Updates in Insulin Therapy
Terrence Swade, MD
Objectives
• Review general diabetes management and
non-insulin therapies
• Review newer insulin molecules
• Review general concepts of using insulin
therapy in diabetics
AACE Comprehensive Care Plan
Disease management from
a multidisciplinary team
Antihyperglycemic
pharmacotherapy
Comprehensive
Care Plan
Comprehensive diabetes
self-education for the
patient
Therapeutic lifestyle
change
3
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
Noninsulin Agents
Available for T2D
Class
-Glucosidase
inhibitors
Primary Mechanism of Action
 Delay carbohydrate absorption from
intestine
 Decrease glucagon secretion
 Slow gastric emptying
 Increase satiety
 Decrease HGP
 Increase glucose uptake in muscle
 Decrease HGP?
 Increase incretin levels?
Agent(s)
Acarbose
Miglitol
Available as
Precose or generic
Glyset
Pramlintide
Symlin
Metformin
Glucophage or generic
Colesevelam
WelChol


Increase glucose-dependent insulin
secretion
Decrease glucagon secretion
Alogliptin
Linagliptin
Saxagliptin
Sitagliptin
Nesina
Tradjenta
Onglyza
Januvia
Dopamine-2 agonist

Activates dopaminergic receptors
Bromocriptine
Cycloset
Glinides

Increase insulin secretion
Nateglinide
Repaglinide
Starlix or generic
Prandin
Amylin analogue
Biguanide
Bile acid sequestrant
DPP-4 inhibitors
DPP-4, dipeptidyl peptidase; HGP, hepatic glucose production.
Garber AJ, et al. Endocr Pract. 2016;22:84-113.
Inzucchi SE, et al. Diabetes Care. 2015;38:140-149.
Continued on next slide
4
Noninsulin Agents
Available for T2D
Class
Primary Mechanism of Action

GLP-1 receptor
agonists
SGLT2 inhibitors
Sulfonylureas




Agent(s)
Available as
Increase glucose-dependent insulin
secretion
Decrease glucagon secretion
Slow gastric emptying
Increase satiety
Albiglutide
Dulaglutide
Exenatide
Exenatide XR
Liraglutide
Tanzeum
Trulicity
Byetta
Bydureon
Victoza
Increase urinary excretion of glucose
Canagliflozin
Dapagliflozin
Empagliflozin
Invokana
Farxiga
Jardiance
Glimepiride
Glipizide
Glyburide
Amaryl or generic
Glucotrol or generic
Diaeta, Glynase,
Micronase, or generic
Pioglitazone
Rosiglitazone
Actos
Avandia

Increase insulin secretion

Increase glucose uptake in muscle
and fat
Decrease HGP
Thiazolidinediones

GLP-1, glucagon-like peptide; HGP, hepatic glucose production; SGLT2, sodium glucose cotransporter 2.
Garber AJ, et al. Endocr Pract. 2016;22:84-113.
Inzucchi SE, et al. Diabetes Care. 2015;38:140-149.
Continued from previous slide
5
Monotherapy, Dual Therapy, and Triple
Therapy for T2D
Dual therapy*
Triple therapy*
Metformin (or other firstline agent) plus
First- and second-line
agent plus
Metformin
GLP1RA
GLP1RA
GLP1RA
SGLT2I
SGLT2I
SGLT2I
DPP4I
TZD†
DPP4I
TZD†
Basal insulin†
AGI
Basal insulin†
DPP4I
TZD†
Colesevelam
Colesevelam
SU/glinide†
BCR-QR
BCR-QR
AGI
AGI
SU/glinide†
SU/glinide†
Monotherapy*
AGI = -glucosidase inhibitors; BCR-QR = bromocriptine quick release; Coles = colesevelam; DPP4I = dipeptidyl peptidase 4 inhibitors;
GLP1RA = glucagon-like peptide 1 receptor agonists; Met = metformin; SGLT2I = sodium-glucose cotransporter 2 inhibitors; SU =
sulfonylureas; TZD = thiazolidinediones.
*Intensify therapy whenever A1C exceeds individualized target. Boldface denotes little or no risk of hypoglycemia or weight gain, few
adverse events, and/or the possibility of benefits beyond glucose-lowering.
† Use
with caution.
