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Sugar and Spice status post NICE:
Hypoglycemic Management and
Lessons Learned Half a Decade
after the NICE-SUGAR trial
MEGAN ALLEN, PHARMD, BCPS, BCPPS
Disclosure Statement

I do not have any conflicts of interest to disclose
Pharmacist Objectives

Discuss the pathophysiology of type 1 and 2 diabetes mellitus (DM)

Compare and contrast the pharmacologic management between
type 1 and 2 DM

Define hypoglycemia and discuss the available treatment options
Technician Objectives

Discuss the pathophysiologic mechanism of types 1 and 2 diabetes
mellitus (DM)

Differentiate between the common pharmacologic management
of types 1 and 2 DM

Define hypoglycemia and understand the urgency of
pharmacologic treatment
Types 1 and 2 DM
OVERVIEW
Defining Diabetes

Diabetes – disorder of the metabolic homeostasis controlled by insulin,
resulting in abnormalities of carbohydrate (CHO) and lipid metabolism

Type 1 DM – caused by absolute insulin deficiency, the result of a loss of
beta cells of the pancreas

Type 2 DM - caused by a progressive loss of insulin secretion

Other

Gestational DM

Cystic fibrosis-related DM (CFRD)

Drug or chemical induced diabetes

Monogenic diabetes
Diabetes Care Volume 39, Supplement 1, January 2016
Diagnostic Tests

Plasma glucose criteria

Fasting plasma glucose (FPG) ≥ 126 mg/dL

2 – h plasma glucose (2 – h PG) after 75 grams oral glucose tolerance
test (OGTT) ≥ 200 mg/dL

A1C ≥ 6.5%

Classic symptoms of hyperglycemia or hyperglycemic crisis +
random plasma glucose ≥ 200 mg/dL
Diabetes Care Volume 39, Supplement 1, January 2016
Age
Red blood cell
turnover
A1C
Considerations
Hemoglobinopathies
/ Anemias
Diabetes Care Volume 39, Supplement 1, January 2016
Race / Ethnicity
Increased Risk for Diabetes

Overweight/obese adults + 1 or more additional risk factor for
diabetes


Testing should begin at 45 yo for ALL patients


Considered in children and adolescents who are overweight/obese + 2
risk factors for diabetes
Repeat tests if normal q3years
FPG (100 – 125 mg/dL) or 2 – h OGTT (140 – 199 mg/dL) or A1C (5.7 –
6.4%) can be used to test for prediabetes
Diabetes Care Volume 39, Supplement 1, January 2016
Type 1 and 2 DM
CLASSIFICATION
Type 1 DM
Immune-mediated

“Insulin dependent diabetes” or
“juvenile-onset diabetes”

5-10% of diabetes

Cellular-mediated destruction of
the pancreatic beta cells

Autoimmune markers: islet cell
autoantibodies, autoantibodies to
insulin, GAD, tyrosine
phosphatases, ZnT8

Genetic predispositions

Environmental markers
Diabetes Care Volume 39, Supplement 1, January 2016
Idiopathic

No known etiology

Permanent insulinopenia and
prone to ketoacidosis with no
evidence of beta cell
autoimmunity

More common in African or Asian
ancestry
Type 1 DM
Onset
Clinical
Presentation
Diabetes Care Volume 39, Supplement 1, January 2016
•Presents at any age
•No longer a “childhood” disease
•Polyuria, polydipsia
•Diabetic ketoacidosis (DKA)
Type 1 DM Recommendations

Blood glucose rather than A1C should be used to diagnoses acute
onset

Inform relatives of patients with type 1 DM of the opportunity to be
tested
Diabetes Care Volume 39, Supplement 1, January 2016
Type 2 DM

“Non-insulin dependent diabetes” or “adult-onset diabetes”

Insulin resistance and relative insulin deficiency

Etiologies

Excess weight increases insulin resistance

Insulin secretion is defective
Diabetes Care Volume 39, Supplement 1, January 2016
Type 2 DM
Onset and Risk
Factors
Clinical Presentation
• Any age
• Overweight/obesity
• Genetic
predisposition
• Racial/ethnic
subgroups
• Mild polyuria,
polydipsia, nausea
• Hypertension,
hyperlipidemia,
acanthosis nigricans
• Rarely ketoacidosis
Diabetes Care Volume 39, Supplement 1, January 2016
Type 2 DM Recommendations

