Sitagliptin Therapy in Hospitalized Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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High blood glucose levels in hospitalized patients with diabetes are associated with increased risk of medical complications and death. Improved glucose control with insulin injections may improve clinical outcome and prevent some of the hospital complications. Glargine (Lantus®) insulin injection is the most common treatment of diabetes in the hospital. Sitagliptin (Januvia®)is effective in lowering blood glucose. In a recent pilot study aiming to determine differences in glycemic control between treatment with sitagliptin (Januvia®) alone or in combination with basal insulin and basal bolus regimen in general medicine and surgery patients with type 2 diabetes (T2D). The investigators found that treatment with sitagliptin alone or in combination with basal insulin resulted in similar glycemic control compared to basal bolus regimen. The investigators will conduct a prospective RCT aimed to determine the safety and efficacy of sitagliptin therapy for in-hospital and post-discharge management of general medicine and surgical patients with T2D. A total of 280 patients with known history of diabetes will be randomized to receive sitagliptin plus basal (glargine) insulin once daily (group 1), or basal bolus regimen with glargine once daily and aspart or lispro insulin before meals (group 2). If needed, patients in the treatment groups will receive correction doses of rapid-acting insulin in the presence of hyperglycemia (BG > 140 mg/dl). The overall hypothesis is that treatment with sitagliptin in combination with basal insulin in patients with type 2 diabetes will result in a similar improvement in hospital and post-discharge glycemic control and in a lower frequency of hypoglycemic events than treatment with basal bolus insulin regimen with glargine once daily and lispro insulin before meals. Patients will be recruited at Grady Memorial Hospital, Emory University Hospital, University of Michigan, Ohio State University and Temple University

Detailed Description
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Specific Aim 1: To determine whether in-hospital glycemic control, as measured by mean daily blood glucose concentration and frequency of hypoglycemic events, is different between treatment with sitagliptin (Januvia®) in combination with basal insulin (glargine) and basal bolus regimen (glargine and rapid-acting insulin analog) in general medicine and surgery patients with T2D. Patients with T2D treated with diet and/or OAD or with low total daily dose insulin therapy (≤0.6 unit/kg/day) will be randomized to receive sitagliptin plus glargine insulin (group 1) or basal bolus regimen with glargine once daily and rapid-acting insulin (lispro or aspart) before meals (group 2). If needed, patients in the 2 treatment groups will receive supplemental (correction) doses of rapid-acting insulin before meals for BG > 140 mg/dl. Specific Aim 2: To determine the efficacy and safety of an A1C based discharge algorithm in controlling BG after discharge in patients with T2D. Patients who participate in the in-hospital (Aim 1) arm will be invited to enroll in this open label prospective outpatient study. The total duration of the study is 6 months. Patients with HbA1c ≤ 7% will be discharged on the combination of metformin and sitagliptin (Janumet ®) twice daily. Those with HbA1c between 7% and 9% will be discharged on metformin and sitagliptin (Janumet ®) twice daily plus glargine insulin at 50% of the inpatient glargine dose. Those with HbA1c > 9% will be discharged on metformin and sitagliptin (Janumet ®) twice-daily plus glargine insulin at 80% of the inpatient dose.

Official Title
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Randomized Controlled Trial on the Safety and Efficacy of Sitagliptin Therapy for the Inpatient Management of General Medicine and Surgery Patients With Type 2 Diabetes

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Sitagliptin
* Drug: Basal Bolus
* Drug: Metformin and Sitagliptin
* Drug: Glargine
* Drug: Glargine 50%
* Drug: Glargine 80%


