Liberal versus tight Glycemic Control

in critically ill

Dr. Shihan Mahmud Redwanul Huq

Associate Consultant-
Internal Medicine & Critical care
Square Hospitals Ltd
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 Prevalence of hyperglycemia in Hospitalized patients

• The prevalence of hyperglycemia among hospitalized patients is

32%–38% [1]
• 1/3 with newly discovered hyperglycemia / stress hyperglycemia
(HbA1c <6.5%)
• Reported in 55%-80% critically ill patients [2]

1. Smiley D., Umpierrez G.E. Management of hyperglycemia in hospitalized patients. Ann N Y

Acad Sci. 2010;1212:1–11.
2.NICE-SUGAR trial March 26, 2009 N Engl J Med 2009; 360:1283-1297
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 Total In-patient Mortality

16.00%
14.00% 16.0%
12.00%
10.00%
8.00%
6.00%
4.00%
2.00% 3.0%
1.7%
0.00%
Normoglycemia Known Diabetes New
Hyperglycemia
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 UKPDS
A 1% Decrease in HbA1c Is Associated with a Large Reduction in Complications

Microvascular
37% complications (eg, kidney
disease and blindness)

Amputation or fatal
43% peripheral blood vessel
disease
HbA1c

1%
21% Deaths related to
diabetes

14% Heart attack

12% Stroke
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Stratton IM, et al. BMJ. 2000;321(7258):405-412. 4

 Control of Hyperglycaemia in Critically Ill Patients

• Reduces
– ICU & in-hospital mortality
– Blood stream infection
– AKI (also HD or HF)
– RBC transfusion
– Critical-illness polyneuropathy

• Accelerates weaning from MV

• Shortens ICU & hospital stay

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 Tight glycemic control ?
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 Leuven Surgical trial (2001)

• 1548 surgical ICU patients

• IIT (intensive insulin therapy/insulin infusion)
targeting a blood glucose 80-110 mg/dl (4.4 to 6.1
mmol/L)
• Insulin infusion only if BG>215 mg/dl (11.9 mmol/L)
Results:
significantly reduce ICU & hospital mortality, reduce
critical illness polyneuropathy,AKI,blood stream
infections,transfusion requirement.
Hypoglycemia 5%
 Leuven Medical trial

• 1200 medical ICU patients

• Tight control 80-110 (4.4-6.1 mmol/L)
• Conventional 180-200 mg/dl (10-11.1 mmol/L)

Results:
• No mortality benefit
• Reduce length of stay both ICU &
hospital,duration of ventilation,AKI
• More hypoglycemia (18% vs 3%)
 NICE-SUGAR trial
March 26, 2009
N Engl J Med 2009; 360:1283-1297

• 6104 medical & surgical ICU patients

• IIT control 81-108mg/dl (4.5 -6 mmol/L)
• Conventional < 180 mg/dl ( <10 mmol/L)
Results:
• Higher hypoglycemia (6.8% vs 0.5%)
• Higher mortality in IIT group
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 GluControl Trial
• 1101 mixed ICU patients
• IIT (4.4-6.1 mmol/L)
• Conventional 140-180 mg/dl
(7.8-10 mmol/L)
Results:
No mortality difference
• Increases hypoglycemia in IIT
group.
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VISEP trial
multi-center RCT investigating tight glycemic control
among 537 patients in Germany with severe sepsis.
Terminated early due to
harm (patients treated with tight
glycemic control experienced an
increased rate of severe
hypoglycemia and severe adverse
events).
10
 Recommendation ( SCCM, ADA 2020)s

Target blood glucose

140-180 mg/dl (7.7-10 mmol/L)
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 Diabetic Vs Non-diabetic

• In nondiabetic populations,
• hyperglycemia and higher glycemic variability correlate with mortality. 

