Sitagliptin in Non-Diabetic Patients Undergoing Cardiac Surgery

Study Overview
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Brief Summary
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The purpose of this study is to compare sitagliptin and placebo for the prevention of high blood glucose during surgery.

Detailed Description
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About 80% of patients develop high glucose after cardiac surgery. High glucose is linked to an increased risk of hospital complications. High glucose increases the risk of wound infection, kidney failure and death. Patients with high glucose are treated with insulin given through an arm vein or by frequent insulin injections under the skin. This study will determine if sitagliptin can prevent the development of high glucose after heart surgery. Sitagliptin is a diabetes pill approved by the Food and Drug Administration (FDA) to treat patients with diabetes.

Official Title
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Sitagliptin for the Prevention and Treatment of Stress Hyperglycemia in Non-Diabetic Patients Undergoing Cardiac Surgery

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Drug: Sitagliptin
* Drug: Placebo
* Drug: Regular Human Insulin
* Drug: Insulin glargine
* Drug: Supplemental insulin (Insulin lispro)
* Drug: Supplemental insulin (Insulin aspart)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females between the ages of 18 and 80 years undergoing, cardiac surgery No previous history of diabetes No previous history of hyperglycemia Exclusion Criteria: Patients with hyperglycemia (blood glucose > 125 mg/dL); or glycated hemoglobin (HbA1c) > 6.5%; or previous treatment with oral antidiabetic agents or insulin Severely impaired renal function (serum creatinine ≥3.0 mg/dL or GFR < 30 mL/min) or clinically significant hepatic failure Moribund patients and those at imminent risk of death (brain death or cardiac standstill) Subjects with gastrointestinal (GI) obstruction or adynamic ileus or those expected to require GI suction Patients with clinically relevant pancreatic or gallbladder disease Treatment with oral or injectable corticosteroid Mental condition rendering the subject unable to understand the scope, and consequences of the study Female subjects who are pregnant or breast feeding at time of enrollment into the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sitagliptin<br>Subjects undergoing cardiac surgery with no history of diabetes and with normal blood glucose (BG) will be randomized to take sitagliptin. Subjects with stress hyperglycemia (defined as a BG >180 mg/dL) in the intensive care unit (ICU) will continue to receive sitagliptin and will be started on continuous intravenous insulin (Regular Human Insulin) adjusted to achieve and maintain a BG target between 110 - 180 mg/dL following standard hospital protocol. Additionally, once moved to the regular floors and out of ICU, the subjects can receive insulin glargine, insulin lispro, and/or insulin aspart depending on the blood glucose level. | Drug: Sitagliptin<br>* Subjects will take one pill daily until the day prior to them being discharged from the hospital. Sitagliptin will be dispensed orally at 100 mg/day and at a lower dose 50 mg for patients with glomerular filtration rate (GFR) < 30-50. If the calculated GFR drops to 30 mL/min/1.73m2 or below, patients will receive study medication 25mg daily<br>* Other names: Januvia;Drug: Regular Human Insulin<br>* Continuous intravenous insulin given to ICU patients with a BG > 180 mg/DL for two consecutive readings and will be started on Regular Human Insulin adjusted to achieve and maintain a BG target between 110 - 180 mg/dL following standard hospital protocol. Intravenous insulin infusion will be continued until the patient is able to eat and/or transferred to non-ICU service. In previous studies, average length of insulin infusion in patients with stress hyperglycemia was 16.9±19 hours and the amount of IV insulin requirement was 18.6±24.3 U/day.