Clinical trial NCT02408120
Conditions: Diabetes Mellitus, Type 2
Keywords: Hyperglycemia Hypoglycemia
Sponsor: Emory University
Start date: 2015-10-01; Completion date: 2019-12-11
Enrollment: 226 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to test whether using extra doses of aspart insulin to correct blood sugars before meals improves the care of patients with type 2 diabetes in the hospital who are already receiving the standard of care treatment with glargine and aspart insulin injections to control blood sugar levels. Studies done in the past indicate that blood sugar levels are controlled on the standard treatment of insulin and that most patients do not need the small extra dose of insulin at bedtime. The investigators want to test if there is any benefit to giving patients extra doses of insulin during the day to correct the high blood sugars.

Detailed description:
The management of patients with Type 2 diabetes involves treatment with two different types of insulin injections to control blood sugar levels. The doses of the two types of insulins, glargine insulin and aspart insulin are adjusted daily through the hospital stay based on blood sugar levels. Many times, in addition to glargine and aspart insulin at meals, additional small doses of aspart insulin are given to correct high blood sugar levels. It has not been determined if using these extra doses of aspart insulin to correct blood sugars before meals improves care of the patients. Studies done in the past indicate that blood sugar levels are well controlled on the standard treatment of the two insulins and that most patients do not need the small extra dose of insulin at bedtime. This study will test if insulin supplementation improves glycemic control and prevents hypoglycemia in insulin treated patients with type 2 diabetes mellitus.

Arms: arm 1: Subjects will consist of hospitalized patients with type 2 diabetes and be randomized to receive insulin glargine once daily and insulin aspart divided in three equal doses before meals. Supplemental insulin aspart will be given before meals and at bedtime to subjects with blood glucose (BG) levels \>140 mg/dL. arm 2: Subjects will consist of hospitalized patients with type 2 diabetes and be randomized to receive insulin glargine once daily and insulin aspart divided in three equal doses before meals. Supplemental insulin aspart will be given before meals and at bedtime to subjects with blood glucose (BG) levels \>260 mg/dL.
Interventions: intervention 1: Insulin glargine intervention 2: Insulin aspart intervention 3: Supplemental insulin aspart
Intervention descriptions: intervention 1: Half of total daily dose (TDD) will be given as insulin glargine and will be given once daily, at the same time of the day.

Daily insulin dose will be adjusted as follow:

* If the fasting and pre-dinner BG is between 100 - 140 mg/dL in the absence of hypoglycemia the previous day: no change
* If the fasting and pre-dinner BG is between 140 - 180 mg/dL in the absence of hypoglycemia: increase basal insulin by 10% every day
* If the fasting and pre-dinner BG is \>180 mg/dL in the absence of hypoglycemia the previous day: increase basal insulin dose by 20% every day
* If the fasting and pre-dinner BG is between 70 - 99 mg/dL in the absence of hypoglycemia: decrease TDD (basal and prandial) insulin dose by 10% every day
* If a patient develops hypoglycemia (BG \<70 mg/dL), the insulin TDD (basal and prandial) should be decreased by 20%. intervention 2: Half of total daily dose will be given as insulin aspart and in three equally divided doses before each meal. To prevent hypoglycemia, if a subject is not able to eat, the dose of aspart will be held.

Daily insulin dose will be adjusted as follow:

* If the fasting and pre-dinner BG is between 100 - 140 mg/dL in the absence of hypoglycemia the previous day: no change
* If the fasting and pre-dinner BG is between 140 - 180 mg/dL in the absence of hypoglycemia: increase basal insulin by 10% every day
* If the fasting and pre-dinner BG is \>180 mg/dL in the absence of hypoglycemia the previous day: increase basal insulin dose by 20% every day
* If the fasting and pre-dinner BG is between 70 - 99 mg/dL in the absence of hypoglycemia: decrease TDD (basal and prandial) insulin dose by 10% every day
* If a patient develops hypoglycemia (BG \<70 mg/dL), the insulin TDD (basal and prandial) should be decreased by 20%. intervention 3: Insulin aspart will be administered following the supplemental insulin scale protocol.

For the arm receiving supplemental insulin aspart at BG levels greater than 140 mg/dL, then supplemental insulin scale is as follows:

* BG \>141-180 mg/dL; 2-4 units of insulin aspart
* BG between 181-220 mg/dL; 3-6 units of insulin aspart
* BG between 221-260 mg/dL; 4-8 units of insulin aspart
* BG between 261-300 mg/dL; 5-10 units of insulin aspart
* BG between 301-350 mg/dL; 6-12 units of insulin aspart
* BG between 351-400 mg/dL; 7-14 units of insulin aspart
* BG \> 400 mg/dL; 8-16 units of insulin aspart

For the arm receiving supplemental insulin aspart at BG levels greater than 260 mg/dL, then supplemental insulin scale is as follows:

* BG between 261-300 mg/dL; 5-10 units of insulin aspart
* BG between 301-350 mg/dL; 6-12 units of insulin aspart
* BG between 351-400 mg/dL; 7-14 units of insulin aspart
* BG \> 400 mg/dL; 8-16 units of insulin aspart

Protocol documents:
Prot_SAP_000.pdf: 
 
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IRB00078695 
NCT02408120 
Title: Benefits of Insulin Supplementation for Correction of Hyperglycemia in Patients 
with Type 2 Diabetes Treated with Basal Bolus Insulin Regimen 
Principal Investigator: Priyathama Vellanki, M.D. 
 
12/14/2017 
 
 


 
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Title: Benefits of Insulin Supplementation for Correction of Hyperglycemia in Patients 
with Type 2 Diabetes Treated with Basal Bolus Insulin Regimen 
Principal Investigator: Priyathama Vellanki, M.D. 
Assistant Professor of Medicine 
 
 
 
Emory University School of Medicine 
 
Co-Investigators: 
Guillermo E. Umpierrez, M.D. 
Professor of Medicine 
Emory University School of Medicine 
 
Francisco Pasquel, M.D. 
Assistant Professor of Medicine 
Emory University School of Medicine 
 
J. Sonya Haw, M.D. 
 
 
 
Clinical Instructor of Medicine 
 
 
 
Emory University School of Medicine 
 
Statistical Support: 
 
Limin Peng Ph.D. 
 
