Type 2 Diabetes
Conditions
Keywords
Diabetes, Linagliptin, hospital hyperglycemia, inpatient diabetes
Brief summary
This study is a prospective, randomized, open label trial to compare the safety and efficacy of linagliptin (an oral anti diabetic medication) given orally once daily to an insulin regimen of glargine once daily plus rapid-acting insulin before meals. Both of these treatment groups will be given corrective doses of rapid-acting insulin analogs (aspart, lispro or glulisine) before meals if their blood sugars are \> 140 mg/dl. The patients will be monitored for their blood sugars while the hospital. If patients are agreeable to participate in the discharge part of the study, the investigators will randomized them to a treatment group based on their admission HbA1c. The investigators will follow these patients for 3 months with phone calls and clinic visits, and will monitor their blood sugars. This is to compare the efficacy of linagliptin and our discharge treatment algorithm in controlling blood sugars as out patients.
Detailed description
Specific Aim 1: To determine whether in-hospital glycemic control, as measured by mean daily glucose concentration and frequency of hypoglycemic events, is different between treatment with linagliptin (Tradjenta®) plus correction doses with a rapid-acting insulin analog before meals and a basal bolus regimen with glargine once daily and rapid-acting insulin analog before meals in general surgery patients with T2D. 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 arm (Aim 1) will be invited to enroll in this open label prospective outpatient study. The total duration of the study is 3 months.
Interventions
DRUGLinagliptin
Linagliptin once daily + correction doses of rapid acting insulin if needed
DRUGBasal Bolus
Basal bolus regimen with glargine once daily and rapid-acting insulin (lispro or aspart) before meals + + correction doses of rapid acting insulin if needed
DRUGLinagliptin + 50% Glargine dose on discharge
Patients with admission HbA1c between 7% and 9% will be discharged on previous oral anti-diabetic agents plus linagliptin, and consider glargine insulin at 50% of daily hospital dose for 3 months.
DRUGLinagliptin + 80% Glargine
Patients with admission HbA1c ≥ 9% will be discharged on previous oral anti-diabetic agents plus linagliptin, and consider glargine insulin at 80% of daily hospital dose for 3 months.
Sponsors
Boston Medical Center
Rush University
University of Denver
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Males or female surgical non-ICU patients ages between18 and 80 years 2. A known history of T2D \> 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 (≤ 0.5 units/kg/day) insulin therapy. 3. Subjects with a BG \>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
1. Age \< 18 or \> 80 years. 2. Subjects with increased BG concentration, but without a history of diabetes (stress hyperglycemia). 3. 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) (43). 4. Treatment with dipeptidyl peptidase-4 (DPP4) inhibitor or Glucagon-like peptide-1 (GLP1) analogs during the past 3 months prior to admission. 5. Acute critical illness or coronary artery bypass graft (CABG) surgery expected to require admission to a critical care unit. 6. Subjects with gastrointestinal obstruction or adynamic ileus or those expected to require gastrointestinal suction. 7. Patients with clinically relevant pancreatic or gallbladder disease. 8. Patients with previous history of pancreatitis 9. Patients with acute myocardial infarction, clinically significant hepatic disease or significantly impaired renal function (GFR \< 30 ml/min). 10. Chronic use of steroid with total daily dose (prednisone equivalent) \>5 mg/day 11. Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study. 12. Pregnancy or breast feeding at time of enrollment into the study. 13. Patients who received supplemental sliding scale insulin \>72 hours prior to randomization 14. Patients who received basal insulin \> 48 hours prior to randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Differences in Glycemic Control | Inpatient (average 5 days) and outpatient up to 12 weeks | Determine differences in glycemic control as measured by mean daily BG concentration between linagliptin alone and basal bolus therapy group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hyperglycemia | Inpatient (average 5 days) and outpatient up to 12 weeks | Subjects with BG \> 300 mg/dl |
| Daily Dose of Insulin | Inpatient (average 5 days) and outpatient up to 12 weeks | Total daily dose of insulin |
