Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes (IONM)

Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes (HEART2D)

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).

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2; Acute Myocardial Infarction
• Intervention / Treatment: Drug: Insulin lispro; Drug: Human insulin isophane suspension (NPH); Drug: Insulin glargine; Drug: Human insulin isophane suspension; Drug: Human insulin 30/70

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
• Enrollment (Actual): 1116
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada
      • For additional information regarding investigative sites for this trial, please call 1-877-CTLILLY (1-877-285-4559, 1-317-651-4559), Monday-Friday, 9:00 AM to 5:00 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician
• Croatia
  • Zagreb, Croatia
    • For additional information regarding investigative sites for this trial, please call 1-877-CTLILLY (1-877-285-4559, 1-317-651-4559), Monday-Friday, 9:00 AM to 5:00 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician
• Czech Republic
  • Praha, Czech Republic
    • For additional information regarding investigative sites for this trial, please call 1-877-CTLILLY (1-877-285-4559, 1-317-651-4559), Monday-Friday, 9:00 AM to 5:00 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician
• Germany
  • Dresden, Germany
    • For additional information regarding investigative sites for this trial, please call 1-877-CTLILLY (1-877-285-4559, 1-317-651-4559), Monday-Friday, 9:00 AM to 5:00 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician
• Hungary
  • Budapest, Hungary
    • For additional information regarding investigative sites for this trial, please call 1-877-CTLILLY (1-877-285-4559, 1-317-651-4559), Monday-Friday, 9:00 AM to 5:00 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician
• India
  • New Delhi, India
    • For additional information regarding investigative sites for this trial, please call 1-877-CTLILLY (1-877-285-4559, 1-317-651-4559), Monday-Friday, 9:00 AM to 5:00 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician
• Israel
  • Jerusalem, Israel
    • For additional information regarding investigative sites for this trial, please call 1-877-CTLILLY (1-877-285-4559, 1-317-651-4559), Monday-Friday, 9:00 AM to 5:00 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician
• Lebanon
  • Beirut, Lebanon
    • For additional information regarding investigative sites for this trial, please call 1-877-CTLILLY (1-877-285-4559, 1-317-651-4559), Monday-Friday, 9:00 AM to 5:00 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician
• Poland
  • Warsaw, Poland
    • For additional information regarding investigative sites for this trial, please call 1-877-CTLILLY (1-877-285-4559, 1-317-651-4559), Monday-Friday, 9:00 AM to 5:00 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician
• Romania
  • Brasov, Romania
    • For additional information regarding investigative sites for this trial, please call 1-877-CTLILLY (1-877-285-4559, 1-317-651-4559), Monday-Friday, 9:00 AM to 5:00 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician
• Russian Federation
  • Saint Petersburg, Russian Federation
    • For additional information regarding investigative sites for this trial, please call 1-877-CTLILLY (1-877-285-4559, 1-317-651-4559), Monday-Friday, 9:00 AM to 5:00 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician
• Slovakia
  • Nitra, Slovakia
    • For additional information regarding investigative sites for this trial, please call 1-877-CTLILLY (1-877-285-4559, 1-317-651-4559), Monday-Friday, 9:00 AM to 5:00 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician
• Slovenia
  • Maribor, Slovenia
    • For additional information regarding investigative sites for this trial, please call 1-877-CTLILLY (1-877-285-4559, 1-317-651-4559), Monday-Friday, 9:00 AM to 5:00 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician
• South Africa
  • Parktown, South Africa
    • For additional information regarding investigative sites for this trial, please call 1-877-CTLILLY (1-877-285-4559, 1-317-651-4559), Monday-Friday, 9:00 AM to 5:00 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician
• Spain
  • Barcelona, Spain
    • For additional information regarding investigative sites for this trial, please call 1-877-CTLILLY (1-877-285-4559, 1-317-651-4559), Monday-Friday, 9:00 AM to 5:00 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician
• Turkey
  • Istanbul, Turkey
    • For additional information regarding investigative sites for this trial, please call 1-877-CTLILLY (1-877-285-4559, 1-317-651-4559), Monday-Friday, 9:00 AM to 5:00 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician
• United Kingdom
  • Liverpool, United Kingdom
    • For additional information regarding investigative sites for this trial, please call 1-877-CTLILLY (1-877-285-4559, 1-317-651-4559), Monday-Friday, 9:00 AM to 5:00 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Postprandial: Premeal insulin lispro +/- bedtime NPH	Drug: Insulin lispro; Patient adjusted dose, three times a day (TID), injected subcutaneous (SC) before each meal until patient completes study; Other Names: 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%
Active Comparator: 2; Fasting: NPH/insulin glargine or human insulin 30/70	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 Names: Human insulin 70/30 (in the United States)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced a Primary Combined Outcome	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.	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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced Death From Any Cause or Any One of the Primary Outcomes	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.	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)