 
 
Associate Professor  
 
 
 
Rollins School of Public Health 
 
 
 
Emory University 
 
 
 
 
Correspondence: 
 
Priyathama Vellanki, M.D. 
Assistant Professor of Medicine 
 
 
 
Emory University School of Medicine 
 
 
 
49 Jesse Hill Jr Dr 
 
 
 
Atlanta, GA 30303 
 
 
 
Tel: 404- 778 1687 
 
 
 
E-mail: pvellan@emory.edu 


 
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RESEARCH OBJECTIVES AND SPECIFIC AIMS  
Several observational and randomized controlled trials (RCT) have reported that inpatient 
hyperglycemia is associated with an increased risk of complications and mortality (1-5).  Several 
interventional trials have shown that treatment of hyperglycemia in critically ill and non-ICU 
patients is associated with shorter length of hospital stay and lower rates of hospital 
complications. Several prospective, randomized trials in general medicine and surgical patients 
with type 2 diabetes (T2DM) have shown that treatment with basal bolus insulin regimen results 
in better glycemic control and lower rate of hospital complications compared to treatment with 
sliding scale regular insulin in patients (4; 6-8).  Indeed, basal bolus regimen is recommended in 
clinical guidelines by multiple professional societies (9; 10) for treatment of inpatient 
hyperglycemia and T2DM in non-ICU patients.  
While basal bolus regimens are recommended, they consist of multiple daily injections. 
In addition, they require correction of blood glucose (BG) levels with supplemental (corrective) 
doses of insulin based on BG levels (4; 6; 7; 11; 12).  Data from our group has shown that 
simplified regimens such as a basal-plus regimen may be just as effective for glycemic control as 
a basal bolus regimen (11).  Additionally, recent data from one of our RCTs showed that 
corrective doses of insulin at bedtime for mild to moderate hyperglycemia, a standard of care 
practice, may not be necessary (13).  Glycemic control, rates of hypoglycemia or total daily dose 
(TDD) of insulin did not differ whether corrective doses of insulin were given or not for bedtime 
hyperglycemia. Similar to this trial, several trials from our group with different basal bolus 
regimens show that the amount of supplemental insulin per day is between 5-9 units/day (See 
Table 1).  It is possible that the use of insulin supplements may increase the risk of hypoglycemic 
events, an independent marker of mortality (14).These small amounts of daily supplemental 
insulin requirements raise the question of whether corrective doses of insulin before meals and 
bedtime are beneficial in inpatient treatment for T2DM.   
Currently, no RCTs have prospectively evaluated the need for corrective doses of insulin 
as part of a basal bolus regimen in the inpatient setting.  We propose to study the safety and 
efficacy of the standard practice of correcting mild to moderate hyperglycemia (BG 140-260 
mg/dL) before meals and bedtime in patients treated with basal bolus insulin regimen. A glucose 
> 260 mg/dL was picked arbitrarily. We hypothesize that correction of mild-moderate 
hyperglycemia with rapid-acting insulin analogs (standard of care) will not improve 
glycemic control or complication rates and may increase the risk of hypoglycemia.   If 
supplemental insulin is not necessary to correct mild-moderate hyperglycemia, inpatient 
management of hyperglycemia in patients with T2DM may be simplified, may reduce the risk of 
hypoglycemia and save costs.  
Specific Aim:  To test whether correction of mild-moderate hyperglycemia (BG > 140 
mg/dL) with supplemental doses of rapid-acting insulin analogs improves glycemic control, 
complication rates, and rates of hypoglycemia in hospitalized patients with type 2 diabetes 
treated with basal bolus insulin regimen. Patients with T2DM admitted to the hospital 
receiving basal bolus therapy will be randomized to receive insulin correction before meals and 
at bedtime for BG >140 mg/dL, while others will be followed without insulin supplementation 
except for severe hyperglycemia (BG > 260 mg/dL).  


 
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Table 1: Total and Supplemental Insulin needs in Basal Bolus Arm of RCT 
Trial 
Number 
Mean TDD Insulin 
Mean daily SSI  
RABBIT 2D (7) 
65 
42 units/day 
5 units/day 
RABBIT 2 Surgery (6) 104 
33 units/day 
9 units/day 
POC Study 
206 
42 units/day 
6 units/day 
Basal-Plus (11) 
144 
32 units/day 
7 units/day 
DEAN Trial (12) 
67 
57 units/day 
8 units/day 
 
 
 
II. 
BACKGROUND AND CURRENT STATUS OF WORK IN THE FIELD. 
Inpatient Glycemic Control in non-ICU setting.  A large body of evidence suggests that in 
hospitalized patients with and without diabetes, the presence of hyperglycemia is associated with 
increased risk of complications and death (2-5; 15-20). Prospective RCTs in critical care patients 
have shown that aggressive glycemic control reduces short- and long-term mortality, multi-organ 
failure, systemic infections, and length of hospital and ICU stay [7, 9-11]. Similar complication 
reductions has been shown in patients admitted to general medicine and surgery services as well. 
In the non-ICU setting, practice guidelines for the management of hyperglycemia in patients with 
T2DM favor the use of physiologic (basal-nutritional-correction dose) insulin regimens over 
sliding scale regular insulin (SSRI) (4; 5).  Several RCTs have shown that a basal bolus regimen 
improves glycemic control and reduces hospital complications in general medicine and surgery 
patients with T2DM (5-7; 21; 22).  
Treatment with basal insulin glargine alone or in combination with rapid-acting insulin analogs 
before meals (basal bolus regimen) result in fairly constant BG values during the day (see 
preliminary data below). We have shown that with the exception of a small and non-significant 
rise in BG concentration before lunch (noontime), treatment with glargine insulin allows 24 
hours of BG control with low rates of hypoglycemia, severe hyperglycemia and minimal 
requirement of insulin supplements (~5-9 U/day) (6; 7). In particular, our data indicate that BG 
concentration remains relatively constant during the evening with a low rate of severe 
hyperglycemia (0.1% of BG >400 mg/dl) despite minimal use of insulin supplements (see 
preliminary data). This small dose of supplemental insulin used in our previous studies raises the 
question of its necessity as part of a basal bolus regimen.   
Several RCT have shown that hypoglycemia occurs in 12% and 33% of general medicine and 
surgery patients treated with basal bolus insulin regimens, respectively (6; 7; 11; 12).  In the 
RABBIT-surgery trial (6), general surgery patients were treated with a total insulin dose of 0.5 
unit/kg/day, given half as glargine once daily and half as glulisine before meals. A total of 17% 
of patients had a BG <70 mg/dL and 4% had a value <40 mg/dL.  More recently, the Basal Plus 
trial (11) reported that 12% and 5% of patients treated with basal bolus with glargine and 
glulisine or with basal plus correction (supplements), respectively, had a BG <70 mg/dL and 


