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Individualizing Insulin
Therapy in
Type 2 Diabetes
Aligning Specific Insulin Formulations with
Specific Diabetic Patients, Profiles, and Clinical
Parameters
VIVIAN A. FONSECA, MD, FRCP- Program Chair
Professor of Medicine and Pharmacology | Tullis Tulane Alumni
Chair in Diabetes | Chief, Section of Endocrinology | Tulane
University Health Sciences Center | Past President, Science and
Medicine | American Diabetes Association
CME-certified symposium
jointly sponsored by the
University of Massachusetts
Medical School and
CMEducation Resources, LLC
Commercial Support: This
CME activity is supported by
an educational grant from
sanofi-aventis U.S. Inc., A
SANOFI COMPANY
Distinguished Faculty
VIVIAN A. FONSECA, MD,
FRCP Program Chair
Professor of Medicine and
Pharmacology | Tullis Tulane
Alumni Chair in Diabetes |
Chief, Section of
Endocrinology | Tulane
University Health Sciences
Center | Past President,
Science and Medicine |
American Diabetes
Association
CHARLES F. SHAEFER JR.,
MD, FACP
Assistant Clinical Professor of
COI Disclosures
Faculty Member
Relationship
Charles F. Shaefer,
MD, FACP
Consultant:
Sanofi-aventis, BMS-AZ,
Speakers Bureau:
Juan P. Frias, MD
Corporation/Manufacturer
Consultant:
Advisory Board:
Consultant:
Weight
Side
Two-drug
effects...
combinations
Costs
..
Efficacy ( HbA1c)
..
Hypoglycaemia
..
Weight
.
Side
effects..
Costs
More complex
insulin
strategies
Metformin
High
Low risk
Neutral / loss
GI/lacticacidosis
low
If individualised HbA1c target not reached, proceed to two-drug combination
Metformin +
Metformin +
Metformin +
Metformin +
SU
TZD
DPP4i
GLP1-RA
Metformin +
Insulin
High
Moderate risk
Gain
Hypoglycemia
Low
High
Intermediate
Intermediate
Intermediate
Low risk
Low risk
Low risk
Low risk
Gain
Loss
Loss
Loss
Edema, HF,
GI
GI
GI
fract
High
High
High
High
If individualised HbA1c target not reached, proceed to three-drug combination
SU+
TZD
or DPP4i
or GLP1-RA
or Insulin
TZD+
SU
or DPP4i
or GLP1-RA
or Insulin
DPP4i+
SU
or TZD
or Insulin
GLP1-RA+
SU
or TZD
or Insulin
Insulin+
TZD
or DPP4i
or GLP1-RA
If combination therapy that includes basal insulin did not achieve HbA1c target after 3-6
months, proceed to a more complex insulin strategy usually in combination with one or two
non-insulin agents
in
Type 2 Diabetes Mellitus
Progressive nature of the -cell
dysfunction in type 2 diabetes mellitus
important cause of secondary failure of
oral therapy
For some patients, its the only therapy that
will get blood glucose to target
Proven effective
Can be continually titrated
Usually well accepted by patients:
Small needles and insulin pens
IF enthusiastically recommended by health
care provider
Long-term follow-up
Study
Microvascular
CVD
Mortality
UKPDS1,2
DCCT/EDIC3.4
Action to Control
Cardiovascular Risk in
Diabetes (ACCORD)5
Not available
ADVANCE6
Veterans Affairs Diabetes Trial
(VADT)7
UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865.
Holman RR, et al. N Engl J Med. 2008;359:1577-1589.
3
The Diabetes Control and Complications Trial Research Group.
N Engl J Med. 1993;329;977-986. 4Nathan DM, et al. N Engl J Med. 2005;353:2643-2653.
5
Gerstein HC, et al. N Engl J Med. 2008;358:2545-2559. 6Patel A, et al. N Engl J Med. 2008;358:2560-2572.
7
Duckworth W, et al. N Engl J Med. 2009;360:129-139.
1
2
Recent Meta-Analysis of
Intensive Glucose Control Trials
Pooled analysis of the UKPDS, ACCORD, ADVANCE, and VADT trials yielded a 16% overall reduction in
nonfatal MI. The absolute overall risk reduction was 9 events per 1000 patients over 5 years of treatment.