Testing in asymptomatic patients who are obese/overweight with 1
or more risk factors

Consider testing in children and adolescents who are obese/overweight
with 2 or more risk factors

All patients, testing should begin at age 45

FPG, 2 – plasma glucose, A1C are all appropriate tests
Diabetes Care Volume 39, Supplement 1, January 2016
Type 1 and 2 DM
MONITORING AND GOALS
Glycemic Monitoring

Self-monitoring of blood glucose (SMBG) may guide treatment
decisions for self-management for patients on insulin regimens


Prior to meals/snacks, postprandially, bedtime, prior to exercise, if
hypoglycemia is suspected, and driving
Continuous glucose monitoring (CGM) may help lower A1C in adults
with Type 1 DM

Supplemental tool for SMBG for patients with hypoglycemia
unawareness and/or frequent hypoglycemic episodes
Diabetes Care Volume 39, Supplement 1, January 2016
A1C Testing

Perform at least twice yearly in patients who are meeting goals with
stable glycemic control

Perform quarterly in patients who have had therapy changes or are
not meeting glycemic goals

May consider point of care A1C testing for more timely treatment
changes
Diabetes Care Volume 39, Supplement 1, January 2016
A1C Goals
< 6.5%
< 8%
Why measure A1C?
Microvascular
Complications
Cardiovascular
Disease
Glycemic
Targets
Diabetes Care Volume 39, Supplement 1, January 2016
•Improved glycemic control is associated with decreased
microvascular complications and neuropathic complications
•Appropriate as long as significant hypoglycemic is not a barrier
•Lower risk of CVD events with intensive glucose control
•Risks of intensive glycemic control may outweigh benefits in
higher-risk patients
•Needs to be discussed with the patient
•Preprandial vs. postprandial glucose monitoring
Glycemic Recommendations
Target
Goal
A1C
< 7%
Preprandial glucose
80 – 130 mg/dL
Peak postprandial glucose
< 180 mg/dL
Diabetes Care Volume 39, Supplement 1, January 2016
Type 1 DM
PHARMACOLOGIC MANAGEMENT
Recommendations


Insulin therapy

Multiple-dose insulin injections

Continuous insulin infusion
Education

Matching prandial insulin dose to CHO intake, premeal blood glucose,
and anticipated activity
Diabetes Care Volume 39, Supplement 1, January 2016
Diabetes Control and
Complications Trial (DCCT)


Intensive insulin therapy or continuous insulin infusions was integral in
improved glycemia and outcomes

Benefit: better microvascular, macrovascular, and all-cause mortality

Risk: high rate of severe hypoglycemia
Since the study, insulin analogs have been developed to decrease
hypoglycemia
Diabetes Care Volume 39, Supplement 1, January 2016
Rapid-Acting Insulins
Insulin
Onset
Peak
Duration
Lispro
(Humalog®)
15 – 30 min
0.5 – 2.5 hours
≤ 5 hours
Aspart
(Novolog®)
15 – 20 min
1 – 3 hours
3 – 5 hours
Glulisine
(Apidra®)
12 – 30 min
1.6 – 2.8 hours
3 – 4 hours
Oral Inhalation
Afrezza®
~15 min
~ 53 min
2.5 – 3 hours
Insulin lispro U-200
(Humalog® U-200)
15 min
0.5 – 1.5 hours
3 – 5 hours
Insulin. In: Lexi-Comp Online™. Hudson, OH, Inc. [Accessed 21 Oct 2016].
Rapid-Acting Insulins

Lispro or aspart preferred

Fast onset of action

May give immediately post meal

Fairly predictable pharmacokinetic profiles

Mixing insulins

Either can be mixed with NPH

Do not mix with long-acting insulins
Short-Acting Insulin
Insulin
Onset
Peak
Duration
Regular
(Humulin R®, Novolin R®)
15 – 30 min
U-100: 2.5 – 5 hours
U-500: 4 – 8 hours
U-100: 4 – 12 hours
U-500: 13 – 24 hours
Regular U-500
(Humulin R® U-500)
30 min
8 hours
Up to 24 hours
Insulin. In: Lexi-Comp Online™. Hudson, OH, Inc. [Accessed 21 Oct 2016].
Intermediate-acting Insulin

Onset
Peak
Duration
NPH
(Humulin®,
Novolin®)
1 – 2 hours
4 – 12 hours
14 – 24 hours
Pro