<br>* Other names: Novolin-R, Humulin-R;Drug: Insulin glargine<br>* When regular insulin is discontinued, if needed, insulin glargine will be given once daily. Patients who required continuous insulin infusion at an average rate >2U/h will be transitioned to basal (to be given approx. 4 hours prior to discontinuing the insulin drip) starting at a dose 0.2 U/Kg/d. Subjects with a BG at 140-200 mg/dL will start glargine at 0.2 U/kg weight per day. And subjects with BG between 201-400 mg/dL will start glargine at 0.2 U/Kg/day The basal insulin dose will be adjusted as follow: If fasting and pre-dinner BG is between 100 - 180 mg/dL in the absence of hypoglycemia the previous day: no change If fasting and pre-dinner BG is between 180 - 240 mg/dL in the absence of hypoglycemia: increase glargine by 10% every day If fasting and pre-dinner BG is > 241 mg/dL in the absence of hypoglycemia the previous day: increase glargine dose by 20% every day If fasting and pre-dinner BG is < 100 mg/dL in the absence of hypoglycemia: stop glargine<br>* Other names: Lantus (glargine);Drug: Supplemental insulin (Insulin lispro)<br>* Insulin lispro will be administered before meals in addition to scheduled insulin dose following the supplemental insulin scale protocol. At bedtime, half of supplemental sliding scale insulin starting at BG >240 mg/dL will be given. For the subjects receiving supplemental insulin lispro with BG levels greater than 180 mg/dL, then supplemental insulin scale is as follows: BG between 181-220 mg/dL; 2-4 units of insulin lispro BG between 221-260 mg/dL; 3-5 units of insulin lispro BG between 261-300 mg/dL; 4-6 units of insulin lispro BG between 301-350 mg/dL; 5-7 units of insulin lispro BG between 351-400 mg/dL; 6-8 units of insulin lispro BG > 400 mg/dL; 7-9 units of insulin lispro<br>* Other names: Humalog;Drug: Supplemental insulin (Insulin aspart)<br>* Insulin aspart will be administered before meals in addition to scheduled insulin dose following the supplemental insulin scale protocol. At bedtime, half of supplemental sliding scale insulin starting at BG >240 mg/dL will be given. For the subjects receiving supplemental insulin aspart with BG levels greater than 180 mg/dL, then supplemental insulin scale is as follows: BG between 181-220 mg/dL; 2-4 units of insulin aspart BG between 221-260 mg/dL; 3-5 units of insulin aspart BG between 261-300 mg/dL; 4-6 units of insulin aspart BG between 301-350 mg/dL; 5-7 units of insulin aspart BG between 351-400 mg/dL; 6-8 units of insulin aspart BG > 400 mg/dL; 7-9 units of insulin aspart<br>* Other names: Novolog;|
| Placebo Comparator: Placebo<br>Subjects undergoing cardiac surgery with no history of diabetes and with normal blood glucose (BG) will be randomized to take a placebo. Subjects with stress hyperglycemia (defined as a BG >180 mg/dL) in the intensive care unit (ICU) will continue to receive a placebo and will be started on continuous intravenous insulin (Regular Human Insulin) adjusted to achieve and maintain a BG target between 110 - 180 mg/dL following standard hospital protocol. Additionally, once moved to the regular floors and out of ICU, the subjects can receive insulin glargine, insulin lispro, and/or insulin aspart depending on the blood glucose level. | Drug: Placebo<br>* One pill daily until discharge<br>Drug: Regular Human Insulin<br>* Continuous intravenous insulin given to ICU patients with a BG > 180 mg/DL for two consecutive readings and will be started on Regular Human Insulin adjusted to achieve and maintain a BG target between 110 - 180 mg/dL following standard hospital protocol. Intravenous insulin infusion will be continued until the patient is able to eat and/or transferred to non-ICU service. In previous studies, average length of insulin infusion in patients with stress hyperglycemia was 16.9±19 hours and the amount of IV insulin requirement was 18.6±24.3 U/day.<br>* Other names: Novolin-R, Humulin-R;Drug: Insulin glargine<br>* When regular insulin is discontinued, if needed, insulin glargine will be given once daily. Patients who required continuous insulin infusion at an average rate >2U/h will be transitioned to basal (to be given approx. 