Sitagliptin in Non-Diabetic Patients Undergoing General Surgery

Study Overview
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Brief Summary
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The purpose of this study is to compare sitagliptin with a placebo for the prevention of high glucose after general surgery.

Detailed Description
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Approximately 30-40% of hospitalized patients will develop stress hyperglycemia (high glucose in response to surgery or illness). High glucose is linked to an increased risk of hospital complications including 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. Recent studies have found that inpatient therapy with oral dipeptidyl peptidase-4 inhibitor (DPP4-I) is an effective alternative to insulin in improving glycemic control with low risk of hypoglycemia in general medicine and surgical patients. Sitagliptin is an oral medication approved by the Food and Drug Administration (FDA) to treat patients with diabetes. The aim of this study is to determine whether treatment with sitagliptin once daily can prevent the development of stress hyperglycemia during the postoperative period in non-diabetic patients undergoing general surgery.

Official Title
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Prevention of Stress Hyperglycemia With the Use of DPP-4 Inhibitors in Non-diabetic Patients Undergoing Non-cardiac Surgery, a Pilot Study

Conditions
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Hyperglycemia

Intervention / Treatment
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* Drug: Sitagliptin
* Drug: Placebo
* Drug: Supplemental insulin (insulin lispro)
* Drug: Supplemental insulin (insulin aspart)
* Drug: Long acting basal insulin (insulin detemir)
* Drug: Long acting basal insulin (insulin glargine)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Undergoing non-cardiac surgery No previous history of diabetes or hyperglycemia Fasting blood glucose level of <126 mg/dl Blood glucose <126mg/dl at the time of randomization (could occur at any time of the day) Exclusion Criteria: History of hyperglycemia (blood glucose equal to or above 126 mg/dl or HbA1C greater than 6.5%) or previous treatment with oral antidiabetic agents or insulin Patients undergoing cardiac surgery Patients anticipated to require ICU care following surgery Severely impaired renal function (GFR < 30 ml/min) or clinically significant hepatic failure Moribund patients and those at imminent risk of death (brain death or cardiac standstill) Patients with gastrointestinal obstruction or adynamic ileus or those expected to require gastrointestinal suction Patients with clinically relevant pancreatic or gallbladder disease Treatment with oral (> 5 mg/day) or injectable corticosteroid Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study Pregnancy or breast-feeding at time of enrollment

