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1
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.
2
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
54 year old patient with T2DM
a. Pioglitazone (Actos®)b. Exenatide (Byetta®)c. Sitagliptin (Januvia®)d. Canaglifozin (Invokana®)e. Insulin
3
• On metformin 1000 bid, glipizide 10 qd• A1C 9.1
What would you add now?
54 year old patient with T2DM
a. Pioglitazone (Actos®)b. Exenatide (Byetta®)c. Sitagliptin (Januvia®)d. Canaglifozin (Invokana®)e. Insulin
4
• On metformin 1000 bid, glipizide 10 qd• A1C 9.1
What would you add now?
5
Approximate A1C Lowering
Metformin
~ A1C Reduction (%)
1.0-2.01.0-2.0
Byetta, Bydureon, Victoza
Januvia,Onglyza,Tradjenta,Nesina
SulfonylureaAvandia, Actos 0.5-1.5
0.5-1.5
0.5-0.8Invokana 0.8-1.0
6
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
7
Improving Insulin Acceptance
• Don’t threaten as a punishment• Address patient concerns/pre-
conceptions, e.g.– Not a personal failure– Complications are not inevitable– Can potentially stop insulin later
• Consider insulin pens
8
Profiles of Available Insulins In
sulin
Effe
ctNPH
Glargine (Lantus)Regular
0 6 12 18 24
Time (hours)
Detemir (Levemir)
Lispro (Humalog)Aspart (Novolog)Glulisine (Apidra)
Basal
BolusNutritionalCorrection
Which regimen will you start?
a. NPH at bedtime
b. Lantus® at bedtime
c. NPH/regular bid ac
d. NPH at bedtime + regular tid ac
9
Which regimen will you start?
a. NPH at bedtime
b. Lantus® at bedtime
c. NPH/regular bid ac
d. NPH at bedtime + regular tid ac
10
11
Same Effects in T2DM with Insulin Given QD, BID, or QID
-0.5
-1.7 -1.9 -1.8-1.6-2
-1
0
1
2
Change in A1C (%)
ControlAM
NPHQID N/R
HS NPH
BID NPH
Yki-Jarvinen H, et al. N Engl J Med. 1992;327:1426-1433.
* * * *
Least weight gain
12
Evidence Supports Initiating Insulin…
Type RegimenNPH
QD, BIDGlargine
Detemir
Lispro, aspart, glulisine TID
Pre-mix QD, BID, TID
Other combinations QD, BID, TID, QID
Sequential Insulin Strategies in T2DM diabetes.
Inzucchi S E et al. Dia Care 2012;35:1364-1379
Copyright © 2011 American Diabetes Association, Inc.
14
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®)
$
$$
$$
15
Insulin Cost*
Item Cost ($) / Item
$/1000 units (~33 units/day)
NPH 10 ml vial 24.88 24.88
NPH Box of 5 (3 ml pens) 294.28 196.18
Lantus 10 ml vial 226.68 226.68
Lantus Box of 5 (3 ml pens) 351.62 234.41
U500 20 ml vial 1130.00 113.00
*Walmart 2/8/14
16
The Treat-to-Target Trial NPH vs. Glargine (Lantus®)
Mean FBG on Preceding 2 Days
Increase in Insulin Dosage
> 180 8
140-180 6
120-140 4
100-120 2
Start With 10 IU Insulin qHS & Adjust Weekly
Riddle et al, Diabetes Care 26, 3080-3086, 2003
17
qHS NPH and qHS Lantus® have Similar Effects on A1C, FPG
(T2DM)
Riddle et al, Diabetes Care 26, 3080-3086, 2003
0 4 12 16 20 248
150
200
0 4 12 16 20 248
7
8
6
9
A1
C (
%)
FP
G (
mg
/dl)
NPHGlargine (Lantus)
Slightly Less Hypoglycemia: with Glargine (Lantus) vs. NPH
17.7
5.12.5
13.9
31.8
0
5
10
15
20
< 72 mg/dl <56 mg/dl Severe
Num
ber
of
even
ts/p
atie
nt/y
ear
NPH Lantus
Riddle et al, Diabetes Care 26, 3080-3086, 2003
*
**
19
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!