4 hours prior to discontinuing the insulin drip) starting at a dose 0.2 U/Kg/d. Subjects with a BG at 140-200 mg/dL will start glargine at 0.2 U/kg weight per day. And subjects with BG between 201-400 mg/dL will start glargine at 0.2 U/Kg/day The basal insulin dose will be adjusted as follow: If fasting and pre-dinner BG is between 100 - 180 mg/dL in the absence of hypoglycemia the previous day: no change If fasting and pre-dinner BG is between 180 - 240 mg/dL in the absence of hypoglycemia: increase glargine by 10% every day If fasting and pre-dinner BG is > 241 mg/dL in the absence of hypoglycemia the previous day: increase glargine dose by 20% every day If fasting and pre-dinner BG is < 100 mg/dL in the absence of hypoglycemia: stop glargine<br>* Other names: Lantus (glargine);Drug: Supplemental insulin (Insulin lispro)<br>* Insulin lispro will be administered before meals in addition to scheduled insulin dose following the supplemental insulin scale protocol. At bedtime, half of supplemental sliding scale insulin starting at BG >240 mg/dL will be given. For the subjects receiving supplemental insulin lispro with BG levels greater than 180 mg/dL, then supplemental insulin scale is as follows: BG between 181-220 mg/dL; 2-4 units of insulin lispro BG between 221-260 mg/dL; 3-5 units of insulin lispro BG between 261-300 mg/dL; 4-6 units of insulin lispro BG between 301-350 mg/dL; 5-7 units of insulin lispro BG between 351-400 mg/dL; 6-8 units of insulin lispro BG > 400 mg/dL; 7-9 units of insulin lispro<br>* Other names: Humalog;Drug: Supplemental insulin (Insulin aspart)<br>* Insulin aspart will be administered before meals in addition to scheduled insulin dose following the supplemental insulin scale protocol. At bedtime, half of supplemental sliding scale insulin starting at BG >240 mg/dL will be given. For the subjects receiving supplemental insulin aspart with BG levels greater than 180 mg/dL, then supplemental insulin scale is as follows: BG between 181-220 mg/dL; 2-4 units of insulin aspart BG between 221-260 mg/dL; 3-5 units of insulin aspart BG between 261-300 mg/dL; 4-6 units of insulin aspart BG between 301-350 mg/dL; 5-7 units of insulin aspart BG between 351-400 mg/dL; 6-8 units of insulin aspart BG > 400 mg/dL; 7-9 units of insulin aspart<br>* Other names: Novolog;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Stress Hyperglycemic Events in the Intensive Care Unit (ICU) | Number of participants who developed stress hyperglycemia (BG >180 mg/dl) during coronary artery bypass grafting (CABG) or after CABG requiring continuous IV insulin infusion (CII) while in the ICU. | Post-Surgery (Up to 4 Days) | 
| Number of Subjects With Persistent Hyperglycemia | Number of subjects with persistent hyperglycemia (2 consecutive fasting and/or premeal BG > 180 mg/dL, or with average daily BG >180 mg/dl) who require insulin glargine (rescue therapy) after discontinuation of continuous intravenous insulin (CII) | Post-Surgery (Up to 10 Days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Need for Continuous Intravenous Insulin (CII) for Treatment of Hyperglycemia | Number of subjects with hyperglycemia (BG >180 mg/dL) who require CII in the ICU. | Post-Surgery (Up to 4 Days) | 
| Mean Daily Intensive Care Unit (ICU) Blood Glucose (BG) Concentration | The blood glucose levels will be assessed throughout the day using a glucose meter. An average will be calculated. The normal BG range for someone with diabetes is 80-130 mg/dL. | Post-Surgery (Up to 4 Days) | 
| Mean Amount of Insulin Therapy in the Intensive Care Unit (ICU) | The mean number of insulin infusions given per day (unit/day) while subjects are in the ICU. The more insulin given, the more hyperglycemic events experienced. | Post-Surgery (Up to 4 Days) | 
| Duration of Continuous Intravenous Insulin (CII) | Mean number of hours on continuous intravenous insulin (CII) after ICU discharge. | Post-Intensive Care Unit (ICU) Discharge (Up to 4 Days) | 
| Mean Units Subcutaneous (SQ) Insulin Required | Mean number of supplemental insulin units (lispro or aspart) administered after receiving insulin glargine (SQ insulin). | Post-Surgery (Up to 10 Days) | 