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 Arm<br>Participants will receive sitagliptin beginning the day prior to surgery and continuing daily during hospitalization (up to 10 days post-surgery). Point of care (POC) testing will be done four times daily, before meals and at bedtime, or every 6 hours for patients who are not eating (NPO). Patients developing hyperglycemia during or after surgery will be treated with insulin per standard of care. Patients with fasting and/or premeal blood glucose levels >180 mg/dl will receive supplemental insulin provided on a sliding scale. Patients with two consecutive fasting and/or premeal blood glucose levels >180 mg/dl, or with average daily blood glucose levels >180 mg/dl will be started on rescue therapy with subcutaneous insulin once daily plus correction doses by a sliding scale. | Drug: Sitagliptin<br>* Participants will take 100 mg/day for patients with glomerular filtration rate (GFR) > 50 and 50 mg/day for GFR 30 - 49, beginning on the day prior to surgery and continuing through hospitalization, up to 10 days.<br>* Other names: Januvia;Drug: Supplemental insulin (insulin lispro)<br>* Supplemental 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 blood glucose (BG) >240 mg/dL will be given. If a patient is unable to eat, supplemental insulin will be administered every 6 hours with the lowest number of units for that appropriate BG level. For subjects receiving supplemental insulin lispro with BG levels greater than 180 mg/dL, the 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>* Supplemental 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 blood glucose (BG) >240 mg/dL will be given. If a patient is unable to eat, supplemental insulin will be administered every 6 hours with the lowest number of units for that appropriate BG level. For subjects receiving supplemental insulin aspart with BG levels greater than 180 mg/dL, the 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: NovoLog;Drug: Long acting basal insulin (insulin detemir)<br>* Long acting basal insulin therapy will be provided as needed, and will be given once daily, at the same time of day. Participants with blood glucose (BG) >180 mg/dL= start detemir at 0.2 units per kg weight per day and will follow the following adjustment schedule: Fasting and pre-meal BG between 100-180 mg/dl without hypoglycemia the previous day: no change Fasting and pre-meal BG between >180-240 mg/dl: increase detemir or glargine dose by 10% every day Fasting and pre-meal BG >241 mg/dl: increase detemir or glargine dose by 20% every day Fasting and pre-meal BG <100 mg/dl: reduce detemir or glargine by 20% or stop if patient is already on less than 0.1 units/kg of body weight<br>* Other names: Levemir;Drug: Long acting basal insulin (insulin glargine)<br>* Long acting basal insulin therapy will be provided as needed, and will be given once daily, at the same time of day. Participants with blood glucose (BG) >180 mg/dL= start detemir at 0.2 units per kg weight per day and will follow the following adjustment schedule: Fasting and pre-meal BG between 100-180 mg/dl without hypoglycemia the previous day: no change Fasting and pre-meal BG between >180-240 mg/dl: increase detemir or glargine dose by 10% every day Fasting and pre-meal BG >241 mg/dl: increase detemir or glargine dose by 20% every day Fasting and pre-meal BG <100 mg/dl: reduce detemir or glargine by 20% or stop if patient is already on less than 0.1 units/kg of body weight<br>* Other names: Lantus;|
| Placebo Comparator: Placebo Arm<br>Participants will receive a placebo tablet beginning the day prior to surgery and continuing daily during hospitalization (up to 10 days post-surgery). Point of care (POC) testing will be done four times daily, before meals and at bedtime, or every 6 hours for patients who are not eating (NPO). Patients developing hyperglycemia during or after surgery will be treated with insulin per standard of care. Patients with fasting and/or premeal blood glucose levels >180 mg/dl will receive supplemental insulin provided on a sliding scale. Patients with two consecutive fasting and/or premeal blood glucose levels >180 mg/dl, or with average daily blood glucose levels >180 mg/dl will be started on rescue therapy with subcutaneous insulin once daily plus correction doses by a sliding scale. | Drug: Placebo<br>* Participants will take one pill daily beginning on the day prior to surgery and continuing through hospitalization, up to 10 days.<br>Drug: Supplemental insulin (insulin lispro)<br>* Supplemental 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 blood glucose (BG) >240 mg/dL will be given. If a patient is unable to eat, supplemental insulin will be administered every 6 hours with the lowest number of units for that appropriate BG level. For subjects receiving supplemental insulin lispro with BG levels greater than 180 mg/dL, the 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>* Supplemental 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 blood glucose (BG) >240 mg/dL will be given. If a patient is unable to eat, supplemental insulin will be administered every 6 hours with the lowest number of units for that appropriate BG level. For subjects receiving supplemental insulin aspart with BG levels greater than 180 mg/dL, the 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: NovoLog;Drug: Long acting basal insulin (insulin detemir)<br>* Long acting basal insulin therapy will be provided as needed, and will be given once daily, at the same time of day. Participants with blood glucose (BG) >180 mg/dL= start detemir at 0.2 units per kg weight per day and will follow the following adjustment schedule: Fasting and pre-meal BG between 100-180 mg/dl without hypoglycemia the previous day: no change Fasting and pre-meal BG between >180-240 mg/dl: increase detemir or glargine dose by 10% every day Fasting and pre-meal BG >241 mg/dl: increase detemir or glargine dose by 20% every day Fasting and pre-meal BG <100 mg/dl: reduce detemir or glargine by 20% or stop if patient is already on less than 0.1 units/kg of body weight<br>* Other names: Levemir;Drug: Long acting basal insulin (insulin glargine)<br>* Long acting basal insulin therapy will be provided as needed, and will be given once daily, at the same time of day. Participants with blood glucose (BG) >180 mg/dL= start detemir at 0.2 units per kg weight per day and will follow the following adjustment schedule: Fasting and pre-meal BG between 100-180 mg/dl without hypoglycemia the previous day: no change Fasting and pre-meal BG between >180-240 mg/dl: increase detemir or glargine dose by 10% every day Fasting and pre-meal BG >241 mg/dl: increase detemir or glargine dose by 20% every day Fasting and pre-meal BG <100 mg/dl: reduce detemir or glargine by 20% or stop if patient is already on less than 0.1 units/kg of body weight<br>* Other names: Lantus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Stress Hyperglycemia | The number of participants with at least one episode of stress hyperglycemia. Stress hyperglycemia is defined as a blood glucose > 180 mg/dL. | Up to time of discharge from hospital, an average of 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Requiring Supplemental, Subcutaneous Insulin | Number of patients requiring subcutaneous insulin, either sliding scale insulin or basal insulin | Up to time of discharge from hospital, an average of 10 days | 
| Total Daily Dose of Insulin for Patients Requiring Supplemental Insulin | Total daily dose of insulin for patients requiring supplemental insulin during surgery and recovery in participants receiving sitagliptin and those receiving the placebo | Up to time of discharge from hospital, an average of 10 days | 
| Length of Hospital Stay | Total length of hospital stay | Up to time of discharge from hospital, an average of 10 days | 
| Number of Participants With Hypoglycemic Events | Number of participants experiencing at least one episode of mild hypoglycemia (blood glucose < 70 mg/dL) or clinically significant hypoglycemia (blood glucose < 54 mg/dL) | Up to time of discharge from hospital, an average of 10 days | 
| Number of Patients Transferred to the ICU Immediately After Surgery or During Hospitalization | The number of patients who were transferred to the ICU immediately following surgery or anytime while hospitalized after surgery. | Up to time of discharge from hospital, an average of 10 days | 
| Number of Days in the ICU | The number of days a participant spent in the ICU following surgery, when transfer to the ICU was required. | Up to time of discharge from hospital, an average of 10 days | 
| Number of Participants With Hospital Readmissions After Discharge | Readmissions to the study hospital occurring within 30 days of hospital discharge were documented. There were no follow up phone calls or appointments with participants so any hospital readmissions to hospitals other than the one where the surgery occurred are not known. | Up to 40 days (average time of discharge from the hospital plus 30 days) | 
| Number of Participants With Emergency Room Visits After Discharge | Emergency room visits to the study hospital occurring within 30 days of hospital discharge were documented. There were no follow up phone calls or appointments with participants so any emergency room visits to hospitals other than the one where the surgery occurred are not known. | Up to 40 days (average time of discharge from the hospital plus 30 days) | 
| Number of Participants Experiencing Complications | The number of subjects who experience complications including: wound infection, respiratory failure, pneumonia, acute kidney injury with a rise in creatinine by 38 micromoles/Liter from baseline, major adverse cardiac events, bacterial septic infection, and death. Participants will be followed for 30 days following hospital discharge and all complications will be documented. | Up to 40 days (average time of discharge from the hospital plus 30 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stress hyperglycemia, blood glucose