Events/Total (n/n)
Relative Risk
(95% CI)
Risk Difference
(95% CI)
Event
Intensive
Conventional
Nonfatal MI
611/14,662
598/13,140
0.84 (0.75-0.94)
9 (16 to 3)
Fatal MI
540/14,662
437/13,140
0.94 (0.75-1.18)
3 (10 to 4)
Nonfatal stroke
423/14,662
362/13,140
0.98 (0.82-1.17)
3 (7 to 2)
Fatal stroke
PAD
88/14,662
409/9534
76/13,140
433/8017
0.87 (0.63-1.20)
0 (2 to 1)
0.91 (0.79-1.03)
3 (5 to 1)
0.5
n = 27,802
1.0
2.0
In the overall analysis, intensive glucose control had no significant effect on either:
CV mortality (relative risk 0.97 [95% CI, 0.76-1.24])
or
all-cause mortality (relative risk 0.98 [95% CI, 0.84-1.15])
PAD: peripheral arterial disease
Kelly TN, et al. Ann Intern Med. E-pub ahead of print.
4 years
Mean Int: 8.21.0%
Mean Std: 8.31.0%
Median Int: 6.4%a
Median Std: 7.5%a
Rate of progression of diabetic retinopathy:
Intensive: 7.3%
Standard: 10.4%
(P=0.003)
ACCORD Study Group and ACCORD Eye Study Group. N Engl J Med.
Drives
Drives risk
risk of
of
complications
complications
Generation
Generation of
of aa
bad
bad glycemic
glycemic
legacy
legacy
9.5
9.0
8.5
HbA1c (%)
8.0
7.5
7.0
6.5
6.0
1
10 11 12 13 14 15 16 17
Upper broken line: theoretical reconstruction of prior diabetes progression based on UKPDS
Implications of ACCORD,
ADVANCE, and VADT for
Microvascular Risk
Microvascular disease
1.4 P = 0.03
P = 0.04
1.2
1.0
0.8
0.6
0.4
1997
1999
2001
2003
2005
2007
Conventional therapy
438
498
571
620
651
686
Sulfonyurea-insulin
963
1151
1292
1409
1505
1571
No. of events
HR (95%CI)
HR (95%CI)
HR (95%CI)
HR (95%CI)
9%
Sulfonylurea insulin
7.6
Mean A1C
8
%
7.1
6.6
7%
ULN
6%
5%
0%
P=0.007
1
2
3
4
5
Years from Randomization
ULN = upper limit of normal (6.2%)
Wright A, et al. Diabetes Care. 2002;25:330-336.
HbA1c at Baseline
All pts
<8.5%
8.5
10.1%
>10.1%
3,031
1,025
956
972
HbA1c (%)
9.5
7.6
9.3
11.7
34
36
33
33
Hypertension (%)
69
71
69
66
11
11
15
47
43
47
51
41
42
40
40
6.5
Baseline HbA1c
6.5
Baseline HbA1c
9.1
MET only
8.8
SU only
8.7
MET + SU
Mean HbA1c
at baseline
Mean HbA1c
at 24 weeks
HbA1c <7%
(% patients)
HbA1c
8.9
0/1 OAD
p = 0.0198
p = 0.0006
7.1
7.0
6.9
7.1
7.0
54.7
52.7
68.1*
50.4
56.4
Pooled analysis
* p = 0.0001 vs all taking SU
No significant difference in
body weight
p = 0.0006
Confirmed hypoglycemia
(% pts with BG < 50 mg/dL)
p = 0.0122
0/1
2
Met
OAD OAD only
SU
only
MET
+ SU
p = 0.9547
0/1
p = 0.1830
2
Met
OAD OAD only
SU
only
MET
+ SU
with
insulin glargine or comparator (63% other insulins, 32% OADs,
6% dietary)
Comparator, r = 0.241, p < 0.001
Insulin glargine, r = 0.195, p < 0.001
<8
89
Overall
<50
50 to <65 65
<50 50 to <65 65
Baseline age (years)
*This trend was not observed for comparators Leahy JL, et al. Diabetes 2011;60(Suppl.1):23
100
CSII
MDI
OHA
80
p = 0.0012
60
51.1%
44.9%
40
26.7%
20
0
0
90
180
270
360
450
Days in remission
SII = continuous subcutaneous insulin infusion; MDI = multiple daily insulin injections;
HA = oral hyperglycaemic agents
Weng J, et al. Lancet 2008;371:175360.