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
6
7
8
Current Insulin Options
Type
Basal Insulins
Prandial Insulins
Premixed Insulins
Human
U-100 NPH
U-100 regular human insulin
U-500 regular human insulin
Technosphere inhaled insulin
U-100 70/30 RHI
Analog
U-100 glargine
U-100 glargine equivalent*
U-100 detemir
U-100 degludec
U-200 degludec
U-300 glargine
U-100 lispro
U-100 aspart
U-100 glulisine
U-200 lispro
U-100 50/50 lispro
U-100 70/30 aspart
U-100 75/25 lispro
U-100 70/30
degludec/aspart
•
Analogue insulins are associated with less hypoglycemia than human insulins, although these
differences are not always statistically significant
*In the US, U-100 glargine equivalent is not approved as a biosimilar product.
Singh SR, et al. CMAJ. 2009;180:385-397. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA. FDA.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm477734.htm.
9
Pharmacokinetics of Available Insulins
Agent
Onset (h)
Peak (h)
Duration (h)
2-4
4-10
10-16
~1-4
No
pronounced
peak*
Up to 24†
BasalPrandial
Basal
NPH
Glargine
Detemir
Degludec
Regular U-500
Prandial
Regular
Aspart
Glulisine
Lispro
Inhaled insulin
≤0.5
~0.5-1
<0.5
~2-3
~2-3
~0.5-2.5
Considerations
Greater risk of nocturnal hypoglycemia compared to insulin
analogs
Less nocturnal hypoglycemia compared to NPH



Inject 30 min before a meal
Indicated for highly insulin resistant individuals
Use caution when measuring dosage to avoid
inadvertent overdose
Up to 8


Must be injected 30-45 min before a meal
Injection with or after a meal could increase risk for
hypoglycemia
~3-5


Can be administered 0-15 min before a meal
Less risk of postprandial hypoglycemia compared to
regular insulin
12-24
* Exhibits a peak at higher dosages.
† Dose-dependent.
NPH, Neutral Protamine Hagedorn.
Moghissi E et al. Endocr Pract. 2013;19:526-535. Humulin R U-500 (concentrated) insulin prescribing information. Indianapolis: Lilly USA, LLC.
10
Pharmacokinetic Profiles of
Insulins
Insulin Level
Rapid (lispro, aspart, glulisine, inhaled)
Short (regular)
Intermediate (NPH)
Long (glargine, degludec)
Long (detemir)
0
2
4
6
8
10
12
14
16
18
20
22
24
Hours
11
Adapted from Hirsch I. N Engl J Med. 2005;352:174-183.
Insulin Concentrations
Concentration
Units/mL
Units/vial
Units/pen
U-100
100
1000
(10 units per vial)
300
(3 mL/pen)
U-200
200
Not available in vials
600
(3 mL/pen)
U-300
300
Not available in vials
450
(1.5 mL/pen)
U-500
500
10,000
(20 units/vial)
1500
(1.5 mL/pen)
•
•
•
Insulin pens significantly reduce the risk of dosing errors and hypoglycemic events
Pens completely eliminate the need for converting doses based on the volume of insulin
injected
Dosing errors with U-500 insulin vials are common and dangerous but can be avoided with
newly available pens
–
5-fold higher insulin dose relative to the same volume of a U-100 insulin
Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA. Newton C, et al. AACE Annual Meeting. 2013 [abstract 271]. Segal AR,
et al. Am J Health Syst Pharm. 2010;67:1526-1535.
12
13
Common Principles in AACE/ACE and ADA/EASD
T2D Treatment Algorithms
• Individualize glycemic goals based on patient
characteristics
• Promptly intensify antihyperglycemic therapy to
maintain blood glucose at individual targets
– Combination therapy necessary for most patients
– Base choice of agent(s) on individual patient medical
history, behaviors and risk factors, ethno-cultural
background, and environment
• Insulin eventually necessary for many patients
• SMBG vital for day-to-day management of blood sugar
– All patients using insulin
– Many patients not using insulin
Garber AJ, et al. Endocr Pract. 2016;22:84-113.
Inzucchi SE, et al. Diabetes Care. 2015;38:140-149.