| Length of Hospital Stay | During Hospitalization | Length of hospital stay (ONLY for inpatient arms 1 and 2) |
| Number of Participants Requiring ICU Care During Hospitalization | During Hospitalization-average 5 days | Need for intensive care unit (ICU) care (transfer to ICU) during hospitalization |
| Hospital Complications | During Hospitalization-average 5 days | Subjects with composite complication (ONLY for inpatient arms 1 and 2) |
| Acute Renal Failure During Hospitalization | During Hospitalization-average 5 days | Subjects with Acute renal failure (ONLY for inpatient arms 1 and 2) |
| Hospital Mortality | During Hospitalization-average 5 days | Hospital mortality (ONLY in-patient). Mortality is defined as death occurring during hospital stay. |
| Hypoglycemia <70 mg/dl | Inpatient (average 5 days) and outpatient up to 12 weeks | Subjects with Hypoglycemia \<70 mg/dl |
| Subjects With Wound and Other Infections | During Hospitalization and outpatient up to 12 weeks | Subjects with wound and other infections. |
| HbA1c Level | Admission to the hospital and 12-week follow-up outpatient visit | HbA1c level at admission (for in-patient arms) and HbA1c level at 12-week follow-up outpatient visit (for discharge arms). |
| Hypoglycemia < 40 mg/dl | Inpatient and up to 12 weeks outpatient | Subjects with Hypoglycemia \< 40 mg/dl |
| Emergency Room Visits | 3 months after discharge | Number of ER visits ONLY for outpatient arms 3,4, and 5. |
| Subjects With Surgical Reinterventions | Inpatient and up to 12 weeks outpatient | Subjects with surgical re-interventions. |
| Outpatient Mortality | 3 months after discharge | Deaths among patients after hospital discharge. |
| Fasting BG Concentration | During Hospitalization (average 5 days) and outpatient up to 12 weeks | Average - per hospital stay - fasting BG concentration (for in-hospital groups), and average - per outpatient follow-up period - fasting BG concentration (for discharge groups) |
Countries
United States
Participant flow
Recruitment details
Participants were recruited between February 2014 and October 2016. Patients who participated in the in-hospital study period were invited to enroll in the prospective outpatient study. Of 250 in-patient participants, 224 accepted enrollment into outpatient study.
Pre-assignment details
Of the 295 subjects consented, there were 15 screen failures. 30 (out of remaining 280 patients) were excluded from participation: 11 patients stayed \<24 hours, 1 patient received corticosteroids, and 18 patients didn't receive medication. Therefore, 250 patients started the study.
Participants by arm
| Arm | Count |
|---|---|
| Linagliptin In-hospital Linagliptin once daily+ correction doses of aspart or lispro if needed
Linagliptin: Linagliptin once daily + correction doses of rapid acting insulin if needed | 128 |
| Basal Bolus In-hospital Glargine once daily and rapid-acting insulin before meals + correction doses of aspart or lispro if needed
Basal Bolus: Basal bolus regimen with glargine once daily and rapid-acting insulin (lispro or aspart) before meals + + correction doses of rapid acting insulin if needed | 122 |
| Linagliptin on Discharge Patients with admission A1C \< 7% will be discharged on same pharmacologic regimen (oral agents, insulin therapy) or linagliptin 5 mg/day. If contraindication to oral anti-diabetics (OAD), discharge patient on linagliptin once daily.
Linagliptin: Patients with admission A1C \< 7% will be discharged on same pharmacologic regimen (oral agents, insulin therapy) or linagliptin 5 mg/day for 3 months. | 92 |
| Linagliptin+50%Glargine Dose on d/c Patients with admission HbA1c between 7% and 9% will be discharged on previous oral anti-diabetic agents plus linagliptin, and consider glargine insulin at 50% of daily hospital dose. Patient who did not receive glargine in the hospital, discharge on previous OAD + linagliptin once daily, and consider starting glargine at 0.15 unit/kg/day.
Linagliptin + 50% Glargine dose on discharge: Patients with admission HbA1c between 7% and 9% will be discharged on previous oral anti-diabetic agents plus linagliptin, and consider glargine insulin at 50% of daily hospital dose for 3 months. | 93 |
| Linagliptin+80%Glargine Dose on d/c Patients with admission HbA1c ≥ 9% will be discharged on previous oral anti-diabetic agents plus linagliptin, and consider glargine insulin at 80% of daily hospital dose. Patient who did not receive glargine in the hospital, discharge on previous OAD + linagliptin once daily, and consider starting glargine at 0.15 unit/kg/day.