1400
p < 0.0001
1200
p = 0.006
1000
800
600
400
200
0
-200
Before therapy
After therapy
At 1 year
1.4
1.2
Insulin Secretion
(mU/kg per min)
1.0
0.8
0.6
0.4
0.2
0.0
Before
glargine
After 8 weeks
of glargine
2.5
p = 0.043
2.0
1.5
1.0
0.5
0.0
Before
glargine
After 8 weeks
of glargine
100
3.0
Remission
IGT
2.0
1.5
NGT
IGT
80
NGT
2.5
*#
Non-remission
1.0
HOMA-
In AIRins (IU/ml)
40
*#
20
0
At 1
Before After
therapy therapy year
Remission
60
Non-remission
Befor
e
thera
py
After
thera
py
At 1
year
p < 0.05 vs NGT; p < 0.01 vs NGT; #p < 0.01 vs before therapy; p
< 0.01 vs IGT; *p < 0.05 vs remission group; p < 0.01 vs remission
group
Hu Y, et al. Diabetes Care 2011;34:184853.
Most physicians
Most patients
Insulin Facts
Strength U100 (100 units per mL) U500
available and others in trials
Vials and syringes:
Vials 10 mL (1000 units) - new 3 ml hospital
vials.
Syringes (0.3, 0.5, 1.0 mL); 28-31 gauge; 5/16
or 1/2 inch needles.
Vials are good for 1 month after opening
Pens 3 mL (300 units)
Needles 3/16, 5/16, 1/2 inch, 29-31 gauge,
(nano4 mm and 32 gauge)
Expiration time after opening varies by
product
Glycemic Control
Over Time
Glycemic Control by
Baseline A1C
Baseline A1C
7%
Glargine
Rosiglitazone
8.5%
A1C
9%
10%
11%
9.0%
8.0%
7.5%
12
16
Time (weeks)
20
24
0.5%
1.0%
1.5%
2.0%
2.5%
3.0%
3.5%
A1C
7.0%
6.5%
8%
*
Glargine
Rosiglitazone
9.0
%
8.5
%
8.0
%
7.5
%
7.0
%
6.5
%
6.0
%0
Glycemic Control
Over Time
Hypoglycemia
Cumulative Number of Events
(Documented PG 56 mg/dL)
A1C
900
800
Glargine
NPH
700
600
500
400
300
200
100
1
2
1
6
2
0
Weeks of Treatment
2
4
PG = plasma glucose
Riddle MC, et al. Diabetes Care. 2003;26:30803086
0
0
24
48
72
Time (days)
A Qualified A1c by
Hypoglycaemia
Hypoglycaemia
~ 0.40.6% ?
NPH
Glargine
A1c
Basal Insulins
Rate of Hypoglycemia,
events/100 patient-years
3500
NPH
GLAR
3000
2500
P = .004
2000
1500
1000
6.0
7.0
8.0
9.0
10.0
A1C, %
LIS received bedtime NPH and prandial NPH; RHI received
NPH at bedtime only.
a
16
LIS
RHI
14
12
10
8
6
4
2
P < .05
0
5.5
6.0
6.5
7.0
7.5
A1C, %
1. Mullins P, et al. Clin Ther. 2007;29:1607-1619.
2. Lalli C, et al. Diabetes Care. 1999;22:468-477.
8.0
More
frequentb
Basal +
Less
frequentc
Human
a
a
In contrast with other studies, this meta-analysis found that adding OADs to
insulin regimens increased the risk of nocturnal hypoglycemia despite lower
insulin TDD,
Insulin
TDD:
basal, 39 U;
twice-daily,
50 U; prandial,
butdoses,
some
included
trials
allowed
SUs 65
U.
a
P < .05 within group.