14
ADA/EASD T2D Treatment Algorithm
Healthy eating, weight control, increased physical activity & diabetes education
Monotherapy
Metformin
Efficacy*
Hypo risk
Weight
Side effects
Costs
high
low risk
neutral/loss
GI / lactic acidosis
low
If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Dual
therapy†
Efficacy*
Hypo risk
Weight
Side effects
Costs
Metformin
Metformin
Sulfonylurea
Thiazolidinedione
DPP-4
inhibitor
SGLT2
inhibitor
GLP-1 receptor
agonist
Insulin (basal)
high
moderate risk
gain
hypoglycemia
low
high
low risk
gain
edema, HF, fxs
low
intermediate
low risk
neutral
rare
high
intermediate
low risk
loss
GU, dehydration
high
high
low risk
loss
GI
high
highest
high risk
gain
hypoglycemia
variable
+
Metformin
+
Metformin
+
Metformin
+
+
Metformin
+
If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):
Metformin
Metformin
+
Triple
therapy
Metformin
+
Sulfonylurea
+
Thiazolidinedione
+
TZD
Metformin
+
+
DPP-4
Inhibitor
+
SU
SGLT-2
Inhibitor
+
SU
SU
Metformin
+
GLP-1 receptor
agonist
+
Metformin
+
Insulin (basal)
+
TZD
SU
or
DPP-4-i
or
DPP-4-i
or
TZD
or
TZD
or
TZD
or
DPP-4-i
or
SGLT2-i
or
SGLT2-i
or
SGLT2-i
or
DPP-4-i
or
Insulin§
or
SGLT2-i
or
Insulin§
or
Insulin§
or GLP-1-RA
or GLP-1-RA
or
or
Insulin
§
Insulin
or GLP-1-RA
§
If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:
Metformin
Combination
injectable
therapy‡
+
Basal Insulin +
Mealtime Insulin or
GLP-1-RA
15
Inzucchi SE, et al. Diabetes Care. 2015;38:140-149.
Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379.
ADA/EASD T2D Treatment Algorithm: Sequential
Insulin Strategies
#
Injections
Complexity
Basal Insulin
1
low
(usually with metformin +/other non-insulin agent)
• Start: 10U/day or 0.1-0.2 U/kg/day
• Adjust: 10-15% or 2-4 U once-twice weekly to
reach FBG target.
• For hypo: Determine & address cause;
ê dose by 4 units or 10-20%.
2
3+
Add 1 rapid insulin* injections
before largest meal
If not
controlled after
FBG target is reached
(or if dose > 0.5 U/kg/day),
treat PPG excursions with
meal-time insulin.
(Consider initial
GLP-1-RA
trial.)
Change to
premixed insulin* twice daily
• Start: 4U, 0.1 U/kg, or 10% basal dose. If
A1c<8%, consider ê basal by same amount.
• Start: Divide current basal dose into 2/3 AM,
1/3 PM or 1/2 AM, 1/2 PM.
• Adjust: é dose by 1-2 U or 10-15% oncetwice weekly until SMBG target reached.
• Adjust: é dose by 1-2 U or 10-15% oncetwice weekly until SMBG target reached.
• For hypo: Determine and address cause;
ê corresponding dose by 2-4 U or 10-20%.
• For hypo: Determine and address cause;
ê corresponding dose by 2-4 U or 10-20%.
If not
controlled,
consider basalbolus.
Add ≥2 rapid insulin* injections
before meals ('basal-bolus’†)
If not
controlled,
consider basalbolus.
mod.
high
• Start: 4U, 0.1 U/kg, or 10% basal dose/meal.‡ If
A1c<8%, consider ê basal by same amount.
• Adjust: é dose by 1-2 U or 10-15% once-twice
weekly to achieve SMBG target.
• For hypo: Determine and address cause;
ê corresponding dose by 2-4 U or 10-20%.
Flexibility
more flexible
less flexible
16
Inzucchi SE, et al. Diabetes Care. 2015;38:140-149.
Efficacy and Safety of U-100 Glargine
Equivalent
Severe
(BG <70 mg/dL or S/S)
(between bedtime and waking)
(Requiring assistance)
†
22.3
21.3
0.0
Glar-Eq
Glar
10.0
0.0
Glar-Eq
BL = 8.3
-1.29
2
2
2
Glar-Eq
Glar
0
Glar
8.3
-1.34
†
Weight
†
Glar
-1.0
-2.0
4
Insulin Dose
U/kg/day
 A1C (%)
0.0
8.1
5.0
A1C
Glar-Eq
†
7.6
No. events
20.0
Nocturnal
1.0
0.5
0.5
0.48
0.0
Glar-Eq
Glar
 Weight (kg)
40.0
Overall
Episodes per
patient-year
Episodes per
patient-year
Patients With T2D*
(N=756)
4.0
2.0
†
1.8
2
Glar-Eq
Glar
0.0
*Mean age = 59 y; duration of diabetes = 11-12 y; baseline BMI = 32 kg/m2. †Not significant vs glargine.