 
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only 1% had a BG <40 mg/dL.  In the DEAN trial (12), a basal-bolus regimen using detemir and 
aspart vs. NPH and regular insulin reported that ~one-third of patients had a BG < 60 mg/dl (12).  
Minimizing hypoglycemic events is of major importance in hospitalized patients because it has 
been shown to be an independent risk factor of poor outcome (23-25).  It is not known, however, 
if the use of insulin supplements may have an impact on the overall rate of hypoglycemia in 
patients treated with basal bolus insulin regimen. 
Significance and Innovation:  Inpatient hyperglycemia is reported in up to 30% of general 
medicine and surgical patients. Our data indicate that in patients treated with basal (glargine or 
detemir) insulin, BG values remain relatively flat, without significant differences in use of 
insulin supplements or rate of hypoglycemia (6; 7).  Moreover, in a recent study, we showed that 
there were no differences in glycemic control or hypoglycemic episodes with or without the 
correction of mild to moderate hyperglycemia with supplemental insulin at bedtime. All of our 
RCTs showed that supplemental insulin needs are small and are only between 6-9 units/day. 
However, no previous studies have determined if the use of supplemental insulin to correct 
hyperglycemia results in a change in glycemic control or hypoglycemia rates.  It is possible that 
avoiding correction of mild to moderate hyperglycemia with supplemental insulin may result in 
lower rates of hypoglycemia and significant cost in hospitalized patients with T2DM treated with 
basal insulin analogs. Accordingly, the proposed pilot study will provide novel and clinically 
useful information by determining if insulin supplementation will improve glycemic control and 
prevent hypoglycemia in insulin treated patients with T2DM. If insulin supplementation is not 
necessary for glycemic control, this may result in simplified insulin regimens, potentially reduce 
hypoglycemic episodes and save costs.  
 
Preliminary Data:  
Our research team recently reported the results of four 
prospective, multi-center RCT comparing the efficacy 
and safety of different insulin regimens in T2DM 
patients admitted to general medicine and surgical 
services (6; 7; 11; 12).  We have shown that a basal 
bolus regimen results in improved glycemic control 
compared to SSRI.  In particular, these trials showed 
that the amount of supplemental insulin needed is 
very low.   
In the Rabbit trial (Fig 1), 130 nonsurgical insulin 
naïve patients were randomized to receive glargine 
once daily and glulisine before meals (basal bolus) or 
SSRI before meals and at bedtime.  Of these, 65 patients treated with glargine/glulisine (basal 
bolus) had greater improvement in BG control than SSRI with minimal risk of patients with 
Fig 1 


 
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hypoglycemic events (3% of patients in each group had a BG < 60 mg/dL).  A BG target of < 
140 mg/dL was achieved in 66% of patients treated with glargine and glulisine whereas only 
38% of those treated with SSRI achieved target glycemia.  In 
this study, patients in the basal bolus arm required total insulin 
of 42 units/day.  Of this, only 5 units/day were needed as 
supplemental insulin (Table 1). 
In the DEAN trial (12), 130 patients with T2DM were treated 
with detemir once daily and aspart before meals (n=67) or with 
a split-mixed regimen of NPH and regular insulin twice daily 
(n=63) (Figure 2).  Both regimens resulted in equivalent 
glycemic control and a similar rate of hypoglycemic events. A 
BG target <140 mg/dL before meals was achieved in 45% of 
patients in the detemir/aspart group and in 48% in the 
NPH/regular group.  The TDD of insulin in the detemir arm 
was 57 units/day and of that the supplemental dose was only 8 units/day.  
In the Rabbit-Surgery trial (Figure 3), 211 general non-
cardiac surgery patients with T2DM were randomized to a 
basal bolus regimen with glargine once daily and glulisine 
before meals (n=104) or to SSRI before meals (n=107). 
Study outcomes included differences in daily BG levels and a 
composite of hospital complications including postoperative 
wound infection, pneumonia, respiratory failure, acute renal 
failure, and bacteremia. The mean daily glucose after the 
1st day of BB and SSRI was 145±32 mg/dl and 172±47 
mg/dl, respectively, p<0.01. BG readings <140 mg/dl 
were recorded in 55% of patients in basal bolus and 31% 
in the SSRI group, p<0.001.  There were reductions with 
basal bolus as compared with SSRI in the composite 
outcome (24.3% and 8.6%, OR: 3.39 (95% CI: 1.50-
7.65); p=0.003).  We concluded that treatment with 
basal improved glycemic control and reduced hospital 
complications compared to SSRI in surgery patients 
with T2DM. The TDD of insulin in the basal bolus 
group was 33 units daily with 9 units/day of 
supplemental insulin. The basal bolus group in this 
study received more supplemental insulin than patients 
in the basal bolus arms of our other RCTs. This is 
likely because ~ 30% of patients in the Rabbit-Surgery 
trial underwent abdominal surgery and were likely 
Fig 2 
120
140
160
180
200
220
0
1
2
3
4
5
6
7
8
9
10
11
Blood Glucose (mg/dL)
Duration of Treatment (days)
1         2         3         4         5         6        7         8         9        10
Randomi-
zation
Figure 4.  Basal Bolus vs. Basal Plus
8.6
1.0
2.9
0.0
3.8
24.3
1.0
10.3
2.8
10.3
0
5
10
15
20
25
30
Composite
Mortality
Wound 
Infection
Pneumonia
Acute Renal 
Failure
Outcome Frequency, %
Figure 3.   Postoperative Complications
P=0.003
P=NS
P=0.05
P=0.10
P=0.24
Glargine+Glulisine
Sliding Scale Insulin
* Composite of hospital complications: wound infection, pneumonia, 
respiratory failure, acute renal failure, and bacteremia.
120
140
160
180
200
220
Blood Glucose (mg/dL)
*
*
*
*
Figure 5.  BG before meals and at bedtime
Breakfast
Lunch           
Dinner
Bedtime
*p<0.001
Glargine+Glulisine
Sliding Scale Insulin