ACCORD1
ORIGIN2
Insulin +
Metformi
Insulin
n
Avils-Santa2
Bergenstal3
Insuli
n
Insulin +
Metformin
Insuli
n
Insulin +
Metform
in
Number of
Subjects
24
19
22
21
22
20
Duration of
Study
(months)
12
12
Insulin
Dosage at
End (U/day)
24
36
120
92
136
99
A1C at End
(%)
7.9
7.2
7.5
6.5
7.0
7.1
Weight Gain
(kg)
* P < 0.01
4.6
0.9*
3.2
0.5*
0.5
1.4
Insulin Therapy
Arguments for Basal and Prandial Options
Basal treatment
Prandial treatment
regimen should be
adjusted to meals and activity
level, not vice versa
Basal Insulin
The Simple Way to Add Insulin
Bedtime or morning long-acting
insulin OR
Bedtime intermediate-acting insulin
Daily dose: 10 UCheck
or 0.2 U/kg
FBG daily
Increase dose by 2 U every 3 days
until FBG is 3.97.2 mmol/L (70130
mg/dL)
If FBG is >10 mmol/L (>180 mg/dL),
increase dose by 4 U every 3 days
In the event of
hypoglycaemia or FBG
level <3.9 mmol/L (<70
mg/dL), reduce bedtime
insulin dose by 4 units,
or by 10% if >60 units
Final
doses
Treat to
Target1
0.41 U/kg
(Glar)
0.69 U/kg
(Glar)
0.66 U/kg
(NPH)
0.60 to 0.64
U/kg (Glar)
OADs
Measure
Basal-plus
Basal
insulin +
OADs
1 bolus
+ basal
insulin +
OADs
2
boluses
+ basal
insulin +
OADs
3
boluses
+ basal
insulin +
OADs
ADA/EASD1
AACE/ACE2
IDF3
10 U/d
Not specified,
but low
2 U every 3 d
2 U every 3 d
4U
Not specified,
but low
2 U every 3 d
2 U every 3 d
Basal algorithms
Initial dose
Titration
Prandial algorithms
Initial dose
Titration
a
b
b
b
See back of program book for study designs and A1C targets.
a
P < .01 vs control group; b P < .05 vs control group.
4. Riddle MC, et al. Diabetes. 2011;60(suppl 1):A113 [abstract 409-PP].
1. Raccah D, et al. Diabetes Metab. 2012;38:507-514.
5. Riddle MC, et al. Diabetes. 2012;61(suppl 1):A4 [abstract 14-OR].
2. Meneghini L, et al. Endocr Pract. 2011;17:727-736.
6. www.clinicaltrials.gov. NCT00384085.
3. Rosenstock J, et al. Diabetes. 2011;60(suppl 1):A20 [abstract 73-OR].
7. Rodbard HW, et al. Diabetes. 2013;62(suppl 1):A66 [abstract 256-OR].
A1C
BBT
Sw SU
Sw + SU
BL
8.5
8.4
8.3
EOT
7.7
7.9
7.9
Hypoglycemia, symptoms with prompt recovery after administration of 1. Raccah D, et al. Diabetes Metab. 2012;38:507-514.
oral carbohydrate; severe hypoglycemia, symptomatic with assistance 2. Meneghini L, et al. Endocr Pract. 2011;17:727-746.
needed and BG < 36 mg/dL or prompt recovery with oral carbohydrate, 3. www.clinicaltrials.gov. NCT00384085.
IV glucose, or glucagon.
4. Rodbard HW, et al. Diabetes. 2013;62(suppl 1):A66 [abstract 256-OR].
94%
86%
56%
47%
Period, mo/y
7/2007
10/2006
1/2005
4/2004
7/2003
10/2002
1/2002
14%
4/2001
7/2000
Insulin Units
Delivered by Insulin
Pens vs All Other
Methods, %
100
90
80
70
60
50
40
30
20
10
0
Japan
USA
Europe
Worldwide
Retrospective, longitudinal, pre-post analysis using a medical and pharmacy claims database. N=486 patients
previously treated with insulin and followed up for at least 2 years after converting from a vial and syringe to an
insulin pen.
CI = confidence interval.
Cobden D et al. Pharmacotherapy. 2007;27:948-962.
P<0.05
P<0.05
14,000
12,000
10,000
P<0.05
8000
6000
4000
2000
0
Annual Treatment
costs Per Patient, $
0
Retrospective, longitudinal pre-post analysis in patients with T2DM. Patients were followed up for at least 2
years after converting from a syringe to an insulin pen.