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 admitted to medicine and surgery services. A known history of Type 2 Diabetes > 1 month, receiving either diet alone, oral antidiabetic agents: sulfonylureas and metformin as monotherapy or in combination therapy (excluding DPP-4 inhibitors) or low-dose (≤ 0.6 units/kg/day) insulin therapy. Subjects with a blood glucose >140 mg and < 400 mg/dL at time of randomization without laboratory evidence of diabetic ketoacidosis (serum bicarbonate < 18 mEq/L or positive serum or urinary ketones). Exclusion Criteria: Age < 18 or > 80 years. Subjects with increased BG concentration, but without a history of diabetes (stress hyperglycemia). Subjects with a history of type 1 diabetes (suggested by BMI < 25 requiring insulin therapy or with a history of diabetic ketoacidosis and hyperosmolar hyperglycemic state, or ketonuria) [46]. Treatment with DPP4 inhibitor or Glucagon like peptide 1 (GLP1) analogs during the past 3 months prior to admission. Acute critical illness or coronary artery bypass graft (CABG) surgery expected to require admission to a critical care unit. Subjects with gastrointestinal obstruction or adynamic ileus or those expected to require gastrointestinal suction. Medical or surgical patients expected to be kept NPO for >24-48 hours after admission or after completion of surgical procedure. Patients with clinically relevant pancreatic or gallbladder disease. Patients with acute myocardial infarction, clinically significant hepatic disease or significantly impaired renal function (GFR < 30 ml/min). Treatment with oral or injectable corticosteroid = or > prednisone 5 mg/per day. Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study. Female subjects 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sitagliptin + glargine (Hospital)<br>Sitagliptin and glargine once daily + correction doses of aspart or lispro if needed | Drug: Sitagliptin<br>* Sitagliptin will be taken orally at 100 mg or 50 mg once a day per renal function.<br>* Other names: Januvia;Drug: Glargine<br>* Patients with blood glucose between 140-200 mg/dL during hospitalization will receive 0.2 units per kg weight per day. Patients with blood glucose between 201-400 mg/dL during hospitalization will receive 0.25 units per kg weight per day.<br>* Other names: Lantus;|
| Active Comparator: Basal bolus (Hospital)<br>Glargine once daily and rapid-acting insulin before meals + correction doses of aspart or lispro if needed | Drug: Basal Bolus<br>* Basal bolus regimen with glargine once daily and rapid-acting insulin (lispro or aspart) before meals + + correction doses of rapid acting insulin if needed<br>* Other names: Glargine (Lantus) + aspart (Novolog) or lispro (Humalog);|
| Experimental: Metformin and Sitagliptin<br>Patients with HbA1c ≤ 7% will be discharged on the combination of metformin and sitagliptin (Janumet ® 500/50 mg) twice daily for 6 months | Drug: Metformin and Sitagliptin<br>* Janumet is a combination of metformin and sitagliptin. Patients with HbA1c ≤ 7% will be discharged on the combination of metformin and sitagliptin (Janumet ® 500/50 mg) twice daily for 6 months.<br>* Other names: Janumet;|
| Experimental: Metformin and sitagliptin + glargine 50%<br>Patients with HbA1c between 7% and 9% will be discharged on metformin and sitagliptin (Janumet ® 500/50 mg) twice daily plus glargine insulin (50% of the inpatient glargine dose) for 6 months | Drug: Metformin and Sitagliptin<br>* Janumet is a combination of metformin and sitagliptin. Patients with HbA1c ≤ 7% will be discharged on the combination of metformin and sitagliptin (Janumet ® 500/50 mg) twice daily for 6 months.<br>* Other names: Janumet;Drug: Glargine 50%<br>* Glargine will be prescribed at 50% of daily hospital dose.<br>|
| Experimental: Metformin and sitagliptin + glargine 80%<br>Patients with HbA1c > 9% will be discharged on metformin and sitagliptin (Janumet ® 500/50 mg) twice daily plus glargine insulin (80% of the inpatient glargine dose) for 6 months | Drug: Metformin and Sitagliptin<br>* Janumet is a combination of metformin and sitagliptin. Patients with HbA1c ≤ 7% will be discharged on the combination of metformin and sitagliptin (Janumet ® 500/50 mg) twice daily for 6 months.<br>* Other names: Janumet;Drug: Glargine 80%<br>* Glargine will be prescribed at 80% of daily hospital dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Blood Glucose Concentration After First Day of Treatment | The average blood glucose (BG) concentration after the first day of treatment | Duration of Hospitalization (Up to 10 Days) | 
| Mean Percentage of Blood Glucose Readings Between 3.9 - 7.8 mmol/L | Differences in glycemic control as measured by mean daily blood glucose (BG) concentration between sitagliptin once daily and basal bolus therapy with glargine once daily plus supplemental lispro insulin in hospitalized patients with T2D. | Duration of Hospitalization (Up to 10 Days) | 
| Mean Percentage of Blood Glucose Readings Between 3.9 - 10.0 mmol/L | Differences in glycemic control as measured by mean daily blood glucose (BG) concentration between sitagliptin once daily and basal bolus therapy with glargine once daily plus supplemental lispro insulin in hospitalized patients with T2D. | Duration of Hospitalization (Up to 10 Days) | 
| Mean Percentage of Blood Glucose Readings Between 5.6 - 7.8 mmol/L | Differences in glycemic control as measured by mean daily blood glucose (BG) concentration between sitagliptin once daily and basal bolus therapy with glargine once daily plus supplemental lispro insulin in hospitalized patients with T2D. | Duration of Hospitalization (Up to 10 Days) | 
| Mean Percentage of Blood Glucose Readings Greater Than 13.3 mmol/L | Differences in glycemic control as measured by mean daily blood glucose (BG) concentration between sitagliptin once daily and basal bolus therapy with glargine once daily plus supplemental lispro insulin in hospitalized patients with T2D. | Duration of Hospitalization (Up to 10 Days) | 
| Change in HbA1C | The mean HbA1C measured at 3 months and 6 months post hospitalization. HbA1C is an indicator of diabetes control; below 6.0% is normal, 6.0% to 6.4% indicates prediabetes, and 6.5% or over indicates diabetes. | Post Hospital Discharge Month 3, Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Hypoglycemic Event | The number of participants who had a hypoglycemic event during hospitalization. | Duration of Hospitalization (Up to 10 Days) | 
| Total Daily Insulin Dose | Daily insulin requirement (units per day). | Duration of Hospitalization (Up to 10 Days) | 
| Length of Hospital Stay | Length of hospital stay in days. | Duration of Hospitalization (Up to 10 Days) | 
| Acute Renal Failure Rate | Acute renal failure is defined as a clinical diagnosis of acute renal failure with documented new-onset abnormal renal function (increment > 0.5 mg/dL from baseline). | Duration of Hospitalization (Up to 10 Days) | 
| Hospital Mortality Rate | Mortality is defined as death occurring during admission. | Duration of Hospitalization (Up to 10 Days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, DPP4 inhibitors, Sitagliptin, Glargine, RCT, basal insulin, hospital hyperglycemia, inpatient diabetes