Linagliptin + 80% Glargine: Patients with admission HbA1c ≥ 9% will be discharged on previous oral anti-diabetic agents plus linagliptin, and consider glargine insulin at 80% of daily hospital dose for 3 months. | 39 |
| Total | 474 |
Baseline characteristics
| Characteristic | Linagliptin+80%Glargine Dose on d/c | Total | Linagliptin In-hospital | Basal Bolus In-hospital | Linagliptin on Discharge | Linagliptin+50%Glargine Dose on d/c |
|---|---|---|---|---|---|---|
| Age, Continuous Discharge | 50.7 years STANDARD_DEVIATION 11.5 | 56.7 years STANDARD_DEVIATION 11.3 | NA years | NA years | 58.8 years STANDARD_DEVIATION 10 | 57.1 years STANDARD_DEVIATION 11.7 |
| Age, Continuous In-hospital | NA years | 57.8 years STANDARD_DEVIATION 11.3 | 58 years STANDARD_DEVIATION 11 | 58 years STANDARD_DEVIATION 12 | NA years | NA years |
| Race/Ethnicity, Customized Discharge Black | 23 Participants | 111 Participants | 0 Participants | 0 Participants | 42 Participants | 46 Participants |
| Race/Ethnicity, Customized Discharge Hispanic | 5 Participants | 28 Participants | 0 Participants | 0 Participants | 13 Participants | 10 Participants |
| Race/Ethnicity, Customized Discharge Other | 4 Participants | 7 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Discharge White | 6 Participants | 75 Participants | 0 Participants | 0 Participants | 36 Participants | 33 Participants |
| Race/Ethnicity, Customized In-hospital Black | 0 Participants | 117 Participants | 59 Participants | 58 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized In-hospital Hispanic | 0 Participants | 33 Participants | 21 Participants | 12 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized In-hospital Other | 0 Participants | 10 Participants | 4 Participants | 6 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized In-hospital White | 0 Participants | 90 Participants | 44 Participants | 46 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States Discharged | 39 Participants | 224 Participants | 0 Participants | 0 Participants | 92 Participants | 93 Participants |
| Region of Enrollment United States In-hospital | 0 Participants | 250 Participants | 128 Participants | 122 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Discharge Female | 7 Participants | NA Participants | NA Participants | NA Participants | 54 Participants | 49 Participants |
| Sex: Female, Male Discharge Male | 32 Participants | NA Participants | NA Participants | NA Participants | 38 Participants | 44 Participants |
| Sex: Female, Male In-hospital Female | NA Participants | NA Participants | 66 Participants | 58 Participants | NA Participants | NA Participants |
| Sex: Female, Male In-hospital Male | NA Participants | NA Participants | 62 Participants | 64 Participants | NA Participants | NA Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 128 | 0 / 122 | 0 / 92 | 0 / 93 | 0 / 39 |
| other Total, other adverse events | 25 / 128 | 15 / 122 | 3 / 92 | 1 / 93 | 0 / 39 |
| serious Total, serious adverse events | 1 / 128 | 0 / 122 | 12 / 92 | 14 / 93 | 9 / 39 |
Outcome results
Primary
Differences in Glycemic Control
Determine differences in glycemic control as measured by mean daily BG concentration between linagliptin alone and basal bolus therapy group.
Time frame: Inpatient (average 5 days) and outpatient up to 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Linagliptin In-hospital | Differences in Glycemic Control | 171 mg/dl | Standard Deviation 47 |
| Basal Bolus In-hospital | Differences in Glycemic Control | 159 mg/dl | Standard Deviation 41 |
| Linagliptin on Discharge | Differences in Glycemic Control | 126 mg/dl | Standard Deviation 22 |
| Linagliptin+50%Glargine Dose on d/c | Differences in Glycemic Control | 132 mg/dl | Standard Deviation 28 |
| Linagliptin+80%Glargine Dose on d/c | Differences in Glycemic Control | 142 mg/dl | Standard Deviation 24 |
Secondary
Acute Renal Failure During Hospitalization
Subjects with Acute renal failure (ONLY for inpatient arms 1 and 2)
Time frame: During Hospitalization-average 5 days
Population: Acute renal failure during hospitalization is applicable ONLY for inpatient arms (1 and 2)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Linagliptin In-hospital | Acute Renal Failure During Hospitalization | 6 Participants |
| Basal Bolus In-hospital | Acute Renal Failure During Hospitalization | 4 Participants |
Secondary
Daily Dose of Insulin
Total daily dose of insulin
Time frame: Inpatient (average 5 days) and outpatient up to 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Linagliptin In-hospital | Daily Dose of Insulin | 0.09 units/kg/day | Standard Deviation 0.17 |
| Basal Bolus In-hospital | Daily Dose of Insulin | 0.31 units/kg/day | Standard Deviation 0.15 |
| Linagliptin on Discharge | Daily Dose of Insulin | 0.23 units/kg/day | Standard Deviation 0.1 |
| Linagliptin+50%Glargine Dose on d/c | Daily Dose of Insulin | 0.18 units/kg/day | Standard Deviation 0.1 |
| Linagliptin+80%Glargine Dose on d/c | Daily Dose of Insulin | 0.24 units/kg/day | Standard Deviation 0.1 |
Secondary
Emergency Room Visits
Number of ER visits ONLY for outpatient arms 3,4, and 5.