• Among patients with diabetes:

• Hyperglycemia does not generally correlate with mortality.
• Hypoglycemia still does correlate with mortality.
• Glycemic variability may still correlate with mortality.
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 Other variables affecting mortality

• Acute hyperglycemia or Stress hyperglycemia

• Hypoglycemia
• Glycemic variability (GV)
• Glycemic Gap
• Time in the target range (TITR).
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 Glycemic variability
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PATIENT B HAS RELATIVELY SMALL VARIATIONS DURING THE DAY AND ON

DIFFERENT DAYS;
PATIENT A HAS MARKED BLOOD GLUCOSE VARIATIONS ON THE SAME DAY PATIENT

C HAS MARKED BLOOD GLUCOSE VARIATIONS ON DIFFERENT DAYS  

 Glycemic Gap
• The gap between admission glucose and
A1C-derived average glucose (ADAG) 
• ADAG = [(28.7 × HbA1c) - 46.7
• Critically ill patients with diabetes and a
glycemic gap ≥80 mg/dL had significantly
higher ICU mortality and adverse
outcomes than those with a glycemic gap
<80 mg/dL (P < 0.001). 
 This study revealed the presence of a U-shaped relationship between
the glycemic gap and mortality in critically ill patients.
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 Time in target range
Defined as the accumulated time in the target band and
expresses the percentage of time in which a patient's
glycemic level remains within the target range. 

• GluControl study,TITR greater than 50% was

associated with greater survival.

• Omar et al (2015)80% was associated with a significant

reduction in postoperative atrial fibrillation as well as
with shorter mechanical ventilation time, shorter ICU
stay and lower incidence of infection of the operative
wound.
 Diabetes Care in the Hospital
American Diabetes Association Diabetes Care 2016 Jan; 39(Supplement 1): S99-S104

• Consider performing an A1C on all patients with diabetes or hyperglycemia

admitted to the hospital if not performed in the prior 3 months. C
• Insulin therapy should be initiated for treatment of persistent hyperglycemia
starting at a threshold ≥180 mg/dL (10.0 mmol/L). 
• Once insulin therapy is started, a target glucose range of 140–180 mg/dL (7.8–
10.0 mmol/L) is recommended for the majority of critically ill patients A and
noncritically ill patients. C
• More stringent goals, such as 110–140 mg/dL (6.1–7.8 mmol/L) may be
appropriate for selected critically ill patients, who have recent cardiac
surgery, cardiac ischemia, or stroke; as long as this can be achieved
without significant hypoglycemia. C
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 Diabetes Care in the Hospital

• A basal plus bolus correction insulin regimen is the preferred treatment for
noncritically ill patients with poor oral intake or those who are taking nothing by
mouth.
• An insulin regimen with basal, nutritional, and correction components is the
preferred treatment for patients with good nutritional intake. A
• The sole use of sliding scale insulin in the inpatient hospital setting is strongly
discouraged. A
• Reactive rather than proactive
• The treatment regimen should be reviewed and changed if necessary to
prevent further hypoglycemia when a blood glucose value is <70 mg/dL
(3.9 mmol/L). C
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 21

Flow Chart
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 Use BASAL + BOLUS + CORRECTION

BOLUS + CORRECTION In-hospital circumstances may

warrant temporarily holding
other antihyperglycemic
medications (eg. renal or hepatic
Insulin

impairment)

Insulin = treatment of choice

BASAL + BOLUS +
BASAL CORRECTION
Breakfast Lunch Dinner
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 Short-Acting Insulin Analogs

Lispro Aspart
Plasma insulin (pmol/L) 400 500

Plasma insulin (pmol/L)

350 450
400
300
350
250 300
200 250
150 200
150
100
Regular 100
50 50 Regular
0 0
0 30 60 90 120 150 180 210 240 0 50 100 150 200 250 300
Time (min) Time (min)
Meal Meal
SC injection SC injection
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Heinemann, et al. Diabet Med. 1996;13:625–629; Mudaliar, et al. Diabetes Care.

