Visit 5 (Month 6) ]
  Hypoglycemia was defined as any time a patient feels, or another person observes, that the patient is experiencing a sign/symptom which he/she would associate with hypoglycemia (for example, tremors, headache, sweating, disorientation, weakness, etc) or a blood glucose measurement less than 3.5 mmol/L (63 mg/dL).
• Number of Episodes of Self-Reported Hypoglycemia Reported by Participants With Self-Reported Hypoglycemia During Month 6 [ Time Frame: Visit 5 (Month 6) ]
  Hypoglycemia was defined as any time a patient feels, or another person observes, that the patient is experiencing a sign/symptom which he/she would associate with hypoglycemia (for example, tremors, headache, sweating, disorientation, weakness, etc) or a blood glucose measurement less than 3.5 mmol/L (63 mg/dL).
• Number of Participants With Self-Reported Hypoglycemia During Month 9 [ Time Frame: Visit 6 (Month 9) ]
  Hypoglycemia was defined as any time a patient feels, or another person observes, that the patient is experiencing a sign/symptom which he/she would associate with hypoglycemia (for example, tremors, headache, sweating, disorientation, weakness, etc) or a blood glucose measurement less than 3.5 mmol/L (63 mg/dL).
• Number of Episodes of Self-Reported Hypoglycemia Reported by Participants With Self-Reported Hypoglycemia During Month 9 [ Time Frame: Visit 6 (Month 9) ]
  Hypoglycemia was defined as any time a patient feels, or another person observes, that the patient is experiencing a sign/symptom which he/she would associate with hypoglycemia (for example, tremors, headache, sweating, disorientation, weakness, etc) or a blood glucose measurement less than 3.5 mmol/L (63 mg/dL).
• Number of Participants With Self-Reported Hypoglycemia During Month 12 [ Time Frame: Visit 7 (Month 12) ]
  Hypoglycemia was defined as any time a patient feels, or another person observes, that the patient is experiencing a sign/symptom which he/she would associate with hypoglycemia (for example, tremors, headache, sweating, disorientation, weakness, etc) or a blood glucose measurement less than 3.5 mmol/L (63 mg/dL).
• Number of Episodes of Self-Reported Hypoglycemia Reported by Participants With Self-Reported Hypoglycemia During Month 12 [ Time Frame: Visit 7 (Month 12) ]
  Hypoglycemia was defined as any time a patient feels, or another person observes, that the patient is experiencing a sign/symptom which he/she would associate with hypoglycemia (for example, tremors, headache, sweating, disorientation, weakness, etc) or a blood glucose measurement less than 3.5 mmol/L (63 mg/dL).
• Number of Participants With Self-Reported Hypoglycemia During Month 18 [ Time Frame: Visit 8 (Month 18) ]
  Hypoglycemia was defined as any time a patient feels, or another person observes, that the patient is experiencing a sign/symptom which he/she would associate with hypoglycemia (for example, tremors, headache, sweating, disorientation, weakness, etc) or a blood glucose measurement less than 3.5 mmol/L (63 mg/dL).
• Number of Episodes of Self-Reported Hypoglycemia Reported by Participants With Self-Reported Hypoglycemia During Month 18 [ Time Frame: Visit 8 (Month 18) ]
  Hypoglycemia was defined as any time a patient feels, or another person observes, that the patient is experiencing a sign/symptom which he/she would associate with hypoglycemia (for example, tremors, headache, sweating, disorientation, weakness, etc) or a blood glucose measurement less than 3.5 mmol/L (63 mg/dL).

Original Secondary Outcome Measures (submitted: September 12, 2005)

• Assess the effect of the two treatment strategies on:
• a) the time until the first to occur of one of the following:death from any cause or any one of the primary outcomes
• b) the time until the first to occur of any one of the primary outcomes adjusted for other indicators of metabolic control
• c) the time for the first to occur of any one of the primary outcomes adjusted for major CV risk factors
• d) the time to occurrence for each of the following individual outcomes:
• 1) death from any cause
• 2) CV death
• 3) MI
• 4) stroke
• 5) HACS
• 6) all coronary revascularization procedures
• 7) amputation or revascularization procedures
• 8) congestive heart failure
• 9) the time to coronary angiography
• 10) the incidence and rate of self-reported hypoglycemia

• Current Other Pre-specified Outcome Measures (submitted: June 19, 2009): Summary of Reasons for Deaths [ Time Frame: Randomization (Day 0) to death (18 month initial treatment period, extended treatment follow-up period up to 5.5 years) ]
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
• Official Title: Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes (HEART2D)
• Brief Summary: The primary objective was to demonstrate a difference between two insulin strategies, one targeting postprandial (PP) hyperglycemia and the other targeting fasting and interprandial hyperglycemia, on time until the first combined adjudicated cardiovascular (CV) event (primary outcome defined as CV death, nonfatal myocardial infarction [MI], nonfatal stroke, coronary revascularization, or hospitalized acute coronary syndrome).
• Detailed Description: The purpose of this study is to evaluate the effect of two different treatment strategies on CV outcomes in patients with type 2 diabetes while aiming to achieve and maintain HbA1c <7.0% in both groups. Only patients who have recently experienced an acute MI will be considered for participation in this trial.
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Diabetes Mellitus, Type 2
• Acute Myocardial Infarction