Insulin
Twice daily dosing (less injections)
Con

Variability from dose to dose
Insulin. In: Lexi-Comp Online™. Hudson, OH, Inc. [Accessed 21 Oct 2016].
Long-acting Insulin
Insulin
Onset
Peak
Duration
Detemir
(Levemir®)
3 – 4 hours
3 – 9 hours
5 – 7 hours
Glargine
(Lantus®)
3 – 4 hours
No peak
10.8 to > 24 hours
Degludec
(Tresiba®)
~1 hour
9 hours
> 24 hours
Glargine U-300
(Toujeo®)
6 hours
No peak
36 hours
Insulin. In: Lexi-Comp Online™. Hudson, OH, Inc. [Accessed 21 Oct 2016].
Long-acting Insulin
Detemir
Glargine
Degludec
• Cannot be mixed
with other insulins
• Higher frequency
of injection site
reactions
• Compared to
NPH, ↓ weight
gain, ↓
hypoglycemia,
smoother activity
profile
• Cannot be mixed
with other insulins
• Improved glucose
control
compared to NPH
• May ↓ frequency
of hypoglycemia
• Labeled as once
daily dosing
• Cannot be mixed
with other insulins
• FDA approved in
adults only
• Available as 100
units/mL and 200
units/mL flex
touch pens
Insulin. In: Lexi-Comp Online™. Hudson, OH, Inc. [Accessed 21 Oct 2016].
Combination Insulins
Insulin
Onset
Peak
Duration
Aspart/Degludec
(Ryzodeg® 70/30)
~14 min
2.3 hours
> 24 hours
Aspart protamine +
insulin aspart
(Novolog® Mix
70/30)
10 – 20 min
1 – 4 hours
18 – 24 hours
Lispro protamine +
insulin lispro
(Humalog® Mix
75/25)
15 – 30 min
1 – 6.5 hours
14 – 24 hours
NPH + insulin regular
(Novolin® 70/30)
30 min
2 – 12 hours
18 – 24 hours
Insulin. In: Lexi-Comp Online™. Hudson, OH, Inc. [Accessed 21 Oct 2016].
Insulin Clinical Pearls

Self-mixing

Clear before cloudy

Vials of cloudy insulin must be gently rolled 10 – 20 times to mix
solution

Rotate injection sites to avoid lipodystrophy
I:CHO Ratio

Specifies how many grams of CHO are “covered” by 1 unit of insulin



Example: 1:40  1 unit of insulin covers 40 g of CHO
Calculation

500 / Total Daily Dose (TDD)

Example: Patient is on 20 units of insulin daily, what is the I:CHO ratio?
If the patient eats 50 g of CHO, how much insulin should be
administered?
Correction or Sensitivity Factor


Specifies how many points the blood glucose will drop per unit of
insulin

1800 rule  used for analog insulin

1500 rule  used for regular insulin
Calculation


Sensitivity factor (SF) = 1800 / TDD
May vary depending on time of day
Insulin Pens

Carry insulin in a self-contained cartridge

Advantages



Portable, discreet, convenient

Pre-filled (time-saver)

Accurate dosing
Disadvantages

May be more expensive

No all types of insulin are available

Cannot be mixed
Recommended to rotate injection sites
Insulinpens.com
Inpatient Use of Insulin Pens

Institute for Safe Medication Practices (ISMP)

Recognized ongoing safety concerns and recommends hospitals to
reexamine policies regarding insulin pens for routine use

Safety concerns

Increase risk of infection when pens are used for multiple patients

2013: New York hospital may have exposed patients to HIV, hepatitis B, or hepatitis
C because of the reuse of pens after changing the disposable needle

Risk of needle stick injuries

User technique errors
ISMP Medication Safety Alert Volume 18 (3), February 2013
Pen Exceptions?