20
Start NPH 20 units at bedtime and increase by 10 units every week if average fasting glucose is above 100 and no hypoglycemia (BG <72)
21
Start NPH 10 units at bedtime and increase by 2 units every night if fasting glucose is above 100 and no hypoglycemia (BG < 72)
22
Insulin Titration: MD Vs. Patients
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
Start with 10 units glargine qHS
*Only increase if no values < 72Diabetes Care 28:1282-1288, 2005
23
Patient and MD Insulin Titration Yield Similar Results
0
5
10
15
20
25
30
35
Severe Symptomatic Nocturnal
Incidence of Hypoglycemia
(%)
MD Titration Patient Titration
77.27.47.67.8
88.28.48.68.8
9
MD Titration Patient Titration
A1C (%)
Baseline 24 Weeks
Diabetes Care 28:1282-1288, 2005
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 70c. Add NPH in AMd. Add lispro (Humalog) ac dinner
25
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 70c. Add NPH in AMd. Add lispro (Humalog) ac dinner
26
Patient now on metformin, insulin
• Meds: metformin 1 g bid, NPH 60 hs• A1C 8.0• SMBG
– Before breakfast 80-100– Before lunch 80-100– Before dinner 80-120– Before bedtime 200-250
Best to add rapid-acting insulin ac dinner
Would NOT increase NPH HS (risk for AM hypoglycemia)
Would NOT Add NPH AM (risk for daytime hypoglycemia)
Would NOT change NPHglargine: (glargine = NPH for A1C changes)
278 12 6 10
Matching Insulin to Basal and Nutritional Needs
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) Increase to 70/30, 150 bid
b) Increase to 70/30, 100 tid
c) Split each dose into 2 injections
d) 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) Increase to 70/30, 150 bid
b) Increase to 70/30, 100 tid
c) Split each dose into 2 injections
d) 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
31
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
32
U500 Lets Patient Inject Less
u100
u500
100 units
100 units
Convert Insulin Units U-500 cc: Divide Units by 500
125 units insulin = ?? cc u500
33
150 units insulin =
1 cc
125 units insulin
500 units insulin.25 cc
150 / 500 = .30 cc
175 units insulin = 175 / 500 = .35 cc
Convert U-500 cc Units Insulin: Multiply cc by 500
.30 cc u500 = ?? units insulin
34
.35 cc u500 =
500 units insulin
.30 cc u500
1 cc u500150 units
insulin
.35 X 500 = 175 units
.15 cc u500 = .15 X 500 = 75 units
Include Two Identifiers of Correct Dose on Prescriptions
35
U500 insulin:Sig: Pull to the 25 unit mark (125 units) before breakfast and pull to the 20 unit mark (100 units) before dinner
Better Control with u500
N = 53, 6-52 months f/u Baseline (u-100)
End (u-500)
A1C (%) 9.1 8.1*Insulin dose (units) 391 415*Weight (kg) 134 136Cholesterol (mg/dL) 176 156*TG (mg/dL) 349 252*Severe hypoglycemia (total events in first 12 months f/u) 3 3
36Endocr Pract. 2011 Jul 8:1-15. * P < 0.05
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
QD BID TID0
10
20
30
40
50
60
70
80
90
41
7077
Percentage of Patients with A1C<7
38Diabetes, Obesity and Metabolism, 8, 2006, 58–66
Splitting Large Volume into Two Injection Sites May Improve Effect
39
100 units (1.0 ml)
50 units(o.5 ml)
50 units(0.5 ml)
Depots more than ~ .6 ml not well absorbed
Better Absorption
High Dose Insulin More Effective Injected in Two vs. One Site
40Saryusz-Wolska M. Abstract #109. EASD; Sept. 12-16, 2011; Lisbon.
1-site injection (240 IU)
2-site injection (254 IU)
7
7.5
8
8.5
9
9.5
10
10.5
11
10 10.310.4
8.8
Baseline12months
A1C (%)
Ordering Insulin and Supplies Examples for 90-Day Supply
Vial/syringe = 2 scripts1. NPH 50 units SC qHS,
Disp: 5 vials
2. Syringes, 1 ML 6 MM (15/64”) X 31 G, 100-count box
41
90 days X 50 units/day = 4.5 vialsX 1 vial/1000 units
Shorter, thinner needles hurt less!
Ordering Insulin and Supplies Examples for 90-Day Supply
Pen/needles = 2 scripts 1. NPH 50 units SC qHS, Disp: 3 boxes (5 X 3 mL)
2. Pen needles, 4mm x 32G, 100-count box
42
300 units
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
47
Comments or Questions?
mpendergrass@deptofmed.arizona.edu
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