1. health and fitness
2. disease
3. diabetes

Successful Transition to
Insulin Therapy in T2DM
Merri Pendergrass, M.D., Ph.D.
Endocrinology, University of Arizona
All Faculty, CME Planning Committee Members, and the
CME Office Reviewer have disclosed that they have no
financial relationships with commercial interests that would
constitute a conflict of interest concerning this CME activity.
1
Learning Objectives
Participants should be better able to
• Select a strategy for insulin initiation
• Intensify an insulin regimen
• Understand available modalities (e.g.
vials, pens) for insulin administration
2
54 year old patient with T2DM
• On metformin 1000 bid, glipizide 10 qd
• A1C 9.1
What would you add now?
a.
b.
c.
d.
e.
Pioglitazone (Actos®)
Exenatide (Byetta®)
Sitagliptin (Januvia®)
Canaglifozin (Invokana®)
Insulin
3
54 year old patient with T2DM
• On metformin 1000 bid, glipizide 10 qd
• A1C 9.1
What would you add now?
a.
b.
c.
d.
e.
Pioglitazone (Actos®)
Exenatide (Byetta®)
Sitagliptin (Januvia®)
Canaglifozin (Invokana®)
Insulin
4
Approximate A1C Lowering
~ A1C Reduction (%)
Metformin
Sulfonylurea
Avandia, Actos
Byetta, Bydureon, Victoza
Invokana
Januvia,Onglyza,Tradjenta,
Nesina
1.0-2.0
1.0-2.0
0.5-1.5
0.5-1.5
0.8-1.0
0.5-0.8
5
Insulin for Type 2 Diabetes
•
•
•
•
Safe and effective option
Not a last resort
Can decrease any level of A1C to goal
Indicated if not controlled on non-insulins
6
Improving Insulin Acceptance
• Don’t threaten as a punishment
• Address patient concerns/preconceptions, e.g.
– Not a personal failure
– Complications are not inevitable
– Can potentially stop insulin later
• Consider insulin pens
7
Profiles of Available Insulins
NPH
Detemir (Levemir)
Glargine (Lantus)
Regular
Lispro (Humalog)
Aspart (Novolog)
Glulisine (Apidra)
Insulin Effect
Basal
Bolus
Nutritional
Correction
0
6
12
18
24
Time (hours)
8
Which regimen will you start?
a.
b.
c.
d.
NPH at bedtime
Lantus® at bedtime
NPH/regular bid ac
NPH at bedtime + regular tid ac
9
Which regimen will you start?
a.
b.
c.
d.
NPH at bedtime
Lantus® at bedtime
NPH/regular bid ac
NPH at bedtime + regular tid ac
10
Same Effects in T2DM with
Insulin Given QD, BID, or QID
2
Least
weight gain
1
Change in
0
A1C (%)
-1
-2
Control
AM
NPH
HS
NPH
BID
NPH
QID
N/R
-0.5
-1.7
*
-1.9
-1.8
*
*
Yki-Jarvinen H, et al. N Engl J Med. 1992;327:1426-1433.
-1.6
*
11
Evidence Supports Initiating
Insulin…
Type
NPH
Glargine
Detemir
Lispro, aspart, glulisine
Pre-mix
Other combinations
Regimen
QD, BID
TID
QD, BID, TID
QD, BID, TID, QID
12
Sequential Insulin Strategies in T2DM
diabetes.
Inzucchi S E et al. Dia Care 2012;35:1364-1379
Copyright © 2011 American Diabetes Association, Inc.