BMI = body mass index; Glar-Eq = glargine equivalent (n=376); Glar = insulin glargine (n=380); S/S = signs and symptoms; T2D = type 2 diabetes.
Rosenstock J, et al. Diabetes Obes Metab. 2015;17:734-741.
17
Glycemic Management in Type 2 Diabetes: Efficacy and Safety of Modern
Antihyperglycemic Therapies
GLARGINE U-300
Efficacy and Safety of Glargine
U-300
Severe
(BG <70 mg/dL)
(between midnight and 6:00 am)
(Requiring assistance)
P<0.05
52.5
46.2
0
U-300
U-100
100
50
U-300
BL = 8.5
U-100
8.6
-1.0
-2.0
-1.42
†
U-100
1.0
-1.46
1.0
†
0.62
0.53
0.5
0.0
U-300
U-100
†
0.9
0.9
Glar-Eq
Glar
0.5
0.0
Insulin Dose
U/kg/day
 A1C (%)
0.0
23.5
0
A1C
U-300
†
17.9
Patients (%)
50
Nocturnal
Weight
 Weight (kg)
100
Overall
Patients (%)
Patients (%)
Insulin-Naive T2D Patients*
(N=878)
1.0
0.5
†
0.49
0.71
U-300
U-100
0.0
*Mean age = 58 y; duration of diabetes = 9.8 y; baseline BMI = 33 kg/m2. †Not significant vs glargine U-100.
BMI = body mass index; NS = not significant; T2D = type 2 diabetes.
Bolli GB, et al. Diabetes Obes Metab. 2015;17:386-394.
19
Glucose Control With
Glargine U-300
Add-on to OA, Insulin-Naive
6 Months1
Add-on to OA,
Basal Insulin Users
6 Months2
Basal-Bolus
Insulin Regimen
6 Months3
878
811
807
N
Treatment
Baseline A1C (%)
Gla 100
Gla 300
Gla 100
Gla 300
Gla 100
Gla 300
8.6
8.5
8.2
8.3
8.2
8.2
-0.56
-0.57
-0.83
-0.83
0
 A1C (%)
-0.5
-1
-1.5
-1.46
-1.42
-2
1. Bolli GB, et al. Diabetes Obes Metab. 2015;17:386-394. 2. Yki-Järvinen H, et al. Diabetes Care. 2014;37:3235-3243.
3. Riddle MC, et al. Diabetes Care. 2014;37:2755-2762.
Risk of Hypoglycemia With
Glargine U-300
Pooled Analysis of Phase III Trials
(N=2496)
Favors Glargine 300
Favors Glargine 100
Hypoglycemia any time of day
Relative risk (95% CI)
Confirmed (≤70 mg/dL) or severe
0.91 (0.87-0.96)
Documented symptomatic (≤70 mg/dL)
0.88 (0.82-0.94)
Nocturnal hypoglycemia
Confirmed (≤70 mg/dL) or severe
0.75 (0.68-0.83)
Documented symptomatic (≤70 mg/dL)
0.75 (0.66-0.85)
0.50
1.00
Ritzel R, et al. Diabetes Obes Metab. 2015 Apr 30. doi: 10.1111/dom.12485. [Epub ahead of print].
1.50
Glycemic Management in Type 2 Diabetes: Efficacy and Safety of Modern
Antihyperglycemic Therapies
DEGLUDEC
Efficacy and Safety of Degludec and
Glargine U-100
Nocturnal
Severe
(BG <70 mg/dL or S/S)
(between bedtime and waking)
(Requiring assistance)
1.85
1.0
0.0
Deg
Glar
0.5
BL = 8.2
Deg
-1.06
Glar
0.04
0.02
P=0.017
8.2
-1.19
†
0.2
0.12
0.003
Deg
0.11
0.0
Weight
4.0
Zinman B, et al. Diabetes Care. 2012;35:2464-2471.