Intervention

• Drug: Insulin lispro
  Patient adjusted dose, three times a day (TID), injected subcutaneous (SC) before each meal until patient completes study
  Other Name: Humalog
• Drug: Human insulin isophane suspension (NPH)
  Patient adjusted dose, daily at bedtime, injected subcutaneous (SC) until patient completes study. To be added to the arm only if patient has two consecutive HbA1c values >8.0%
• Drug: Insulin glargine
  Insulin glargine injected subcutaneous (SC) once daily in the evening until patient completes study.
• Drug: Human insulin isophane suspension
  Patient adjusted dose, twice daily, injected subcutaneous (SC) before morning and evening meals until patient completes study.
• Drug: Human insulin 30/70
  Patient adjusted dose, twice daily before the morning and evening meals, injected subcutaneous (SC) until patient completes study. To replace insulin regimen in this arm only if patient has two consecutive HbA1c values >8.0%.
  Other Name: Human insulin 70/30 (in the United States)

Study Arms

• Experimental: 1
  Postprandial: Premeal insulin lispro +/- bedtime NPH
  Interventions:

  • Drug: Insulin lispro
  • Drug: Human insulin isophane suspension (NPH)
• Active Comparator: 2
  Fasting: NPH/insulin glargine or human insulin 30/70
  Interventions:

  • Drug: Insulin glargine
  • Drug: Human insulin isophane suspension
  • Drug: Human insulin 30/70

Publications *

• Raz I, Wilson PW, Strojek K, Kowalska I, Bozikov V, Gitt AK, Jermendy G, Campaigne BN, Kerr L, Milicevic Z, Jacober SJ. Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: the HEART2D trial. Diabetes Care. 2009 Mar;32(3):381-6. doi: 10.2337/dc08-1671.
• Milicevic Z, Raz I, Beattie SD, Campaigne BN, Sarwat S, Gromniak E, Kowalska I, Galic E, Tan M, Hanefeld M. Natural history of cardiovascular disease in patients with diabetes: role of hyperglycemia. Diabetes Care. 2008 Feb;31 Suppl 2:S155-60. doi: 10.2337/dc08-s240.
• Milicevic Z, Raz I, Strojek K, Skrha J, Tan MH, Wyatt JW, Beattie SD, Robbins DC; HEART2D Study. Hyperglycemia and its effect after acute myocardial infarction on cardiovascular outcomes in patients with Type 2 diabetes mellitus (HEART2D) Study design. J Diabetes Complications. 2005 Mar-Apr;19(2):80-7. doi: 10.1016/j.jdiacomp.2004.06.003.
• Raz I, Ceriello A, Wilson PW, Battioui C, Su EW, Kerr L, Jones CA, Milicevic Z, Jacober SJ. Post hoc subgroup analysis of the HEART2D trial demonstrates lower cardiovascular risk in older patients targeting postprandial versus fasting/premeal glycemia. Diabetes Care. 2011 Jul;34(7):1511-3. doi: 10.2337/dc10-2375. Epub 2011 May 18.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 19, 2009): 1116
• Original Enrollment (submitted: September 12, 2005): 1355
• Actual Study Completion Date: October 2007
• Actual Primary Completion Date: October 2007 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Are at least 30 years old
• Have had type 2 diabetes for at least 3 months prior to Visit 1
• Were admitted to the Coronary Care Unit (CCU) within 18 days prior to Visit 1 for an acute MI
• Are capable and willing to do specified study procedures
• Have given informed consent to participate in the study in accordance with local regulations

Exclusion Criteria:

• Were on one of the following therapies prior to admission to the CCU for the recent MI: a)diet therapy only and have glycosylated hemoglobin (HbA1c) <1.15 times the upper limit of normal or b) an intensive basal/bolus insulin regimen
• Are using any oral antihyperglycemic medication at the time of Visit 2 and are unwilling to stop the use of such medication for the duration of the study
• Have substantial myocardial damage, which would significantly outweigh the potential benefit of the treatment strategies for diabetes
• Have the most severe form of congestive heart failure
• Have liver disease so severe that it precludes the patient from following and completing the protocol

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 30 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Croatia, Czech Republic, Germany, Hungary, India, Israel, Lebanon, Poland, Romania, Russian Federation, Slovakia, Slovenia, South Africa, Spain, Turkey, United Kingdom

Administrative Information

• NCT Number: NCT00191282
• Other Study ID Numbers: 5509; F3Z-MC-IONM ( Other Identifier: Eli Lilly and Company )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Chief Medical Officer, Eli Lilly
• Original Responsible Party: Not Provided
• Current Study Sponsor: Eli Lilly and Company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon-Fri 9am-5pm Eastern time (UTC/GMT - 5 hours, EST); Eli Lilly and Company

• PRS Account: Eli Lilly and Company
• Verification Date: January 2011