U-500 insulin

A specific syringe to measure doses is not available

Tuberculin (TB) syringe or a U-100 syringe is recommended


Doses need to be converted depending on syringe type (U-100 markings vs.
volume)
ISMP Recommendations

US Food and Drug Administration approved Humulin R U-500 Kwikpen

Set to measure in 5 unit increments

Hospitals may consider use to eliminate dose conversion errors
ISMP Medication Safety Alert. Quarterly Action Agenda. April 2015
Insulin Pumps

Allows individualization of therapy

Helps to adjust for variables

Timing and type of meals

Timing and type of exercise

Hormonal fluctuations

Allows tracking of missed bolus doses

Weight gain may occur in the first few
months
http://www.isletsofhope.com

Recommended to rotate injection sites
Additional Treatment Options



Pramlintide

Amylin analog which delays gastric emptying, blunts pancreatic secretion of glucagon, and
enhances satiety

Induces weight loss and lowers insulin doses
Pancreas and islet cell transplantation

Pro: normalizes glucose levels

Con: lifelong immunosuppression
Metformin


Incretin-based therapies


May improve metabolic control in overweight/obese patients with poorly controlled diabetes
Data in type 2 DM  now being evaluated in type 1 DM
Sodium-glucose cotransporter 2 inhibitors (SGLTZ)

Data in type 2 DM  now being evaluated in type 1 DM
Diabetes Care Volume 39, Supplement 1, January 2016
Type 2 DM
PHARMACOLOGIC MANAGEMENT
Recommendations

Metformin is preferred initial pharmacologic agent

Insulin therapy in newly diagnosed type 2 DM patients who are
markedly symptomatic and/or elevated blood glucose

Add second agent if noninsulin monotherapy is a maximum
tolerated dose and still not at goal A1C over 3 months

Do not delay insulin therapy when glycemic goals are not met
Diabetes Care Volume 39, Supplement 1, January 2016
Treatment Timeline
Triple therapy
Dual therapy
Metformin
Lifestyle
Modifications
Combination
injectable
therapy
Diabetes Care Volume 39, Supplement 1, January 2016
Combination Therapy

Each additional agent lowers A1C ~ 0.9-1.1%

If A1C target not reached after 3 months, consider combination
therapy with metformin AND


Sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1
receptor antagonist, basal insulin

Meglitinides may be used instead of sulfonylureas in patients with
irregular meal schedules or develop late postprandial hypoglycemia
Considerations

Patient preferences, goals of reducing blood glucose, minimizing side
effects, cost effectiveness
Diabetes Care Volume 39, Supplement 1, January 2016
Diabetes Care Volume 39, Supplement 1, January 2016
Diabetes Care Volume 39, Supplement 1, January 2016
Insulin Therapy

Considered for all patients on dual combination therapy and A1C ≥
9%

Allows for goal to be met faster

Beneficial in those with severe hyperglycemia (BG ≥ 300 – 350 mg/dL
and/or A1C ≥ 10 – 12 %

May simplify regimen as goals are met
Diabetes Care Volume 39, Supplement 1, January 2016
Insulin Regimens

Basal insulin is the most convenient regimen (0.1 – 0.2 units/kg)


May consider intermediate insulin (NPH) in patients without history of
hypoglycemia
Bolus insulin

Added when basal titrated to acceptable fasting blood glucose level,
but A1C not at goal

1 – 3 injections of rapid acting insulin

May consider GLP-1 receptor antagonist

Less data in switching to a twice daily biphasic insulin analog
Diabetes Care Volume 39, Supplement 1, January 2016
Diabetes Care Volume 39, Supplement 1, January 2016
Type 1 and 2 DM
HOSPITALIZED PATIENTS
Inpatient Recommendations

Consider checking A1C on all patients with diabetes or hyperglycemia

Insulin therapy should be initiated for treatment of persistent hyperglycemic (≥
180 mg/dL)

Goal sugars between 140 – 180 mg/dL

May target 110 – 140 mg/dL for selected critically ill patients

Basal + bolus regimen is preferred for noncritically ill patients who are NPO

Sole use of sliding scale insulin is discouraged

Hypoglycemia protocol should be implemented


Treatment plans should be reviewed and changed to prevent hypoglycemia
Should have a structured discharge plan
Diabetes Care Volume 39, Supplement 1, January 2016
Glycemic Targets in Hospitalized
Patients

Hyperglycemia defined as BG > 140 mg/dL

Admission A1C ≥ 6.5% suggests diabetes precedes admission

Hypoglycemia defined as BG < 70 mg/dL


Severe hypoglycemia BG < 40 mg/dL
Moderate vs. Tight glycemic control????
Diabetes Care Volume 39, Supplement 1, January 2016
Normoglycemia in Intensive Care Evaluation –
Survival Using Glucose Algorithm Regulation
(NICE-SUGAR)

Meta-analysis of over 26 studies looking at optimal blood glucose
ranges for critically ill patients

Intensive glucose control (BG 81 – 108 mg/dL) vs. conventional
glucose control (≤ 180 mg/dL)


Primary end point: death from any cause within 90 days after
randomization
Included 6104 patients
N Engl J Med 2009;360:1283-97.