2.4
2.1
Deg
Glar
2.0
0.0
Glar
*Mean age = 59 y; duration of diabetes = 9 y; baseline BMI = 31-32 kg/m2; degludec (n=773); glargine (n=257). †Not significant vs glargine.
BMI = body mass index; Deg = degludec; Glar = glargine; NS = not significant; T2D = type 2 diabetes.
Glar
†
0.1
Deg
0.023
0
†
Glar
-1.0
-2.0
0.39
Insulin Dose
U/kg/day
 A1C (%)
0.0
0.25
0.0
A1C
Deg
P=0.038
 Weight (kg)
†
1.52
Episodes per
patient-year
2.0
Overall
Episodes per
patient-year
Episodes per
patient-year
Insulin-Naive T2D Patients*
(N=1030)
Glucose Control With Degludec
N
Treatment
Baseline A1C (%)
0
Add-on to OA,
Insulin-Naive
52 Weeks1
Add-on to OA,
Basal Insulin Users or
Insulin-Naive
26 Weeks2
Basal-Bolus
Insulin Regimen
52 Weeks3
1030
687
744
Deg
Glar
Deg OD
Deg OD Flex
Glar
Deg
Glar
8.2
8.2
8.4
8.5
8.4
8.3
8.4
 A1C (%)
-0.2
-0.4
-0.6
-0.8
-1
-1.2
-1.4
-1.06
-1.19
-1.07
-1.1
-1.28
-1.26
-1.18
Deg = degludec; Flex = prespecified rotating morning and evening dosing schedule with 8- to 40-h intervals between doses; Glar = glargine; OD =
once daily.
1. Zinman B, et al. Diabetes Care. 2012;35:2464-2471. 2. Meneghini L, et al. Diabetes Care. 2013;36:858-864.
3. Garber AJ, et al. Lancet Endocrinol. 2012;379:1498-1507.
Hypoglycemia With Degludec
N
Deg
Treatment
Overall*
Nocturnal*
15
10
5
0
Add-on to OA,
Insulin-Naive
52 Weeks1
Add-on to OA,
Basal Insulin Users or
Insulin-Naive
26 Weeks2
Basal-Bolus
Insulin Regimen
52 Weeks3
1030
687
744
Glar
Deg OD
Deg OD Flex
Glar
Glar
†
13.63
†
1.84
0.06
0.05
11.09
1.52
1.85
3.6
3.6
3.5
2
1
Deg
1.39
†
0.25
0.39
0.6
0.6
0.8
0
Severe*
0.1
0.05
†
0.003
0.023
2 events
2 events
2 events
0
*Events per patient-year. †P<0.05 vs glargine. Deg = degludec; Flex = prespecified rotating morning and evening dosing schedule with 8- to 40-h
intervals between doses; Glar = glargine; OD = once daily.
1. Zinman B, et al. Diabetes Care. 2012;35:2464-2471. 2. Meneghini L, et al. Diabetes Care. 2013;36:858-864.
3. Garber AJ, et al. Lancet Endocrinol. 2012;379:1498-1507.
Inhaled Insulin
• Inhaled administration
• Rapid-acting insulin
– Peak levels achieved in ~15 minutes
Rave K, et al. J Diabetes Sci Technol. 2008;2:205-212.
Glucose Control with
Inhaled Insulin
Add-on to Metformin and/or Other OAs
24 Weeks
Placebo
N
Inhaled insulin
353
Baseline A1C (%)
8.3
8.3
 A1C (%)
0
-0.2
*
-0.4
-0.6
-0.42
-0.8
-1
-0.82
*
*Difference from placebo (95% CI): -0.40% (-0.57% to -0.23%).
Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.
Inhaled Insulin:
Adverse Events
Patients (%)
Adverse Events*
Inhaled insulin
(n=1991)
Placebo
(n=290)
Active comparators
(n=1363)
Cough
25.6
19.7
5.4
Throat pain or irritation
4.4
3.8
0.9
Headache
3.1
2.8
1.8
Diarrhea
2.7
1.4
2.2
Productive cough
2.2
1.0
0.9
Fatigue
2.0
0.7
0.6
Nausea
2.0
0.3
1.0
*Adverse events of interest occurring in ≥2% of patients receiving inhaled insulin.
Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.