1. Lee WC et al. Clin Ther. 2006;28:1712-1725. 2. Cobden D et al. Pharmacotherapy. 2007;27:948-962.
70%
60%
Treatment Visits. %
Insulins
Sulfonylureas
50%
40%
30%
20%
Year
Turner et al. Diabetes Care 2014;37:985-992
2012
2011
2010
2009
2008
2007
2006
2005
2004
2003
2002
2001
2000
1999
1998
0%
1997
10%
Treatment Visits. %
20%
Long-Acting Insulins
15%
10%
5%
Year
Turner et al. Diabetes Care 2014;37:985-992
2012
2011
2010
2009
2008
2007
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
0%
Summary
Type 2 diabetes is a progressive disease,
marked by declining -cell function over
time
Additional insulin often is required to
achieve metabolic control
Insulin use in type 2 diabetes reduces the
risk of microvascular complications
Important to minimize weight gain and
hypoglycemia
Metformin and Pramlintide/ GLP-1 R
agonists are important agents in
combination with insulin
Summary
When
Why
Which
Long-standing Type 2 DM
Case Study
Long-standing Type 2 DM
Case Study
Long-standing Type 2 DM
Case Study
Relevant Labs
T. cholesterol
210 mg/dl
LDL-cholesterol
131 mg/dl
HDL-cholesterol 38 mg/dl
Triglycerides
182 mg/dl
Non HDL cholesterol 167 mg/dl
LFTs normal
TFTs normal
Question #1
In this patient, all of the following are true except:
1) He would benefit from weight reduction
2) He is at high risk for a cardiovascular event
3) His PPG excursions are most likely modestly
elevated
4) His LDL and TGs are not at goal for T2DM
5) His blood pressure target should be the same as
a patient without diabetes
Please Enter Your Response On Your Keypad
7.0
8.6
10.2
11.8
13.4
14.9
16.5
These estimates are based on ADAG data of ~2,700 glucose measurements over 3 months per A1C
measurement in 507 adults with type 1, type 2, and no diabetes. The correlation between A1C and
average glucose was 0.92. A calculator for converting A1C results into estimated average glucose (eAG),
in either mg/dL or mmol/L, is available at http://professional.diabetes.org/eAG.
ADA. V. Diabetes Care. Diabetes Care 2013;36(suppl 1):S19; Table 8.
Question #2
What antihyperglycemic agent would
you add to his regimen?
1)
2)
3)
4)
5)
6)
7)
Glimepiride 4 mg daily
Pre-dinner low dose regular insulin
GLP-1 RA as bid, qd, or QW
Basal insulin analog
Pioglitazone 15 mg daily
DPP-4 inhibitor
SGLT2 inhibitor
Moving Forward
Patients need to be seen and
evaluated at 3 month intervals
because:
1)Glycemic control tends to decline with
time and therapy may need to be
modified
2)Early signs of complications must be
monitored
7%
DiabetesCare,Diabetologia.19April2012[Epubaheadofprint]
(Adaptedwithpermissionfrom:IsmailBeigiF,etal.AnnInternMed2011;154:554)
Basal insulin + 1
(mealtime) rapid-acting
insulin injection
Basal insulin + 2
(mealtime) rapid-acting
insulin injection
More Flexible
Less Flexible
Number Complexit
of
y of
injectio regimen
ns
Low
Mod
3+
High
10
7
6
0
1
2
Time (weeks)
1
6
2
0
2
4
HbA1c (%)
FPG (mmol/l)
Insulin glargine
NPH
1
Time (weeks)2
1
6
2
0
2
4
Similar hypoglycemia
rates (<30%
symptomatic)
Change in body weight
(kg):
NO
Continue regimen;
check A1C every 3
months
OAD, oral antidiabetic agent; TDD, total daily dose.
a
Continue OADs unless specific contraindications.
A1C 7% after 2 to 3
months
YES
Intensify therapy
Nocturnal hypoglycemia
American Diabetes Association. Practical Insulin: A Handbook for Prescribing Providers. 3rd ed. 2011:1-68; Skyler JS. In: Lebovitz HE, ed.
Therapy for Diabetes Mellitus and Related Disorders.
Alexandria, VA: American Diabetes Association, Inc.; 2004:207-223.
Inzucchi S, et al. Diabetes Care. 2012;35:1364-1379.
Holman RR, et al. N Engl J Med. 2007;357:1716-1730.
Davidson MB, et al. Endocr Pract. 2011;17:395-403.
Postprandial Hyperglycemia
Persists
Basal
Therapy
164 patientsAfter
with baseline
A1c
7.5% on diet, oral agents, or insulin
Gluco
se
mg/dL
160
140
A1C 7% (n=120)
120
100
6
10
12
14
16
Hours
Woerle HJ et al. Diabetes Res Clin Pract 2007;78:280-85
18
20
22
24
Total
Hyperglycemia
(%)
HbA1C
Monnier L et al. Diabetes Care. 2003;26:881-885.