Number of Participants Who Experienced Any One of the Primary Outcomes Adjusted for Indicators of Metabolic Control	Indicators of metabolic control included glycosylated hemoglobin (HbA1c) and fasting blood glucose concentrations.	Randomization (Day 0) until occurrence of primary outcome (18 month initial treatment period, extended treatment follow-up period up to 5.5 years)
Number of Participants Who Experienced Primary Outcomes Adjusted for Metabolic Control and Major Cardiovascular (CV) Risk Factors	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).	Randomization (Day 0) until occurrence of primary outcome (18 month initial treatment period, extended treatment follow-up period up to 5.5 years)
Number of Participants Who Experienced Death From Any Cause		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		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)	Occurrence of myocardial infarction (MI) (fatal, nonfatal, any).	Randomization (Day 0) until myocardial infarction (18 month initial treatment period, extended treatment follow-up period up to 5.5 years)
Number of Participants Who Experienced Stroke	Occurrence of stroke (fatal, nonfatal, any).	Randomization (Day 0) until stroke (18 month initial treatment period, extended treatment follow-up period up to 5.5 years)
Number of Participants Who Experienced Hospitalization for Acute Coronary Syndromes (HACS)		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	Occurrence of all coronary revascularization procedures (angioplasty or coronary artery by-pass surgery) planned after randomization.	Randomization (Day 0) until coronary revascularization procedures (18 month initial treatment period, extended treatment follow-up period up to 5.5 years)
Number of Participants Who Experienced Amputation for Peripheral Vascular Disease Planned After Randomization		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	Occurrence of congestive heart failure (newly diagnosed after Visit 2).	Randomization (Day 0) until congestive heart failure (18 month initial treatment period, extended treatment follow-up period up to 5.5 years)
Number of Participants Who Experienced Revascularization Procedure for Peripheral Vascular Disease Planned After Randomization		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		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	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).	Visit 3 (Month 1)
Number of Episodes of Self-Reported Hypoglycemia Reported by Participants With Self-Reported Hypoglycemia During 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).	Visit 3 (Month 1)
Number of Participants With Self-Reported Hypoglycemia During 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).	Visit 4 (Month 3)
Number of Episodes of Self-Reported Hypoglycemia Reported by Participants With Self-Reported Hypoglycemia During 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).	Visit 4 (Month 3)
Number of Participants With Self-Reported Hypoglycemia During 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).	Visit 5 (Month 6)
Number of Episodes of Self-Reported Hypoglycemia Reported by Participants With Self-Reported Hypoglycemia During 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).	Visit 5 (Month 6)
Number of Participants With Self-Reported Hypoglycemia During 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).	Visit 6 (Month 9)
Number of Episodes of Self-Reported Hypoglycemia Reported by Participants With Self-Reported Hypoglycemia During 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).	Visit 6 (Month 9)
Number of Participants With Self-Reported Hypoglycemia During 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).	Visit 7 (Month 12)
Number of Episodes of Self-Reported Hypoglycemia Reported by Participants With Self-Reported Hypoglycemia During 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).	Visit 7 (Month 12)
Number of Participants With Self-Reported Hypoglycemia During 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).	Visit 8 (Month 18)
Number of Episodes of Self-Reported Hypoglycemia Reported by Participants With Self-Reported Hypoglycemia During 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).	Visit 8 (Month 18)

Other Outcome Measures

Outcome Measure	Time Frame
Summary of Reasons for Deaths	Randomization (Day 0) to death (18 month initial treatment period, extended treatment follow-up period up to 5.5 years)

Collaborators and Investigators

• Sponsor: Eli Lilly and Company

Publications and helpful links

General 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.

Helpful Links

• Lilly Clinical Trial Registry

Study record dates

Study Major Dates

• Study Start: October 1, 2002
• Primary Completion (Actual): October 1, 2007
• Study Completion (Actual): October 1, 2007

Study Registration Dates

• First Submitted: September 12, 2005
• First Submitted That Met QC Criteria: September 12, 2005
• First Posted (Estimate): September 19, 2005

Study Record Updates

• Last Update Posted (Estimate): January 20, 2011
• Last Update Submitted That Met QC Criteria: January 18, 2011
• Last Verified: January 1, 2011

More Information

Terms related to this study

• Keywords: diabetes; MI; heart attack
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Myocardial Infarction; Hyperglycemia; Infarction; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc; Insulin Glargine; Insulin Lispro; Insulin, Isophane; Isophane Insulin, Human; Isophane insulin, beef
• Other Study ID Numbers: 5509; F3Z-MC-IONM (Other Identifier: Eli Lilly and Company)