Safety Considerations
with Inhaled Insulin
•
•
Lung disease
•
Heart failure
Hypoglycemia
Contraindicated in asthma, COPD, and other chronic lung diseases
Perform spirometry to assess lung function before initiating inhaled insulin, after
6 months of therapy, and annually thereafter, even in the absence of pulmonary
symptoms
Do not use in patients with active lung cancer and use with caution in patients
with a history of lung cancer or those at risk for lung cancer
•
Observe for signs and symptoms of fluid retention or heart failure, especially
when used with TZDs
•
Increase frequency of glucose monitoring
Afrezza (insulin human) inhalation powder prescribing information. Danbury, CT: MannKind Corporation; 2014.
Management of Hyperglycemia in
the Noncritical Care Setting
30
Glycemic Targets in Noncritical Care
Setting
• Maintain fasting and preprandial BG <140 mg/dL
• Modify therapy when BG <100 mg/dL to avoid
risk of hypoglycemia
• Maintain random BG <180 mg/dL
• More stringent targets may be appropriate in
stable patients with previous tight glycemic
control
• Less stringent targets may be appropriate in
terminally ill patients or in patients with severe
comorbidities
Moghissi ES, et al. Endocrine Pract. 2009;15:353-369.
Umpierrez GE, et al. J Clin Endocrinol Metab. 2012;97:16-38.
31
Pharmacological Treatment of
Hyperglycemia in Non-ICU Setting
Antihyperglycemic Therapy
SC Insulin
OADs
Not generally recommended
Recommended for most
medical-surgical patients
Continuous IV Infusion
Selected medical-surgical patients
Moghissi ES, et al. Endocrine Pract. 2009;15:353-369.
Umpierrez GE, et al. J Clin Endocrinol Metab. 2012;97:16-38.
Smiley D, et al. J Hosp Med. 2010;5:212-217.
32
Noninsulin Therapies in the Hospital
• Time-action profiles of oral agents can result in delayed
achievement of target glucose ranges in hospitalized patients
• Sulfonylureas are a major cause of prolonged hypoglycemia
• Metformin is contraindicated in patients with decreased renal
function, use of iodinated contrast dye, and any state associated
with poor tissue perfusion (CHF, sepsis)
• Thiazolidinediones are associated with edema and CHF
• α-Glucosidase inhibitors are weak glucose-lowering agents
• Pramlintide and GLP-1 receptor agonists can cause nausea and
exert a greater effect on postprandial glucose
• DPP4 inhibitors may provide safe and effective blood glucose
control when used alone or in combination with basal insulin
Insulin therapy is the preferred approach
33
Glycemic Management Strategies
in Noncritically Ill Patients
• Insulin therapy preferred regardless of type of
diabetes
– Discontinue noninsulin agents at hospital admission of
most patients with type 2 diabetes with acute illness
• Use scheduled SC insulin with basal, nutritional,
and correction components
– Modify insulin dose in patients treated with insulin
before admission to reduce risk for hypoglycemia and
hyperglycemia
• Avoid prolonged therapy with “sliding scale”
insulin alone
Umpierrez GE, et al. J Clin Endocrinol Metab. 2012;97:16-38.
34
Subcutaneous Insulin Options
Basal insulin
Controls blood glucose in the fasting state
• Detemir (Levemir), glargine (Lantus), NPH
Nutritional
(prandial) insulin
Blunts the rise in blood glucose following nutritional
intake (meals, IV dextrose, enteral/parenteral nutrition)
• Rapid-acting: aspart (NovoLog), glulisine (Apidra),
lispro (Humalog)
• Short-acting: regular (Humulin, Novolin)
Correction insulin
Corrects hyperglycemia due to mismatch of nutritional
intake and/or illness-related factors and scheduled insulin
administration
35
Initiating Insulin Therapy in the Hospital
Obtain patient weight in kg
Calculate total daily dose (TDD)
as 0.2-0.4 units per kg/day
Choose the dosing schedule
Give 50%-60% of TDD as basal insulin
Give 40%-50% of TDD as nutritional insulin
Use correction insulin for BG above goal range
Adjust according to results of bedside glucose monitoring
Adjust dose for NPO status or changes in clinical status
36
Insulin Therapy in Patients With
Type 2 Diabetes
• Discontinue noninsulin agents on admission
• Insulin naïve: starting total daily dose (TDD):
– 0.3 U/kg to 0.5 U/kg
– Lower doses in the elderly and patients with renal
insufficiency
• Previous insulin therapy: reduce outpatient
insulin dose by 20%-25%
• Half of TDD as basal insulin given at the same
time of day and half as rapid-acting insulin in 3
equally divided doses (AC)
Umpierrez GE, et al. Diabetes Care. 2007;30:2181-2186.