| Mean Blood Glucose (BG) Concentration After Transition From Intensive Care Unit (ICU) | The blood glucose levels will be assessed throughout the day using a glucose meter after transition form the ICU. The normal BG range for someone with diabetes is 80-130 mg/dL. | Post-Surgery (Up to 4 Days) | 
| Total Insulin Therapy in the Intensive Care Unit (ICU) | Total amount of insulin glargine insulin (units) administered in the ICU per day. | Post-Surgery (Up to 4 Days) | 
| Number of Participants With Severe Hyperglycemic Events During Continuous Insulin Infusion (CII) | Number of participants with two consecutive blood glucose concentrations >180 mg/dL in ICU during CII. | Post-Surgery (Up to 4 Days) | 
| Number of Participants With Hyperglycemia After Transition From Intensive Care Unit (ICU) | Number of participants with blood glucose (BG) >180 after transition from ICU. | Post-Surgery (Up to 10 Days) | 
| Number of Participants With Hypoglycemia During Intensive Care Unit (ICU) Stay | Number of participants with blood glucose (BG) <70 during ICU stay. | Post-Surgery (Up to 4 Days) | 
| Number of Participants With Hypoglycemia After Transition From Intensive Care Unit (ICU) | Number of participants with blood glucose (BG) <70 after transition from ICU. | Post-Surgery (Up to 4 Days) | 
| Number of Participants With Blood Glucose Less Than 40 mg/dl | Number of participants with blood glucose (BG) <40 throughout the duration of hospitalization. | Duration of Hospitalization (Up to 30 Days) | 
| Hospital Mortality Rate | The total number of subject deaths during hospital stay will be recorded. | Post-Surgery (Up to 10 Days) | 
| Intensive Care Unit (ICU) Mortality Rate | The total number of subject deaths during ICU stay will be recorded. | Post-Surgery (Up to 4 Days) | 
| Number of Participants With Cerebrovascular Events | Number of participants that experienced permanent stroke and reversible ischemic neurologic deficit events. | Post-Hospital Discharge (Up to 10 Days) | 
| Hospital Complication Rate | The total number of all complications experienced during hospitalization. Participants may experience more than one complication during hospitalization and these will be included in the hospital complication rate. | Duration of Hospitalization (Up to 30 days) | 
| Length of Stay: Intensive Care Unit (ICU) | Number of days in the ICU after coronary artery bypass graft surgery (CABG). | Post-Surgery (Up to 4 Days) | 
| Length of Hospital Stay After Study Randomization | Number of days in the hospital after a participant is randomized to a study intervention. | Post-Randomization (Up to 9 days) | 
| Number of Participants Re-admitted to the Hospital Due to Wound Infections | Number of subjects readmitted to the hospital within 30 days due to wound infection. | Post-Hospital Discharge (Up to 30 Days) | 
| Number of Participants Re-admitted to the Hospital Not Due to Wound Infections | Number of subjects readmitted to the hospital within 30 days for all causes excluding wound infection. | Post-Hospital Discharge (Up to 30 Days) | 
| Number of Participants With Emergency Room (ER) Visits | Number of subjects returning to the ER up to 30 days (all-cause) after hospital discharge. | Post-Hospital Discharge (Up to 30 Days) | 
| Number of Participants With Infections Not Requiring Hospital Re-admission | Number of subjects with infections not requiring hospital re-admission within 30 days after hospital discharge. | Post-Hospital Discharge (Up to 30 Days) | 
| Number of Subjects Requiring the Use of Inotropes for Greater Than 24 Hours | The number of subjects requiring the use of inotropes for >24 hours post CABG. | Post-Surgery (Up to 2 Days) | 
| Number of Subjects Requiring Re-intubation | The number of subjects requiring re-intubation after CABG. | Post-Surgery (Up to 2 Days) | 
| Number of Subjects Requiring Re-intubation Within 24 Hours | The number of subjects requiring re-intubation with 24 after CABG. | Post-Surgery (Up to 24 Hours) | 
| Number of Subject Requiring Surgical Re-Intervention | The number of subjects that require surgical re-intervention due to mediastinal exploration and post-operative hemorrhage. | Post-Surgery (Up to 10 Days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non diabetic hyperglycemia