 
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NPO.  These patients did not receive prandial 
insulin and therefore the supplemental dose may 
have been higher.  
In the Basal Plus trial (11), we compared the effect 
of a daily dose of glargine with correction doses of 
glulisine to a standard basal bolus regimen in 300 
medical and surgical patients with T2DM. We 
observed similar mean daily BG (Figure 4), pre-
meal glucoses (Figure 5) and hypoglycemic events. 
There were no differences in length of hospital stay 
or hospital complications between patients treated 
with basal plus and basal bolus insulin regimen. 
These results indicate that a simple regimen of a 
daily basal dose of glargine plus correction doses 
with glulisine before meals (as needed) is an 
alternative to basal bolus insulin and results in 
similar glycemic control and hypoglycemia in 
general medicine and surgery patients with T2DM.   
In the basal bolus arm of the study, TDD of insulin 
was 32 units/day and of this only 7 units/day was 
given as supplemental dose.  
In a recently completed study (POC) (13), we 
found that not correcting mild to moderate hyperglycemia at bedtime did not change fasting daily 
glucose levels (Figure 6). Further, there were no changes in mean daily glucose, pre-meal 
glucose or hypoglycemic events (Figure 7).  In this study, TDD of insulin was 42 units/day. Of 
this, only 6 units/day was required as a supplemental dose.   
Frequency of hypoglycemia and hyperglycemia during basal insulin treatment.  The 
frequency of mild hypoglycemia (BG<70 mg/dl) and severe hypoglycemia (BG<40 mg/dl) at 
bedtime among 2,377 patients recruited in different randomized control trials conducted by our 
research team is less than 1.5% and 0.5%, respectively.  The frequency of hypoglycemia is low 
in comparison to patients treated with sulfonylureas (26). Similarly, the frequency of severe 
hyperglycemia (BG>400 mg/dl) is remarkably low (0.08%) among insulin treated patients with 
T2DM (6; 7). 
In summary, during the past decade our research group has provided novel and important 
information to guide health care providers in inpatient management of patients with 
hyperglycemia and diabetes. Our preliminary data indicate that the use of basal insulin alone or 
in combination with rapid-acting insulin analogs (basal bolus regimen) in non-ICU patients with 
T2DM improves glycemic control and reduces the rate of hypoglycemia.  In addition, our studies 
D a y  0
D a y  1
D a y  2
D a y  3
D a y  4
D a y  5
D a y  6
D a y  7
1 0 0
1 5 0
2 0 0
2 5 0
F ig u re  6 : M e a n   D a ily   F a s tin g  G lu c o s e s e
M e a n  F a s tin g  G lu c o s e
(m g /d L )
A ll p  =  N S
F a s tin g
P re -L u n c h
P re -D in n e r
B e d tim e
3  A M
120
140
160
180
F ig u re  7 : P re m e a l G lu c o s e  L e v e ls
M e a n  P r e m e a l G lu c o s e
 (m g /d L )
A ll p = N S


 
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have shown that BG values remain relatively constant during the day and that the need for 
supplemental insulin is low in comparison to the TDD of insulin required.   
IV. Experimental Plan:  
Specific Aim:  To test whether correction of mild-moderate hyperglycemia (140-260 mg/dL) 
with supplemental doses of rapid-acting insulin analogs improves glycemic control, complication 
rates, and rates of hypoglycemia in patient with type 2 diabetes treated with basal bolus insulin 
regimen.  
 
IV.a. Study Design and Methods: 
A total of 250 general medicine and surgery patients with T2DM treated with basal bolus 
insulin regimen will be included in this pilot RCT.  Half of the patients will be randomized 
to receive insulin supplements before meals and at bedtime for BG >140 mg/dL, while the other 
half will be followed without insulin supplementation except for severe hyperglycemia (BG > 
260 mg/dL).  
 
IV.b. Primary and Secondary Outcomes:  
The primary outcome of the study is to compare differences in mean daily BG levels between 
patients receiving insulin supplementation for correction of hyperglycemia (BG > 140 mg/dL) 
compared to those without insulin supplementation except for correction of severe 
hyperglycemia (BG > 260 mg/dL). 
Secondary outcomes include differences between treatment groups in any of the following 
measures: 1) mean BG before meals, bedtime and 3 AM; 2) number of BG within target; 3) 
number of hypoglycemia (BG < 70 mg/dl); hyperglycemia (BG > 260 mg/dL during the day or 
BG>350 mg/dl at bedtime); 4) daily dose of insulin; 5) length of hospital stay and mortality; 6) 
hospital complications (nosocomial infections, pneumonia, bacteremia, respiratory failure, and 
acute kidney injury [rise of serum creatinine >0.5 mg/dL (or 50%) of baseline value]), 7) 
hypoglycemia symptom assessment in both groups. 
IV.c. Research Plan.   
Patients with T2DM admitted with acute or chronic medical illnesses or for elective and 
emergency surgical illness or trauma would be considered candidates in this study. The goal of 
insulin therapy is to maintain a fasting and pre-meal BG<140 mg/dL while avoiding 
hypoglycemia. Diabetic patients admitted to general medical or surgery areas with a BG > 140 
mg/dL and < 400 mg/dL will be randomized (using a randomization table) to: 
Group 1. Basal bolus insulin regimen with corrective doses of aspart/lispro insulin for BG > 
140 mg/dL (n = 125). 