37
Basal-Bolus Insulin Therapy in
Inpatients With Type 2 Diabetes
(RABBIT 2 Trial)
• 130 nonsurgical insulin-naïve patients age 18-80
with known type 2 diabetes admitted to
noncritical care unit
• Randomly assigned to sliding scale insulin (SSI) or
a basal-bolus regimen with glargine and glulisine
– 0.4 units per kg/day for BG 140-200
– 0.5 units per kg /day for BG >200
– 50% given as glargine and 50% as glulisine
• Oral antidiabetic drugs discontinued
• 2 hypoglycemic events (BG <60 mg/dL) in each
group
Umpierrez GE, et al. Diabetes Care. 2007;30:2181-2186.
38
BG, mg/dL
Rabbit 2 Trial: SSI Resulted in Uncontrolled
Hyperglycemia in Some Patients
300
280
260
240
220
200
180
160
140
120
100
Sliding-scale
Basal-bolus
Hypoglycemia Rate
Basal Bolus Group:
BG <60 mg/dL: 3%
BG <40 mg/dL: none
Admit 1
2
3 4 1 2 3 4
Days of Therapy
5
6
7
SSRI:
BG <60 mg/dL: 3%
BG <40 mg/dL: none
Persistent hyperglycemia (BG >240 mg/dL) is common (15%) with SSI therapy
Umpierrez GE, et al. Diabetes Care. 2007;30:2181-2186.
39
Basal-Bolus Insulin Therapy in
Inpatients With Type 2 Diabetes
(RABBIT 2 Trial)
• Adjusting scheduled insulin regimen
– If fasting and premeal BG >140 mg/dL, dose of
glargine increased by 20%
– For BG <70 mg/dL, glargine reduced by 20%
Umpierrez GE, et al. Diabetes Care. 2007;30:2181-2186.
40
Treatment of Type 1 Diabetes
41
Goals of T1D Management
• Utilize intensive therapy aimed at near-normal
BG and A1C levels
• Prevent diabetic ketoacidosis and severe
hypoglycemia
• Achieve the highest quality of life compatible
with the daily demands of diabetes management
• In children, achieve normal growth and physical
development and psychological maturation
• Establish realistic goals adapted to each
individual’s circumstances
T1D, type 1 diabetes.
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
42
ADA A1C Goals:
Patients with Type 1 Diabetes
Age Group
A1C Goal*
Youth (<18 years)
<7.5%
Adults
<7.0%
Older adults
Healthy†
<7.5%
Complex/intermediate health
<8.0%
Very complex/poor health
<8.5%
*Individualize goal based on patient’s circumstances:
• <6.5% may be appropriate for select patients if achievable without significant hypoglycemia
• <8.5% may be appropriate for patients with history of severe hypoglycemia, hypoglycemia
unawareness, limited life expectancy, advanced complications, or extensive comorbidities
†No
comorbidities, long life expectancy.
T1D, type 1 diabetes.
Chiang JL, et al. Diabetes Care. 2014;37:2034-2054.
43
Effect of Intensive Treatment on
Retinopathy in T1D
DCCT
(N=1441)
DCCT, Diabetes Control and Complications Trial; T1D, type 1 diabetes..
DCCT. N Engl J Med. 1993;329:977-986.
44
Sustained Effect of Intensive
Treatment on Nephropathy in T1D
DCCT-EDIC
(N=1349)
Annual Prevalence
Cumulative Incidence
DCCT, Diabetes Control and Complications Trial; EDIC, Epidemiology of Diabetes Interventions and Complications; T1D, type 1 diabetes.
DCCT EDIC. JAMA. 2003;290:2159-2167.