1999;22:1501–1506. 23
 Insulin analogues (Humalog )are associated with

Less hypoglycemia1,2

Less weight gain1,2

Lower HbA1c1,2

Better PPG and FPG control1,2

1.Nathan DM. et.al. N Engl J Med 2005;353:2643-2653.

2. American Diabetes Association. Standards of Medical Care in
Diabetes 2018.Diabetes Care 2018;41 (1):S74.
@ 2018 Eli Lilly and Company
 Hypoglycemia Rates
Lower nocturnal hypoglycemic episodes1 and rates 2,3

Mean number of episodes/patient/30 days Rates of symptomatic nocturnal hypoglycemia per

patient-year [mean (SD)]

12.8
Regular Human Insulin

0.73

Rapid- Acting Analogue 9.66

Insulin Lispro (Humalog®) 9.48
0.47
*p<0.001.
36% *

difference
Insulin lispro has significantly lower nocturnal hypoglycemia episodes compared Insulin Insulin Insulin
with Regular Human Insulin (p<0.001)
Glulisine Aspart Lispro
Insulin lispro has significantly lower nocturnal hypoglycemia episodes compared with
Insulin Glulisine (p<0.001)
1. Anderson JH, Jr. et al. Arch Intern Med. 1997;157:1249-1255. 2. van Bon AC, et al. Diabetes
Technol Ther. 2011;13(6):607-614 3. Thrasher J, et al. Endocr Pract. 2015 Mar;21(3):247-57

@ 2018 Eli Lilly and Company

ABASAGLAR and Lantus® provide similar HbA1c and FBG
reductions in T2DM
BASAGLAR Lantus®
Baseline HbA1c (%), FBG (mg/dL),
mean ± SD 8.3 ± 1.1 8.3 ± 1.1 mean ± SD 159 ± 45 160 ± 44

n=376a n=380a n=376a n=380a

0.0 0

Change in FBG ± SE (mg/dL)

Change in HbA1c ± SE (%)
-10

-0.5 -20

-30
−46
−48
-1.0 −1.29 -40
−1.34

-50

-1.5 -60
Week 24 Week 24
∆=0.052 ∆=0.28 ± 1.04
95% CI (−0.07 to 0.18) P=ns
P=ns
Lantus® is a registered trademark of sanofi
Study ABEC (phase 3; double-blind) at Week 241
a
Full analysis set; numbers reflect maximum sample size 1. Rosenstock et al. Diabetes Obes Metab 2015;17(8):734–41

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 Calculating Total daily dose

› Type 2 DM on insulin- Add

all insulin doses together
(this is the Total Daily
Dose)

› Convert 2/3rds (about 70%)

of the daily IV insulin
requirement to
subcutaneous insulin

BOEHRINGER INGELHEIM-LILLY ALLIANCE CONFIDENTIAL. FOR TRAINING PURPOSES ONLY.

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 • In once-daily steroids, prandial insulin dosing, often with intermediate-
acting (NPH) insulin, is a standard approach.
• For long-acting glucocorticoids such as dexamethasone and multidose or
continuous glucocorticoid use, long-acting insulin may be required to
control fasting blood glucose
• For patients receiving continuous peripheral or central parenteral
nutrition, human regular insulin may be added to the solution,
particularly if >20 units of correctional insulin have been required in the
past 24 h. A starting dose of 1 unit of human regular insulin for every 10 g
dextrose has been recommended .
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 DKA & HHS
• Management goals include restoration of circulatory volume and tissue perfusion,
resolution of hyperglycemia, and correction of electrolyte imbalance and acidosis.

• In critically ill and mentally obtunded patients with DKA or hyperosmolar

hyperglycemia, continuous intravenous insulin is the standard of care.