 
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Group 2. Basal bolus insulin regimen without corrective doses of aspart/lispro insulin 
except for BG > 260 mg/dL (n = 125). 
The primary medical team (PMT) will decide on the treatment for the surgical and other medical 
problem(s) for which patients are admitted. The study team will provide recommendations for 
discharge as outlined below but will leave it up to the discretion of the PMT. The PMT can also 
decide the medical treatment at discharge including the use of insulin or oral antidiabetic 
agent(s), patient’s discharge orders and referral to the diabetes clinic at discharge.   
IV.d. Basal Bolus Insulin Protocol.   
Patients will be started on basal bolus insulin therapy as previously reported (6; 7; 11; 13).  In 
brief, subjects treated with insulin prior to admission will receive 80% of the outpatient insulin 
dose. Insulin-naïve patients will discontinue oral agents and will receive a starting total daily 
dose (TDD) of insulin of 0.4 U/kg/day for BG between 140-200 mg/dL and 0.5 U/kg/day for BG 
between 201-400 mg/dL. The starting TDD will be 0.3 U/kg/day in patients  ≥70 yrs or with an 
eGFR < 60 ml/min.  Half of TDD will be given as glargine or detemir once daily and half as 
meal time insulin (aspart or lispro) divided in three equal doses before meals.  Insulin dose will 
be adjusted daily to maintain a fasting and pre-dinner BG between 100-140 mg/dL (6; 7).  
Supplement insulin given as aspart or lispro will be given following a “supplemental insulin 
scale” protocol (6; 7; 27). Patients randomized to Group 1 will receive supplements to correct 
BG > 140 mg/dL, and those in Group 2 will not receive supplements except for correction of 
hyperglycemia (BG>260 mg/dL).   Corrective doses for bedtime in group 1 will be given for BG 
> 220 mg/dL.   
Group 1.  Basal bolus regimen with corrective doses of rapid-acting insulin prior to meals.   
Patients Treated with Insulin Prior to Admission 
 Subjects receiving insulin therapy will receive 80% of the total daily outpatient insulin 
dose.  For subjects receiving glargine, detemir, regular, lispro, glulisine or aspart, the 
total daily insulin dose prior to admission will be switched to basal insulin (glargine or 
detemir)/ meal time insulin (aspart/lispro) combination on a unit-for-unit basis.   
 Half of total daily dose will be given as basal insulin (glargine or detemir) insulin and 
half as meal time insulin (aspart/lispro) insulin.   
 Basal insulin (glargine or detemir) insulin will be given once daily, at the same time of 
the day.   
 Patients will receive the full-dose of basal insulin (glargine or detemir) (even if NPO) the 
day of surgery or diagnostic procedure(s).     
 Meal time insulin (aspart/ lispro) insulin will be given in three equally divided doses 
before each meal.  To prevent hypoglycemia, if a subject is not able to eat, the dose of 
meal time insulin (aspart/lispro) will be held. 
 
 


 
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Patients Treated with Oral Agents Prior to Admission  
 Oral antidiabetic drugs (sulfonylureas, repaglinide, nateglinide, metformin, pioglitazone, 
DPP4 inhibitors) and non-insulin injected antidiabetic drugs (pramlinitide, exenatide, 
liraglutide) will be discontinued on admission. 
 
 Starting total daily insulin dose:  
 0.4 units per kilogram of body weight per day when the blood glucose concentration 
at randomization is between 140-200 mg/dL.  
 0.5 units per kilogram of body weight per day blood glucose concentration at 
randomization is between 201-400 mg/dL   
 The starting insulin TDD will be reduced to 0.3 units per kg in patients ≥ 70 years of 
age and/or with an eGFR < 60 ml/min. 
 Half of total daily dose will be given as basal insulin (glargine or detemir) and half as 
meal time insulin (aspart/lispro).   
 Basal insulin (glargine or detemir) will be given once daily, at the same time of the day.   
 Patients will receive the full-dose of basal insulin (glargine or detemir) insulin (even if 
NPO) the day of surgery or diagnostic procedure(s).     
 Meal time insulin (aspart/lispro) will be given in three equally divided doses before each 
meal.  To prevent hypoglycemia, if a subject is not able to eat, the dose of aspart/lispro 
will be held.  
 
Supplemental insulin. Aspart/lispro insulin will be administered following the “supplemental 
insulin scale” protocol.   
 If a patient is able and expected to eat all or most of his/her meals, supplemental aspart or 
lispro insulin will be administered before each meal and at bedtime following the “usual” 
dose of the supplemental insulin scale protocol. 
 If a patient is not able to eat, supplemental aspart or lispro insulin will be administered every 
6 hours following the “sensitive” dose of the supplemental insulin scale protocol. 
 
Insulin adjustment.   
 Daily insulin dose will be adjusted as follow:  
 If the fasting and/or pre-dinner BG is between 100 - 140 mg/dL in the absence of 
hypoglycemia the previous day: no change  
 If the fasting and/or pre-dinner BG is between 140 - 180 mg/dL in the absence of 
hypoglycemia: increase basal insulin by 10% every day 
 If the fasting and/or pre-dinner BG is >180 mg/dL in the absence of hypoglycemia the 
previous day: increase basal insulin dose by 20% every day  
 If the fasting and/or pre-dinner BG is between 70 - 99 mg/dL in the absence of 
hypoglycemia: decrease TDD (basal and prandial) insulin dose by 10% every day 
 If a patient develops unexplained hypoglycemia (BG <70 mg/dL), the insulin TDD (basal 
and prandial) should be decreased by 20%.   
 


 
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Supplemental Insulin (aspart/lispro) prior to meals:  
 
BEFORE MEAL, Supplemental Sliding Scale Insulin (number of units) - Add to scheduled 
insulin dose.   
 