FPG (BHG) = fasting plasma glucose (basal hyperglycemia)
Total
Hyperglycemi
a
(%)
HbA1C
Riddle M, et al. Diabetes Care. 2011;34:2508-2514.
FPG (BHG) = fasting plasma glucose (basal hyperglycemia)
In clinical practice
Premix insulins
Basal-bolus
AIC (%)
Hypoglycemia
P<0.05
HbA1c(%)
N=371 insulin-nave
patients.
Insulin glargine + OADs vs
twice-daily human NPH
insulin (70/30)
Follow-up: 24 weeks
Hypoglycemia*(events/patient year)
P=0.0009
*Confirmed symptomatic
hypoglycemia (blood glucose <60
mg/dL [<3.3 mmol/l]
70
60
50
40
30
20
10
0
0
Time, min
80
60
40
20
0
0
60
Insulin Glulisine
Insulin Concentration, IU/mL
80
Insulin Lispro
140
120
100
80
60
40
20
0
0
Time, min
60
Time, min
Injection-Meal Interval
288
30 m
15 m
252
0m
216
+15 m
Insulin Glulisine2
Injection-Meal
Interval
Insulin Aspart3
Injection-Meal Interval
30 m
15 m
0m
20 m
0m
+20 m
180
144
108
72
-30
0
3
0
6
0
9
0
12
0
15
0
18
0
21
0
24
0
27
0
30
0
-30
8.6 kcal/kg
breakfast
Minutes
Standardized
breakfast
Regular
breakfast
0
3
0
6
0
9
0
12
0
15
0
18
0
21
0
24
0
27
0
30
06
-30
00
3
0
6
0
9
0
12
0
15
0
18
0
21
0
24
0
27
0
36
Minutes
Minutes
4-wk run-in
on 2-3 OADs
Glycemic Target:
Endpoints:
GLAR + 1 GLU (n =
189)
GLAR + stepwise addition of 0-3 GLU
(n = 191)
A1C =
9.4%
60 weeks
BIASP (n =
192)
GLAR
+ 1 GLU (n = 189)
GLAR + 0-3 GLU (n
= 191)
140
120
100
80
60
40
20
0
TDD (units)
GLAR + 1 GLU (n =
189
BIASP (n = 192)
BL 6 12
24
36
Weeks
48
60
GLAR + 1 GLU (n
= 189)
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Rate (EPY)
BL
12
24
36
Weeks
48
60
6
a
2
0
a
a
BL
12
24
36
Weeks
48
60
Stepwise Intensification
1-2-3 Study Design
Insulin-Based Therapy
Case Studies
Case 1
BP = 136/84
Case 1
What would you do next?
1) Refer to comprehensive diabetes
education
2) Treat lipid and BP abnormalities
3) Send blood for A1C to certified lab
4) Recheck glucose and POC A1C
Please Enter Your Response On Your Keypad
Criteria
Impaired fasting
glucose
IFG
Impaired glucose
Tolerance
IGT
Prediabetes
Diabetes
ADA, Standards of medical care in diabetes -2012. Diabetes Care, 2012; 35(suppl
Case 1
His referenced A1C is 7.6%. His random
glucose on CMP was 232 mg/dl. What
would you do next?
1) Initiate metformin and an SGLT2 inhibitor
in combination, optimizing the doses
2) Initiate metformin and optimize the dose
3) Start antihypertensive and statin
4) 1 and 3
5) 2 andPlease
3 Enter Your Response On Your Keypad
AACE:
Case 1
Case 1
What options are available to his
clinician?
1)Add analog basal insulin
2)Add GLP-1 RA
3)Continue current treatment and
recheck in 6 months
4)Add a DPP-4 inhibitor
5)Add an SU (glipizide)
Please Enter Your Response On Your Keypad
Case 1
You have decided to add an analog
basal insulin
Which basal product will you select?
1)NPH at bedtime
2)70/30 premix BID
3)Detemir titrated to a BID dosing
4)Glargine administered once daily
Please Enter Your Response On Your Keypad
Case 1
You decided to add basal insulin glargine at
0.2 u/kg, allowing the patient to self titrate
to what endpoint?