Initiating Basal Insulin
• ~50% patients achieve A1C< 7% with
basal insulin given at bedtime
• For T2DM, effects are similar for qHS
– NPH
– Glargine (Lantus®)
– Detemir (Levemir®)
$
$$
$$
14
Insulin Cost*
NPH
NPH
Cost ($)
$/1000 units
Item
/ Item (~33 units/day)
10 ml vial
24.88
24.88
Box of 5 (3 ml pens) 294.28 196.18
Lantus 10 ml vial
226.68
Lantus Box of 5 (3 ml pens) 351.62
U500
20 ml vial
1130.00
226.68
234.41
113.00
*Walmart 2/8/14
15
The Treat-to-Target Trial
NPH vs. Glargine (Lantus®)
Start With 10 IU Insulin qHS & Adjust Weekly
Mean FBG on Increase in Insulin
Preceding 2 Days
Dosage
> 180
140-180
8
6
120-140
100-120
4
2
Riddle et al, Diabetes Care 26, 3080-3086, 2003
16
qHS NPH and qHS Lantus® have
Similar Effects on A1C, FPG
(T2DM)
Glargine (Lantus)
NPH
9
A1C (%)
FPG (mg/dl)
200
150
8
7
6
0
4
8
12 16
20 24
0
4
Riddle et al, Diabetes Care 26, 3080-3086, 2003
8
12 16
20 24
17
Slightly Less Hypoglycemia:
with Glargine (Lantus) vs. NPH
Number of
events/patient/year
NPH
20
15
Lantus
*
17.7
13.9
10
*
5.1
5
3
*
2.5
1.8
0
< 72 mg/dl
<56 mg/dl
Riddle et al, Diabetes Care 26, 3080-3086, 2003
Severe
Key Factor Contributing to the
Success of the Regimen
•
•
•
•
Not what type of insulin is used
Not how many doses are used
Not what is the initial starting dose
Success depends on
– Adherence
– How regularly and rapidly insulin is
adjusted to achieve targets!
19
20
21
Insulin Titration: MD Vs. Patients
Start with 10 units glargine qHS
Titrated by MD
(N=2315)
Titrated by Patient
(N=2273)
≥ 100 to < 120
0-2*
0-2*
≥ 120 to < 140
2
2
≥ 140 to < 180
4
2
≥ 180
6-8
2
Diabetes Care 28:1282-1288, 2005
*Only increase if no values < 72
22
Patient and MD Insulin Titration
Yield Similar Results
MD Titration Patient Titration
Baseline 24 Weeks
35
9
8.8
8.6
8.4
8.2
A1C (%) 8
7.8
7.6
7.4
7.2
7
30
25
Incidence of 20
Hypoglycemia
15
(%)
10
5
0
MD Titration
Patient Titration
Severe
Symptomatic
Nocturnal
Diabetes Care 28:1282-1288, 2005
23
Question:
• Patient on metformin, NPH 60 hs
• A1C 8.0
• SMBG
– Ac breakfast 80-100
– Ac lunch
80-100
– Ac dinner
80-120
– HS
200-250
What would you do?
a. Change from NPH to glargine (Lantus)
b. Increase NPH to 70
c. Add NPH in AM
d. Add lispro (Humalog) ac dinner
24
Question:
• Patient on metformin, NPH 60 hs
• A1C 8.0
• SMBG
– Ac breakfast 80-100
– Ac lunch
80-100
– Ac dinner
80-120
– HS
200-250
What would you do?
a. Change from NPH to glargine (Lantus)
b. Increase NPH to 70
c. Add NPH in AM
d. Add lispro (Humalog) ac dinner
25
Patient now on metformin, insulin
Would NOT change NPHglargine:
(glargine = NPH for A1C changes)
• Meds: metformin 1 g bid, NPH 60 hs
• A1C 8.0
Would NOT increase
NPH HS (risk for AM
• SMBG
hypoglycemia)
– Before breakfast
– Before lunch
– Before dinner
– Before bedtime
80-100
80-100
80-120
200-250
Would NOT Add NPH
AM (risk for daytime
hypoglycemia)
Best to add rapid-acting insulin ac dinner
26
Matching Insulin to Basal
and Nutritional Needs
8
12
6
10
27
50 year old patient with T2DM,
BMI 40.1, A1C 12, FPG 250,
Metformin 1 g bid, 70/30 100 bid
What is your next step?
a)
b)
c)
d)
Increase to 70/30, 150 bid
Increase to 70/30, 100 tid
Split each dose into 2 injections
Stop 70/30, start U-500 regular insulin
50 year old patient with T2DM,
BMI 40.1, A1C 12, FPG 250,
Metformin 1 g bid, 70/30 100 bid
What is your next step?