Time frame: 3 months after discharge
Population: Emergency visits reported only for outpatient time. Inpatient (hospital) patients cannot have ER visits
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Linagliptin on Discharge | Emergency Room Visits | 11 Visits |
| Linagliptin+50%Glargine Dose on d/c | Emergency Room Visits | 11 Visits |
| Linagliptin+80%Glargine Dose on d/c | Emergency Room Visits | 9 Visits |
Secondary
Fasting BG Concentration
Average - per hospital stay - fasting BG concentration (for in-hospital groups), and average - per outpatient follow-up period - fasting BG concentration (for discharge groups)
Time frame: During Hospitalization (average 5 days) and outpatient up to 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Linagliptin In-hospital | Fasting BG Concentration | 160 mg/dl | Standard Deviation 44 |
| Basal Bolus In-hospital | Fasting BG Concentration | 167 mg/dl | Standard Deviation 44 |
| Linagliptin on Discharge | Fasting BG Concentration | 125 mg/dl | Standard Deviation 22 |
| Linagliptin+50%Glargine Dose on d/c | Fasting BG Concentration | 133 mg/dl | Standard Deviation 27 |
| Linagliptin+80%Glargine Dose on d/c | Fasting BG Concentration | 141 mg/dl | Standard Deviation 25 |
Secondary
HbA1c Level
HbA1c level at admission (for in-patient arms) and HbA1c level at 12-week follow-up outpatient visit (for discharge arms).
Time frame: Admission to the hospital and 12-week follow-up outpatient visit
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Linagliptin In-hospital | HbA1c Level | 7.6 % DCCT | Standard Deviation 1.9 |
| Basal Bolus In-hospital | HbA1c Level | 8.0 % DCCT | Standard Deviation 2 |
| Linagliptin on Discharge | HbA1c Level | 6.6 % DCCT | Standard Deviation 0.8 |
| Linagliptin+50%Glargine Dose on d/c | HbA1c Level | 7.0 % DCCT | Standard Deviation 1 |
| Linagliptin+80%Glargine Dose on d/c | HbA1c Level | 8.6 % DCCT | Standard Deviation 2.7 |
Secondary
Hospital Complications
Subjects with composite complication (ONLY for inpatient arms 1 and 2)
Time frame: During Hospitalization-average 5 days
Population: Composite complication during hospitalization is applicable ONLY for inpatient arms (1 and 2)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Linagliptin In-hospital | Hospital Complications | 14 Participants |
| Basal Bolus In-hospital | Hospital Complications | 11 Participants |
Secondary
Hospital Mortality
Hospital mortality (ONLY in-patient). Mortality is defined as death occurring during hospital stay.