1) FBS < 100 mg/dl
2) A1C < 7%
3) FBS 100-130 mg/dl
4) No more than 0.5u/kg glargine
Please Enter Your Response On Your Keypad
1-1-100 titration1
3-2-1 titration2
2-4-6-8 titration4
1.
2.
3.
4.
3-0-3 titration3
Fairly complex
Used in initial Treat to Target Study
American Diabetes Association. Practical Insulin: A Handbook for Prescribing Providers. 3rd ed. 2011:1-68; Skyler JS. In: Lebovitz HE, ed.
Therapy for Diabetes Mellitus and Related Disorders.
Alexandria, VA: American Diabetes Association, Inc.; 2004:207-223.
Inzucchi S, et al. Diabetes Care. 2012;35:1364-1379.
Holman RR, et al. N Engl J Med. 2007;357:1716-1730.
Davidson MB, et al. Endocr Pract. 2011;17:395-403.
Case 1
Case 2
Case 2
How should you now proceed?
1) Continue to titrate basal insulin to
achieve an FBS of < 100 mg/dl
2) Continue to titrate basal insulin to an
A1C 7%
3) Shift to biphasic insulin BID
4) Shift from titration of basal insulin to
addition of mealtime therapy
Please Enter Your Response On Your Keypad
Case 2
You elected to use rapid acting
mealtime insulin. What therapy will
most easily control the A1C in this
patient with T2D?
1) Add mealtime insulin and continue to
titrate basal analog insulin to achieve a
FBS < 130 mg/dl
2) Add 3 mealtime insulin injections to the
basal
Please Enter Your Response On Your Keypad
3) Add 2 mealtime
insulin injections to the
Case 2
Her SU is stopped
Initiate
Titrate
Summary
Summary
Prevent hypoglycemia as a
cornerstone of diabetes care
Insulin
Pen
Insulin
Pump
Live demonstration of
vial/syringe and pen
Disadvantages
Greater accuracy
Lower rates of
hypoglycemia after
switch
Reduction in complexity
(ease-of-use)
Improved convenience
Greater treatment
satisfaction
Improved quality-of-life
Patients
*
*
P<0.05
60 U dose
63
6
5.51
5.47
5.42
Unit
Unit
5.35
60.23
60.10
58.34
58.39
SR
FP
60.54
61.04
60
5
4.54
4.44
4.47
4.57
57
4
SR
FP
NGFP
KP
57.87
NGFP
58.30
KP
SR, SoloSTAR
FP, FlexPen
NGFP, Next Generation FlexPen
KP, KwikPen
Patients Preferred
Insulin Pen Over
Vial/Syringe
Overall
Preference
Overcome Insulin
Resistance
Glucose
Control
Long-term Use
Lee, et al.
Cobden, et al.
486 diabetic patients switched from
vial/syringe to an insulin pen
Medication adherence increased from
59%
68% (p<0.01)
Lee WC, et al.
Clin Ther to
2006;28:1712-25
Training aids
Reimbursement and
Patient Assistance
Programs
- Sanofi
- Lilly
Bolus delivery
- 2 units per push
- Maximum 36 units/24 hrs
No electronics, no batteries, no
tubing
No programming required
Glucose Monitoring:
Episodic and
Continuous
Episodic Glucose
Monitoring
Continuous Glucose
Monitoring
Convergence of Technologies
Pathway to Artificial Pancreas
Summary
Insulin pens offer a safe, efficacious and costeffective method of insulin delivery
Medications:
- Metformin 1000 mg BID
- Glimeperide 4mg QD
- 70/30 insulin 30U BID (pre-breakfast and pre-dinner,
vial/syringe)
- HCTZ 25 mg QD, lisinopril 20 mg QD, atorvastatin 10 mg
QD
States that she frequently skips prebreakfast insulin injection due to her work
situation
Glucose monitoring: Can only check fasting
glucose 2-3 times a week due to test strip
BP=124/82
Question #1
How would you treat Susana to improve her
A1C?
1.
Add pioglitazone
2.
3.
4.
5.
Question #2
What else would you consider during Susanas
visit?
1.
2.
4.
5.
6.
glargine 45 U QHS
No
No
hypoglycemia
A1C
Gained
6 lbs
Question #3
Susanas A1C is 7.8% and FPG is at goal. What
would you do next to improve her glycemic
control?
1.
2.
3.
4.
5.