• There is no significant difference in outcomes for intravenous human regular insulin

versus subcutaneous rapid-acting analogs when combined with aggressive fluid
management for treating mild or moderate DKA

• Successful transition of patients from intravenous to subcutaneous insulin requires

administration of basal insulin 2–4 h prior to the intravenous insulin being stopped to
prevent recurrence of ketoacidosis and rebound hyperglycemia.
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 Newer Trial; permissive glycemic approach

• A 22-bed mixed ICU of a tertiary hospital in Australia. Patients: We compared 350 consecutive
patients with diabetes
• Liberal group 10 – 14 mmol/L
• Control group 6-10 mmol/L

• Result: In liberal group the prevalence of hypoglycemia was reduced, without

negatively affecting serum creatinine, the white cell count response, or other
clinical outcomes.

Ref: Liberal Glucose Control in ICU Patients With Diabetes: A Before-and-After Study
Luethi Nora et al.March 2018, Critical Care Medicine 46(6):1
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 New trial cont….

• Liberal Glucose Control in Critically Ill Patients with Pre-existing Type 2

Diabetes (LUCID) trial, 2020 ongoing
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 Learning Points

• To know baseline glycemic status, Hb A1C

• Patients with chronic hyperglycemia may be better served with a
more permissive strategy.
• Efforts to reduce glucose should be gentle and cautious (except in
DKA HHS)
• Prevent Hypoglycemia
• Use Basal bolus correction dose insulin.
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Thank You
 QUIZ
(please tick the correct answer. There may be more than one correct answer)

Q-1 What variables corelate with increased mortality in hospitalized

patient ?

• A) RBS 18 mmol/l in a critically ill patient where HbA1C was 8

• B) repeated drop of sugar below 4 mmol/l on insulin whose
HbA1 C on admission was 7.5
• C) In hospital sugar was Fasting 12 , RBS 16 mmol/L where
HbA1 C was 5.5
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 Q-2 : Factors affecting/predicting hypoglycemia while on
insulin ?

A)Intensive sugar control with insulin

B)Sepsis
C)Renal failure
D)Liver failure
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 Q-3:
A 60-year-old diabetic (on diet control) weight 60 kg, admitted for pneumonia.
He is taking regular diet. Fasting sugar 12 mmol/L & 2 h after lunch 18 mmol/L.
What is ideal insulin regimen for him?
A) Basal –Bolus-correction insulin
B) Basal – plus insulin
C) Sliding scale insulin

Q-4 : Ideal starting dosage of insulin would be?

D) Abasaglar 12 U + Humalog R S/C 4+4+4
E) Abasaglar 10 U + sliding scale short acting
F) Humalog Mix (pre-mixed )75/25 S/C 12+0+12
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 • Q-5:
A 50-yr-old patient with DKA was being treated with I.V. insulin
infusion @ 6 U/ hr for 12 hrs then reduced to 4U / hr for next 6 hrs
then 2 U / hr for next 6 hrs. His sugar is now stable & he started
NG feeding and u want to convert to subcutaneous form. What
would be the dose / regimen?

A)Glargin 32 U + Short acting (Regular) 11+11+11 + correction

B)Abasaglar 32 u + Humalog R 8+8+8+8 + correction
C)Short acting regular 22+22+22 plus correction
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 Q-6 : What are the rapid acting insulin analogue?

A) Abasaglar
B) Lispro
C)Aspart
D)Regular human insulin
E) Glulisine
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 Insulin Lispro (rDNA origin) [Humalog®]

First insulin analog &

First rapid-acting analog developed
and commercialized1

Mimic pattern of endogenous

pancreatic insulin secretion1

Indicated for normal glucose control

for patients requiring insulin2

1. Uy, et.al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2012:5 1-10.
2. Insulin Lispro (Humalog Kwikpen 100U/ml) Package Insert, Philippines. PV8110PLP.
@ 2018 Eli Lilly and Company
 AnswerS

Answer 1 : B & C
Ans 2: all ABCD
Ans 3: A
Ans 4: A
Ans 5 : A & B
Ans 6 : B C E
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