Blood Glucose 
 
 
(mg/dL) 
                 Sensitive           Usual 
 
Resistant             
 
______________________________________________________________ 
    ≤ 140                
 
0 
 
   0 
 
 
0 
>141-180 
 
 
2 
 
   3 
 
 
4 
181-220 
 
 
3 
 
   4 
 
 
6 
221-260 
 
 
4 
 
   5 
 
 
8 
261-300 
 
 
5 
 
   6 
 
 
10 
301-350 
 
 
6 
 
   8 
 
 
12 
351-400 
 
 
7 
 
   10 
 
 
14 
> 400  
 
 
8 
 
   12 
 
 
16 
______________________________________________________________ 
 
 
BEDTIME.  Give half of Supplemental Sliding Scale Insulin. 
 
Blood Glucose 
 
 
(mg/dL) 
                 Sensitive           Usual 
 
Resistant             
 
______________________________________________________________ 
<221     
 
 
0 
 
   0 
 
 
0 
221-260 
 
 
1 
 
   2 
 
 
4 
261-300 
 
 
2 
 
   3 
 
 
5 
301-350 
 
 
3 
 
   4 
 
 
6 
351-400 
 
 
4 
 
   5 
 
 
7 
> 400  
 
 
5 
 
   6 
 
 
8 
______________________________________________________________ 
 
The patient’s inpatient primary medical or surgical team may change insulin dose at their 
discretion in the presence of hypoglycemia (BG <70 mg/dL) or severe hyperglycemia (BG >350 
mg/dL).  In addition, the attending and/or study physician may consider using the total 
supplemental insulin dose, patient’s nutritional intake, and results of BG testing to adjust insulin 
regimen.    
Blood glucose monitoring.  BG will be measured before each meal, at bedtime and/or 3 AM (or 
every 6 hours if a patient is not eating) using a glucose meter.  In addition, blood glucose will be 
measured at any time if a patient experiences symptoms of hypoglycemia or if requested by the 
treating physician.  The nursing staff or a research team staff will record all glucose readings in 
the hospital’s blood glucose flow-sheet (electronic chart).   
 


 
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Group 2.  Basal Bolus insulin regimen without corrective doses of rapid-acting insulin 
prior to meals 
Patients Treated with Insulin Prior to Admission 
 Subjects receiving insulin therapy will receive 80% of the total outpatient insulin dose.  
For subjects receiving glargine, detemir, regular, lispro, glulisine or aspart, the total daily 
insulin dose prior to admission will be switched to basal insulin (glargine or detemir) and 
meal time insulin (aspart/lispro) combination on a unit-for-unit basis.   
 Basal insulin (glargine or detemir) will be given once daily, at the same time of the day.   
 Patients will receive the full-dose of basal insulin (glargine or detemir) (even if NPO) the 
day of surgery or diagnostic procedure(s).     
 Meal time insulin (aspart/lispro) will be given in three equally divided doses before each 
meal.  To prevent hypoglycemia, if a subject is not able to eat, the dose of aspart/lispro 
will be held. 
 
Patients Treated with Oral Agents Prior to Admission  
 Oral antidiabetic drugs (sulfonylureas, repaglinide, nateglinide, metformin, Actos, DPP4 
inhibitors) and non-insulin injected antidiabetic drugs (pramlinitide, exenatide) will be 
discontinued on admission. 
 Starting total daily insulin dose:  
 0.4 units per kilogram of body weight per day when the admission and/or blood 
glucose concentration at randomization is between 140-200 mg/dL 
 0.5 units per kilogram of body weight per day when the admission and/or mean blood 
glucose concentration is between 201-400 mg/dL   
 The starting insulin TDD will be reduced to 0.3 units per kg in patients ≥ 70 years of 
age and/or with an eGFR < 60 ml/min. 
 Half of total daily dose will be given as basal insulin (glargine or detemir) and half as 
meal time insulin (aspart or lispro).   
 Basal insulin (glargine or detemir) will be given once daily, at the same time of the day.   
 Patients will receive the full-dose of basal insulin (glargine or detemir) (even if NPO) the 
day of surgery or diagnostic procedure(s).     
 Meal time insulin (aspart/lispro) will be given in three equally divided doses before each 
meal.  To prevent hypoglycemia, if a subject is not able to eat, the dose of aspart/lispro 
will be held.  
 
Supplemental insulin. Aspart or lispro insulin will be administered following the “supplemental 
insulin scale” protocol before meals.   
 If a patient is able and expected to eat all or most of his/her meals, supplemental (aspart or 
lispro) insulin will be administered before each meal following the “usual” dose of the 
supplemental insulin scale. 
 If a patient is not able to eat, supplemental (aspart/lispro) insulin will be administered every 6 
hours following the “sensitive” dose of the supplemental insulin scale protocol. 
 


 
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Insulin adjustment.  Daily insulin dose will be adjusted as follow:  
 If the fasting and/or pre-dinner BG is between 100 - 140 mg/dL in the absence of 
hypoglycemia the previous day: no change  
 If the fasting and/or pre-dinner BG is between 140 - 180 mg/dL in the absence of 
hypoglycemia: increase basal insulin by 10% every day 
 If the fasting and/or pre-dinner BG is >180 mg/dL in the absence of hypoglycemia the 
previous day: increase basal insulin dose by 20% every day  
 If the fasting and/or pre-dinner BG is between 70 - 99 mg/dL in the absence of 
hypoglycemia: decrease basal and prandial insulin TDD by 10% every day 
 If a patient develops unexplained hypoglycemia (BG <70 mg/dL), the basal and prandial 
TDD insulin should be decreased by 20%.   
 
Insulin supplementation (aspart or lispro) prior to meals:  
BEFORE MEAL, Supplemental Sliding Scale (number of units) - Add to scheduled insulin dose.   
Blood Glucose (mg/dL)    Sensitive            Usual                   Resistant              
______________________________________________________________ 
 < 260   
 
 
 0 
 
    0 
                         0 
 
261-300 
 
 
5 
 
   6 
 
 
10 
301-350 
 
 
6 
 
   8 
 
 
12 
351-400 
 
 
7 
 
   10 
 
 
14 
> 400  
 
 
8 
 
   12 
 
 
16 
 
 
 
BEDTIME.  Give half of Supplemental Sliding Scale Insulin  
 
Blood Glucose (mg/dL)    Sensitive            Usual                   Resistant              
______________________________________________________________ 
 < 260   
 
 
 0 
 
    0 
                         0 
 
261-300 
 
 
2 
 
   3 
 
 
5 
301-350 
 
 
3 
 
   4 
 
 
6 
351-400 
 
 
4 
 
   5 
 
 
7 
> 400  
 
 
5 
 
   6 
 
 
8 
 
 
 
The attending physician may change insulin dose as his/her discretion in the presence of 
hypoglycemia (BG <70 mg/dL) or severe hyperglycemia (BG >350 mg/dL).  In addition, the 
attending and/or study physician may consider using the total supplemental insulin dose, 
patient’s nutritional intake, and results of BG testing to adjust insulin regimen.    