a)
b)
c)
d)
Increase to 70/30, 150 bid
Increase to 70/30, 100 tid
Split each dose into 2 injections
Stop 70/30, start U-500 regular insulin
Strategies to Get “More Insulin
Into” Insulin Resistant Patients
• Add additional injections, e.g. 70/30
three time a day
• Split large doses into 2 injections
(smaller depot = better absorption)
• Use more concentrated insulins,
e.g. U-500
30
U-500 is Five Times as
Concentrated as U-100 Insulin
•
•
•
•
U-100 = 100 units/ml
U-500 = 500 units/ml
1 ml U-100 = 100 units = 0.2 ml U-500
U-500 should be considered when total
daily dose (TDD) insulin is > 200 units
• Initial dosing ~ BID
ENDOCRINE PRACTICE Vol 15 No. 1 January/February 2009
31
U500 Lets Patient Inject Less
100 units
u100
100 units
u500
32
Convert Insulin Units  U-500 cc:
Divide Units by 500
125 units insulin = ?? cc u500
125 units insulin
1 cc
.25 cc
500 units insulin
150 units insulin = 150 / 500 = .30 cc
175 units insulin = 175 / 500 = .35 cc
33
Convert U-500 cc  Units Insulin:
Multiply cc by 500
.30 cc u500 = ?? units insulin
.30 cc u500
500 units insulin
1 cc u500
150 units
insulin
.35 cc u500 = .35 X 500 = 175 units
.15 cc u500 = .15 X 500 = 75 units
34
Include Two Identifiers of Correct
Dose on Prescriptions
35
Better Control with u500
N = 53, 6-52 months f/u
A1C (%)
Insulin dose (units)
Weight (kg)
Cholesterol (mg/dL)
TG (mg/dL)
Severe hypoglycemia (total
events in first 12 months f/u)
Endocr Pract. 2011 Jul 8:1-15.
Baseline End
(u-100) (u-500)
9.1
8.1*
391
415*
134
136
176
156*
349
252*
3
3
* P < 0.05
36
Additional Insulin Concentrations
May Become Available Soon
• Insulin degludec (TresibaTM)
– Approved in the EU and Japan
– Under regulatory review in the US
– Developed both as a 100-unit/ml
formulation and a 200-unit/ml formulation
37
70/30 Effective When Given
Once, Twice, or Thrice a Day
90
80
70
60
Percentage 50
of Patients
with A1C<7 40
30
20
70
77
41
10
0
QD
BID
Diabetes, Obesity and Metabolism, 8, 2006, 58–66
TID
38
Splitting Large Volume into Two
Injection Sites May Improve Effect
Depots more than ~ .6 ml not well absorbed
100 units (1.0 ml)
50 units
(0.5 ml)
50 units
(o.5 ml)
Better Absorption
39
High Dose Insulin More Effective
Injected in Two vs. One Site
11
10.5
10
9.5
A1C (%)
9
8.5
10
10.4
8
Baseline
12months
10.3
8.8
7.5
7
1-site injection
(240 IU)
2-site injection
(254 IU)
Saryusz-Wolska M. Abstract #109. EASD; Sept. 12-16, 2011; Lisbon.
40
Ordering Insulin and Supplies
Examples for 90-Day Supply
Vial/syringe = 2 scripts
1. NPH 50 units SC qHS,
Disp: 5 vials
2. Syringes, 1 ML 6 MM
(15/64”) X 31 G, 100count box
90 days X 50 units/day X 1 vial/1000 units = 4.5 vials
Shorter, thinner needles hurt less!
41
Ordering Insulin and Supplies
Examples for 90-Day Supply
Pen/needles = 2 scripts
300
units
1. NPH 50 units SC qHS, Disp: 3 boxes (5 X 3 mL)
2. Pen needles, 4mm x 32G, 100-count box
42
Recommendations - 1
• Start with a single injection of basal
insulin at bedtime
– NPH has lowest cost and similar clinical
effects as Lantus® and Levemir®
– Insulin pens easier but more expensive
• Titrate insulin often to normalize FBG
43
Recommendations - 2
• If FBG at goal (~100) and A1C above
goal, add an injection of a short-acting
insulin before the largest meal
– Regular is cheapest but adherence may be
better with Humalog®, Novolog® or Apidra®
• Consider adding additional pre-meal
injections, based on BG monitoring
44
Recommendations - 3
• Continue metformin
• Stop sulfonylureas if insulin dose is
more than ~20-40 units
• Consider potential risks and benefits of
continuing other non-insulin agents, e.g.
– Multiple agents can get expensive
– Not much incremental A1C benefit
– Invokana®, Byetta®, Victoza® associated
with weight loss
45
Recommendations - 4
• If A1C is above goal with > 200 units of
insulin per day, consider switching to
U-500 bid
46
Comments or Questions?
mpendergrass@deptofmed.arizona.edu
47