Mild
Glimepiride
A1C
A1C
Advances in the
Development of New
Long-acting Insulin
Formulations
Luigi Meneghini, MD, MBA
Professor, Department of Internal Medicine
UT Southwestern Medical Center
ACP Symposium
Duality of Interest Declaration
Outline
Importance of Insulin
Therapy and Glycemic
Control
Limitations of Insulin
Therapy
35%
30,000
30%
25,000
25%
15,000
15%
10,000
10%
5,000
5%
0%
Warfarin
Data given are number and percentage of annual national estimates of hospitalisations. Data from the NEISS-CADES project.
ER visits n=265,802/Total cases n=12,666. ER, emergency room; OAD, oral antidiabetic drugs
Budnitz et al. N Engl J Med 2011;365:200212
Amiel. Diabetic Medicine 2008; 25: 245-254 / UK Hypoglycemia Study Group. Diabetologia 2007;50: 1140
Diurnal distribution of
hypoglycemia in wellcontrolled elderly with T2DM
Desirable characteristics of
injectable basal insulin
Extended duration of action
24 hrs or longer
QD administration
hypoglycemia
Reduced day-to-day variability
Insulin detemir
*
*
*
et al. Diabetes Care. 2003;26:3080-3086. Philis-Tsimikas, et al. Clin Ther. 2006;28 (10).
Duration of Action
PEG-lispro
(~ 71-98 kDa)
Glargine U300
Di-Hexamer
(~ 72kDa)
Hexamer
(~36 kDa)
Monomer
(~6 kDa)
Molecular size
Multi-hexamers
> 5000 kDa
Degludec
Half-life
(hours)
Mean half-life
Glargine
0.4 U/kg
0.6 U/kg
0.8 U/kg
0.4 U/kg
0.6 U/kg
0.8 U/kg
25.9
27.0
23.9
11.8
14.0
11.9
25.4
12.5
Heise et al. Diabetes 2011;60(Suppl. 1):LB11 (37-LB); Heise et al. Diabetologia 2011;54(Suppl. 1):S425 (1046-P)
1.
2.
3.
4.
Polyethylene
Glycol Chain2
~20 kDa
Functional size2,3
7198 kDa
al. ADA 2012: Poster 106-P. Heise et al. ADA 2012: Poster 1000-P.
t al. (Abstract 1033) and Jax T (Abstract 1029), et al. EASD September 2327 2013; Barcelona, Spain,.
A1C
SMBG
FPG
d HW, et al. Diabet Med. 2013 Aug 19. doi: 10.1111/dme.12303. [Epub ahead of print]
NS
NS
Overall hypoglycemia
Nocturnal hypoglycemia
d HW, et al. Diabet Med. 2013 Aug 19. doi: 10.1111/dme.12303. [Epub ahead of print]
P < .05.
B, basal; BBT, basal-bolus therapy; B+OADs, basal
plus OADs; FLEX, flexible basal degludec dosing, 8a
Overall
hypoglycemia
PEG-Lispro
vs
Glargine
Nocturnal
hypoglycemia
P=0.13
Frequency of exercise-related
confirmed hypoglycaemic events
Patient-reported results
IDeg OD
IGlar OD
Overall confirmed
hypoglycaemia
BB, basal bolus; BOT, basal-oral therapy
Heller et al. Diabetes 2013;62(Suppl. 1):A187
Nocturnal confirmed
hypoglycaemia
Group B
(n=17)
(n=17)
Group C
(n=17)
(n=17)
Group D
(n=15)
(n=15)
No INS
INS 10+%
INS 10+% No INS
+10-20g CHO/hr+10-20g CHO/hr No CHO
No CHO
Epinephrine
response
Symptom scores
Degludec
Glargine
aesser A, et al. Diab Obesity & Metabolism 2014; Epub [ahead of print]. DOI: 10.1111/dom.12283
Tue
Wed
T2: A1C
Thu
Fri
Sat
Sun
IDeg OD flex
8h
morning
8h
morning
T1: A1C
morning
24h
40h
evening
40hevening
40hevening
Meneghini et al. Diabetes Care 2013;36:85864; Mathieu et al. J Clin Endocrinol Metab 2013;98:115462
evening
Summary
Longer-acting basal insulin preparations
demonstrate more consistent biologic
effect over a 24-hour period
No increase risk of overall hypoglycemia
and lower risk of nocturnal hypoglycemia
No specific issues regarding exercise or
recovery from hypoglycemia