 
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Blood glucose monitoring.  BG will be measured before each meal, at bedtime and 3 AM (or 
every 6 hours if a patient is not eating) using a glucose meter.  In addition, blood glucose will be 
measured at any time if a patient experiences symptoms of hypoglycemia or if requested by the 
treating physician.  The nursing staff or a research team staff will record all glucose readings in 
the hospital’s blood glucose flow-sheet (chart).   
IV.f. 
Inpatient Hypoglycemia Management: 
For blood glucose < 70 mg/dL, follow hypoglycemia orders below: 
 If patient is alert and can tolerate oral intake, give 20 grams of fast-acting 
carbohydrate (6 oz. fruit juice or regular soda, crackers). 
 If patient not alert and CANNOT tolerate oral intake, give1ampule (50 mL) of D50. 
 Check finger-stick BG q 15 minutes and repeat above treatment until BG > 100 
mg/dL. 
 Once BG > 100 mg/dL, repeat finger-stick BG 1 hour later and treat as follows: 
o If BG < 70 mg/dL, call MD and follow Hypoglycemia Orders (above) 
o If BG 70 – 100 mg/dL, give snack/scheduled meal and recheck BG q 1 hr until 
BG > 100 mg/dL. 
o If BG > 100, no further treatment needed. 
 
IV.g. Treatment recommendations at discharge.  Treatment of diabetes at discharge will not 
be part of the current research proposal; however, the following guide based on admission 
HbA1c will be shared with primary team to help guiding outpatient insulin therapy: 
 Admission A1C < 7% prior to admission:  
 Discharge on same pharmacologic regimen (oral agents, insulin therapy).   
 Assure there are no contraindications to oral agents (i.e., TZDs and heart failure; 
metformin and renal failure). 
 Admission A1C between 7% and 10% prior to admission:   
 Discharge on once daily basal insulin (glargine or detemir) insulin.   
 If no contraindications to oral agents restart oral agents in addition to basal insulin 
(glargine or detemir) at 50% to 80% of total daily hospital dose.  
 Patients not to be treated with oral agents should be instructed to continue taking 
100% of inpatient daily dose of glargine (as monotherapy).   
 Admission A1C ≥  10% prior to admission:   
 Discharge on basal bolus regimen at same inpatient total daily insulin dose.   
 Basal insulin (glargine or detemir) once daily, at the same time of the day.   
 Rapid-acting insulin (aspart/lispro) before meals. 
 Alternative:  If no contraindications to oral agents (i.e., TZDs and heart failure; 
metformin and renal failure) restart oral agents in addition to glargine or detemir once 
daily at 80% of total daily hospital dose.    
 
 


 
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V.   METHODS and PROCEDURES APPLIED to HUMAN SUBJECTS: 
V.a.  Subject Population/Inclusion Criteria. We plan to study a total of 250 male and female 
patients with a known history of T2DM for >3 months, age 18-80 yr, treated with either diet 
alone, any combination of oral antidiabetic agents, non-insulin injectables or insulin therapy. 
Subjects must have a BG >140 mg and <400 mg/dL without laboratory evidence of diabetic 
ketoacidosis (28).   
Exclusion Criteria. Subjects with hyperglycemia without a history of diabetes, acute critical 
illness admitted to the ICU or expected to require ICU admission; receiving continuous insulin 
infusion, clinically relevant hepatic disease, corticosteroid therapy, creatinine ≥ 3.5 mg/dL and/or 
GFR <30, subjects unable to sign consent, and pregnancy which will be excluded by a urine 
pregnancy test. 
 
V.b. Study Sites: The study will be conducted at Grady Memorial Hospital and Emory 
University Hospitals (EUH and EUHM). 
 
VI.   CLINICAL MANAGEMENT GUIDELINES 
 
V.I.a.  Treatment of Hypoglycemia.  Hypoglycemia, defined as a BG level < 70 mg/dL will be 
treated following standard hypoglycemia protocols available at our institutions (6; 7; 29).  
 
V.I.b.  Assessment and Monitoring of Hospital Complications and Mortality. The research 
team will follow patients daily in order to determine presence of infectious and non-infectious 
complications. Nosocomial infections will be diagnosed based on standardized CDC criteria 
(30).   
VII.   Data Analysis. The primary endpoint of this study is mean fasting BG concentration 
between treatment groups. We set the equivalence margin in our non-inferiority hypothesis for 
comparing treatment effect as 18 mg/dL (1 mmol/l). Based on previous studies (6; 7), we 
anticipate a standard deviation of mean fasting BG~50 mg/dL. With a one-sided, two-sample t-test, 
123 subjects would be required for each group to achieve 80% power to detect non-inferiority. Here we 
conservatively set the significance level as 0.025 to ensure sufficient power when a two-sided test is 
used for the primary outcome, we will perform cross-sectional analyses using one-way ANOVA 
or linear models, followed by repeated measures ANOVA or linear models to estimate difference 
between treatment groups while simultaneously examining mean fasting BG across multiple 
days during treatment. Similar analyses will be conducted for continuous secondary outcomes. 
Chi-square tests (or Fisher’s Exact test), Logistic regression, and Poisson regression will be 
conducted to analyzed discrete secondary outcomes. A p-value of <0.05 is considered 
significant. We expect a very low attrition rate in the proposed study. Therefore, a total of 250 


 
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patients (125 patients per group) will be recruited in this pilot study. The proposed methods will 
be implemented by SAS (v9.2). 
 