45
Advances in the Care of Persons With
Type 1 Diabetes
•
•
•
•
Development of insulin analogues
Insulin pump therapy
Home glucose monitoring
Advent of continuous glucose monitoring
(CGM)
46
Principles of Insulin
Therapy in Type 1 Diabetes
• Starting dose based on weight
– Range: 0.4-0.5 units/kg per day
• Daily dosing
– Basal
• 40% to 50% TDI
• Given as single injection of basal analog or 2 injections of NPH per
day
– Prandial
• 50% to 60% of TDI in divided doses given 15 min before each meal
• Each dose determined by estimating carbohydrate content of meal
• Higher TDI needed for obese patients, those with
sedentary lifestyles, and during puberty
TDD, total daily dose.
Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87.
47
Treatment of Type 1 Diabetes
CONTINUOUS SUBCUTANEOUS
INSULIN INFUSION
48
Normal Insulin Secretion
Meal
Bolus (meal)
insulin needs
60
Serum insulin (µU/mL)
Meal
Meal
50
40
30
20
10
Basal (background) insulin needs
0
0
2
4
6
8
10
12
14
16
18
20
22
24
Time
49
CSII With Rapid-Acting Analog
Morning
Bolus
Evening
Night
Bolus
Insulin effect
Bolus
Afternoon
Breakfast
Basal Infusion
Lunch
Dinner
Bedtime
50
CSII, continuous subcutaneous insulin infusion.
Features of Modern Insulin Pumps Not
Shared by MDI
• Variable basal and prandial infusion rates
– Meal profiles (eg, normal and advanced bolus), preset basal rate changes, temporary basal rates, etc
•
•
•
•
On-board calculators for meal insulin boluses
Alarms/reminders (eg, missed bolus)
Ability to download pump data to computer
Integration with CGM for automatic feedback
control and threshold suspend automation
(“semi-closed loop”)
51
CGM, continuous glucose monitoring; MDI, multiple daily injections.
Improved Glucose Control
with CSII
Baseline
8.5
12 months
≥24 months
8.1
7.9
8
*
7.5
7.3
*
7.3
7.6
7.4
7.1
7
6.5
*
6.5
6.6
6
5.5
1-6 years
7-11 years
12-18 years
Age group
*P<0.02 vs baseline.
CSII, continuous subcutaneous insulin infusion.
Ahern JA, et al. Pediatr Diabetes. 2002;3:10-15.
52
Efficacy of CSII
• Switching to CSII results in
– Lower A1C, by ~0.5%-0.6%
– Mean A1C ~7.5%-7.6%
– Less hypoglycemia
– Less glucose variability
– No excessive weight gain
– Greater patient satisfaction and quality of life
CSII, continuous subcutaneous insulin infusion.
Tamborlane WV, et al. Rev Endo Metab Disorders. 2006;7:205-213.
53
Not All Patients Have Good Control on
CSII
Patients with T1D Switched from MDI to Pump Therapy
(N=104)
60
56%
Patients on CSII (%)
50
40
30
27%
A1C on CSII significantly
correlated with prior A1C
on MDI
(r=0.66; P<0.001)
20
17%
10
0
<7.0%
7.0-8.4%
CSII, continuous subcutaneous insulin infusion; T1D, type 1 diabetes.
Nixon R, Pickup JC. Diabetes Technol Ther. 2011;13:93-98.
≥8.5%
54
Treatment of Type 1 Diabetes
CONTINUOUS GLUCOSE
MONITORING
55
Continuous Glucose Monitoring in
Type 1 Diabetes
JDRF Sensor Trial
• Patients
Patients ≥25 Years of Age
– Baseline A1C >7.0%
– Age cohorts
• Improvement sustained for 12
months in patients aged ≥25
years
• No significant difference
between CGM and control
group among patients <25
years of age
JDRF, Juvenile Diabetes Research Foundation.
JDRF CGM Study Group. New Engl J Med. 2008;359:1464-1476.
0.02
0
-0.1
 A1C (%)
• 8-14 years (n=114)
• 15-24 years (n=110)
• ≥25 years (n=98)
P<0.001
0.1
-0.2
-0.3
-0.4
-0.5
-0.5
-0.6
CGM
Control
56
Change in A1C Over Time
JDRF Sensor Trial
(N=322)
Patients ≥25 Years of Age
8.0
A1C (%)
Control
7.5
RT-CGM
7.0
6.5
Baseline
13 weeks
CGM, continuous glucose monitoring; JDRF, Juvenile Diabetes Research Foundation.
JDRF CGM Study Group. New Engl J Med. 2008;359:1464-1476.
26 weeks
57