Time frame: During Hospitalization-average 5 days
Population: Hospital mortality is applicable ONLY for inpatients arms (1 and 2)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Linagliptin In-hospital | Hospital Mortality | 0 Participants |
| Basal Bolus In-hospital | Hospital Mortality | 0 Participants |
Secondary
Hyperglycemia
Subjects with BG \> 300 mg/dl
Time frame: Inpatient (average 5 days) and outpatient up to 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Linagliptin In-hospital | Hyperglycemia | 22 Participants |
| Basal Bolus In-hospital | Hyperglycemia | 18 Participants |
| Linagliptin on Discharge | Hyperglycemia | 6 Participants |
| Linagliptin+50%Glargine Dose on d/c | Hyperglycemia | 11 Participants |
| Linagliptin+80%Glargine Dose on d/c | Hyperglycemia | 7 Participants |
Secondary
Hypoglycemia < 40 mg/dl
Subjects with Hypoglycemia \< 40 mg/dl
Time frame: Inpatient and up to 12 weeks outpatient
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Linagliptin In-hospital | Hypoglycemia < 40 mg/dl | 1 Participants |
| Basal Bolus In-hospital | Hypoglycemia < 40 mg/dl | 0 Participants |
| Linagliptin on Discharge | Hypoglycemia < 40 mg/dl | 1 Participants |
| Linagliptin+50%Glargine Dose on d/c | Hypoglycemia < 40 mg/dl | 0 Participants |
| Linagliptin+80%Glargine Dose on d/c | Hypoglycemia < 40 mg/dl | 1 Participants |
Secondary
Hypoglycemia <70 mg/dl
Subjects with Hypoglycemia \<70 mg/dl
Time frame: Inpatient (average 5 days) and outpatient up to 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Linagliptin In-hospital | Hypoglycemia <70 mg/dl | 2 Participants |
| Basal Bolus In-hospital | Hypoglycemia <70 mg/dl | 14 Participants |
| Linagliptin on Discharge | Hypoglycemia <70 mg/dl | 8 Participants |
| Linagliptin+50%Glargine Dose on d/c | Hypoglycemia <70 mg/dl | 15 Participants |
| Linagliptin+80%Glargine Dose on d/c | Hypoglycemia <70 mg/dl | 10 Participants |
Secondary
Length of Hospital Stay
Length of hospital stay (ONLY for inpatient arms 1 and 2)
Time frame: During Hospitalization
Population: Length of hospital stay is applicable ONLY for inpatient arms (1 and 2)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Linagliptin In-hospital | Length of Hospital Stay | 4 Days |
| Basal Bolus In-hospital | Length of Hospital Stay | 3 Days |
Secondary
Number of Participants Requiring ICU Care During Hospitalization
Need for intensive care unit (ICU) care (transfer to ICU) during hospitalization
Time frame: During Hospitalization-average 5 days
Population: Transfer to ICU is applicable ONLY for inpatient arms (1 and 2)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Linagliptin In-hospital | Number of Participants Requiring ICU Care During Hospitalization | 1 Participants |
| Basal Bolus In-hospital | Number of Participants Requiring ICU Care During Hospitalization | 0 Participants |
| Linagliptin on Discharge | Number of Participants Requiring ICU Care During Hospitalization | 0 Participants |
| Linagliptin+50%Glargine Dose on d/c | Number of Participants Requiring ICU Care During Hospitalization | 0 Participants |
| Linagliptin+80%Glargine Dose on d/c | Number of Participants Requiring ICU Care During Hospitalization | 0 Participants |
Secondary
Outpatient Mortality
Deaths among patients after hospital discharge.
Time frame: 3 months after discharge
Population: Deaths after hospital discharge are applicable ONLY for outpatient arms (3, 4 and 5).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Linagliptin In-hospital | Outpatient Mortality | 0 Participants |
| Basal Bolus In-hospital | Outpatient Mortality | 0 Participants |
| Linagliptin on Discharge | Outpatient Mortality | 0 Participants |
| Linagliptin+50%Glargine Dose on d/c | Outpatient Mortality | 0 Participants |
| Linagliptin+80%Glargine Dose on d/c | Outpatient Mortality | 0 Participants |
Secondary
Subjects With Surgical Reinterventions
Subjects with surgical re-interventions.
Time frame: Inpatient and up to 12 weeks outpatient
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Linagliptin In-hospital | Subjects With Surgical Reinterventions | 6 Participants |
| Basal Bolus In-hospital | Subjects With Surgical Reinterventions | 4 Participants |
| Linagliptin on Discharge | Subjects With Surgical Reinterventions | 5 Participants |
| Linagliptin+50%Glargine Dose on d/c | Subjects With Surgical Reinterventions | 3 Participants |
| Linagliptin+80%Glargine Dose on d/c | Subjects With Surgical Reinterventions | 3 Participants |
Secondary
Subjects With Wound and Other Infections
Subjects with wound and other infections.
Time frame: During Hospitalization and outpatient up to 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Linagliptin In-hospital | Subjects With Wound and Other Infections | 7 Participants |
| Basal Bolus In-hospital | Subjects With Wound and Other Infections | 3 Participants |
| Linagliptin on Discharge | Subjects With Wound and Other Infections | 3 Participants |
| Linagliptin+50%Glargine Dose on d/c | Subjects With Wound and Other Infections | 5 Participants |
| Linagliptin+80%Glargine Dose on d/c | Subjects With Wound and Other Infections | 4 Participants |