3054 intensive control

3012 conventional control
NICE-SUGAR Trial
Intensive Glucose Control
Conventional Glucose Control

829 (27.5%) patients died

751 (24.9%) patients died

206 (6.8%) patients had severe
hypoglycemia

15 (0.5%) patients had severe
hypoglycemia
Results
• Death was not statistically significant different between treatment groups
• The treatment effect was not statistically different between surgical and
medical patients
• Severe hypoglycemia was statistically significant (P < 0.001)
• No significant different in number of days in ICU or hospital
• No significant different in number of mechanical ventilation days
N Engl J Med 2009;360:1283-97.
NICE-SUGAR Conclusions

Intensive glucose control increased mortality in critically ill adults
with a number need to harm of 38

Deaths from cardiovascular causes was more common in the intensive
control group

Severe hypoglycemia was more common with intensive glucose
control

BG < 180 mg/dL resulted in lower mortality than a target of 81 – 108
mg/dL in critically ill adult patients
N Engl J Med 2009;360:1283-97.
NICU-SUGAR: Affecting Clinical
Practice?
Intensive
Glucose
Control
Conventional
Glucose
Control
Glycemic Control after NICESUGAR

Glucose target of 140 – 180 mg/dL when insulin therapy is initiated in
critically ill adults

Tighter goals (110 – 140 mg/dL) if achieved without significant
hypoglycemia

Cardiac surgery patients

Acute ischemic cardiac events

Neurological patients
Diabetes Care Volume 39, Supplement 1, January 2016
Type 1 and 2 DM
HYPOGLYCEMIA
Hypoglycemia

Major limiting factor in glycemic management of types 1 and 2 DM

Mild hypoglycemia may frighten individuals and is inconvenient

Severe hypoglycemia is characterized by cognitive impairment

Progress to unconsciousness

Seizure

Coma

Death

Injury (falls, car accident, etc.)
Diabetes Care Volume 39, Supplement 1, January 2016
Hypoglycemia Signs and Symptoms
Shaky
Weakness or
fatigue
Tachycardia
Irritability
Sweating
Headache
Dizziness
Blurred
Vision
Anxious
Hypoglycemia Recommendations

Ask patients about symptomatic and asymptomatic hypoglycemic
events

Glucose 15 – 20 g is preferred treatment for conscious patients

Glucagon should be prescribed to all individuals at risk of severe
hypoglycemia

Hypoglycemia unawareness or one or more episodes of severe
hypoglycemia necessitates evaluation of treatment regimen

Patients on insulin with severe hypoglycemia or hypoglycemia
unawareness should raise their glycemic targets
Diabetes Care Volume 39, Supplement 1, January 2016
Hypoglycemia Treatment

Ingestion of glucose or carbohydrate

Pure glucose is preferred


Added fat may prolong acute glycemic response

Ongoing insulin activity may result in recurrent hypoglycemia unless
additional food is ingested after recovery
Glucagon

Need to educate family members, roommates, school personnel, child
care providers, etc. on the use of glucagon kits
Diabetes Care Volume 39, Supplement 1, January 2016
Hypoglycemia Prevention

Major part of diabetes management

Recognize situations that increase risk of hypoglycemia


Fasting for tests/procedures

During or after intense exercise

During sleep
Recognize the importance of understanding hypoglycemia

Increase risk of harm to self or others
Diabetes Care Volume 39, Supplement 1, January 2016
Hypoglycemia in the Inpatient
Setting


Treatment

Standardized hypoglycemia protocol is recommended

Nurse initiated treatment protocol for BG < 70 mg/dL

All hypoglycemic events are recommended to be reviewed
Prevention

Considerations: improper prescribing of hypoglycemic medications,
inappropriate management of first episode, nutrition-insulin mismatch,
unexpected interruption of nutrition
Diabetes Care Volume 39, Supplement 1, January 2016
Hypoglycemia Inpatient
Medications

Treat orders as STAT


Orders the pharmacy may not see


Filled and sent to the floor immediately as delays in care can impact
outcomes
15 – 20 g CHO
Common medications (consider hypoglycemic kits)

Glucose gel or glucose tabs

D10, D25, and D50 bolus

Glucagon
Questions?