VIII.   Protection against risks.   
VIII.a. Hypoglycemia.  We expect that <10% of subjects will experience episodes of 
hypoglycemia.  To minimize the risk, outpatient dose of insulin will be reduced by 20% on 
admission; and insulin naïve patients ≥ 70 years of age and/or with an eGFR < 60 will be started 
at a TDD of 0.3 U/kg/day. 
VIII.b. Severe hyperglycemia.  Patients with persistent hyperglycemia (≥3 consecutive BG 
readings > 260 mg/dL or a mean daily BG ≥ 260 mg/dL) after the 1st day of treatment will be 
considered as treatment failure and will be switched to continuous insulin infusion if needed.  
Patients randomized to group 1 will receive insulin supplements for BG>140 mg/dL.  Those 
randomized to group 2 will receive insulin supplements only when BG > 260 mg/dL.  We 
anticipate that less than 1% of patients will experience severe hyperglycemic episodes (BG > 350 
mg/dL). 
VIII.c.   Data and Safety Monitoring Plan (DSMP).  
The DSM committee will review unblended data on safety, treatment compliance, and evaluate 
the efficacy of the intervention being studied in this clinical trial. The DSMC will meet at 6-
month intervals and report on study progress to the IRB.  
 
VIII.d.   Interim Analysis and Stopping Rules.  An independent data safety and monitoring 
board will assess hospital complications and severe hypoglycemic events.  The trial will be 
stopped if there is evidence beyond a reasonable doubt of a difference between groups on 
hospital complications (two-sided alpha level, <0.01) or if severe hypoglycemic events (<40 
mg/dL) are >20%.  
 
IX. Timetable. Our research team has extensive experience in conducting prospective RCTs 
comparing different insulin regimens in T2DM. We have postdoctoral fellows and research 
coordinators in the 2 hospitals affiliated with Emory University.  Based on our experience, we 
can recruit 4 to 8 medical/surgical patients with T2DM per week, thus we anticipate completing 
recruitment in 12 to 18 months.  
X. Potential Benefits to the Subject.  We believe that all subjects will benefit greatly from this 
study.  Intensified BG monitoring and glycemic control may significantly reduce hospital 
complications associated with hyperglycemia and hypoglycemia.   


 
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XI.  Potential Benefits to Society.  This study will provide clinically useful information by 
determining benefits of insulin supplementation prior to meals in improving glycemic control 
and in reducing hypoglycemia in insulin treated patients with T2DM. 
XII.   Risk/Benefit Assessment.  Insulin therapy is the mainstay of diabetes management in 
medical and surgical patients with diabetes.   There are no prospective, randomized studies to 
assess the benefits of insulin supplementation in non-ICU patients with T2DM treated with a 
basal bolus regimen.  Basal bolus regimen has been shown to be effective in general medicine 
and surgery patients; however, some patients may experience mild and moderate hypoglycemia.  
XIII. Therapeutic Alternatives.  Patients can be treated with oral pharmacological agents and 
several different types of insulin are currently available at Grady Hospital and Emory University 
Hospital and other institutions for the treatment of T2DM.   
XIV. Inclusion of women.  We anticipate that ~50% of the study subjects will be female.  No 
patients under the age of 18 and no pregnant women will be included in the study.  Absence of 
pregnancy must be demonstrated by blood or urine testing if clinically indicated (i.e., female 
subjects of child bearing potential).   
XV. 
Inclusion of minorities.  Patients will not be excluded based on race or ethnic origin.  
We anticipate that approximately one-third of patients will be African Americans, Hispanics, and 
Caucasians.   
XVI. Inclusion of children.  No patients under the age of 18 will be recruited in this study. 
XVII. Confidentiality.  Informed consent will follow the procedure of Emory University 
Institutional Review Board. Every potential participant will be informed in writing and verbally 
with the important key points of the study. One of the investigators or research coordinators will 
obtain a witnessed informed consent prior to inclusion of a patient into the study. Data collection 
records with personal identifiers will be stored in locked file cabinets. Presentation of the study 
results at regional or scientific meetings or in publications will not identify subjects. Access to 
research and confidential records will be limited to clinical investigators, coordinators, and the 
IRB at Emory University. 
XVIII.   Payment for Participation.  Participation in this study is voluntary.  Patients will 
receive twenty dollars ($20.00) prior to discharge.  If a participant should stop participation 
before completion, the payment will be prorated at $10.00 per day to a maximum of twenty 
dollars ($20.00).  
XIX. Financial Obligation.  No additional cost to patients or to the institution will be incurred   
for research purposes.  Glargine, detemir, aspart and lispro are formulary drugs and represent the 
standard of care in our institutions. Glargine detemir, aspart and lispro, syringes, glucose meter 
and strips, and oral antidiabetic drugs will not be provided as part of the study.    


 
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XX. 
Research Injuries.  If a patient is injured because of taking part in this study, Dr. 
Vellanki along with the Emory Co-Investigators with the medical facility will make medical care 
available to the patient at patient’s own cost.  Financial compensation for such things as lost 
wages, disability or discomfort due to an injury related to the study is not available.   
XXI. Financial Conflict of Interests.   None of the investigators in this study have any outside 
activities that may represent a conflict of interest.  None of the investigators have an economic 
interest in an outside entity, or act as officers, directors, employees or consultants with such an 
entity, whose financial interest may be affected by this research study. 
XXII. Informed Consent.   After identification of eligible patients these individuals will be 
provided basic information regarding the study and, if interested, they will then be screened by 
research staff using the inclusion/exclusion criteria delineated elsewhere in this protocol.  The 
consent form, potential risks and benefits, and the rights of research participants will be 
explained to the participant by the investigators or research coordinator.  Individuals will be 
asked if they have any questions, and if present, questions will be answered by research staff.  
The principal investigator will also be available at all times to answer questions that participants 
may have during the consent procedure or during the time a participant is enrolled in the study.  
The consent form will be completed in accordance with the IRB guidelines of Emory University.  
A signed copy of the consent form will be provided to the participant and a copy will be placed 
in the file that is maintained for each participant in the study office.   
 
XXIII.   Medical Device Research. Not applicable. 
 
  
 
 


 
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