ACP Insulin SlideCAST 222

Please Take A Moment to Complete the Pre-Program Clinical
Performance and Knowledge Gap Assessment Survey
A Road Map for Clinical Success
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
Welcome and Program

Overview
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
LUIGI F. MENEGHINI, MD,

MBA
Professor | Department of
Internal Medicine | Division of
Endocrinology | University of
Texas Southwestern Medical
Center | Dallas, Texas
JUAN P. FRIAS, MD, FACE
Clinical Assistant Professor of
Medicine | University of
California | San Diego,
California | Chief Medical Officer
| National Research Institute |
Los Angeles, CA
COI Disclosures
Faculty Member
Relationship
Vivian Fonseca, MD Research Support (to

Tulane):
Honoraria for Consulting

and Lectures:
Charles F. Shaefer,
MD, FACP
Consultant:
Grants from Eli Lilly, Abbott, Reata,

Asahi
Glaxo Smith Kline, Takeda, Novo

Nordisk,
sanofi-aventis, Eli Lilly, Pamlabs,
Astra-Zeneca, Abbott, Bristol-Myers
Squibb, Merck,
Boehringer Ingelheim
Sanofi-aventis, BMS-AZ,
Speakers Bureau:
Sanofi-Aventis, Amylin, BI/Lilly, BMSAZ, Novartis
Luigi F. Meneghini, Grant/Research:

MD, MBA
Juan P. Frias, MD
Corporation/Manufacturer
Biodel, Boehringer Ingelheim,

MannKind, Pfizer, sanofi-aventis
Consultant:
Advisory Board:
Novo Nordisk, Sanofi Diabetes

Novo Nordisk, Halozyme
Consultant:
Amylin Pharmaceuticals LLC
Evolving, Multimodal Approaches

for Optimizing HA1c Target Goal
Attainment
and Clinical Outcomes in T2D
The Foundation Role of Insulin Therapy as Part of an
Integrated Treatment Roadmap for Primary CareBased
Management
VIVIAN
A. FONSECA, MD, FRCP- Program Chair
Antihyperglycaemic Therapy in T2DM - ADA

Guidelines 2012
Healthy eating, weight control, increased physical activity
Initial drug
monotherapy
Efficacy (
HbA1c)
Hypoglycaemia
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
Insulin (multiple daily doses)

Inzucchi SE, et al. Diabetes Care & Diabetologia, 19 April 2012 [Epub ahead of print].
Long-Term Benefits of Glycemic

Control
for Microvascular Complications
Long-term benefits persist after intervention
Type 1 (EDIC): Intensive treatment reduces risk of

microvascular complications for at least 8 years
beyond therapy
Type 2 (UKPDS): Tight glycemic control reduces risk of
microvascular effectseven 10 years after treatment
Long-term benefits not seen consistently
No reduction of microvascular complications* in

Veterans Affairs Diabetes Trial (VADT) intensive arm
Results suggest a metabolic memory

idemiology
of Diabetes Interventions
and Complications;
(legacy)
effect
United Kingdom Prospective Diabetes Study
or conversion from normo- to micro- or macroalbuminuria
t al. Diabetes Care. 2006;29(2):340-344.

et al. N Engl J Med. 2008;359(15):1577-1589.
m for DCCT/EDIC Research Group. JAMA. 2003;290(16):2159-2167.
et al. Diabetologia. 2009;52(7):12191226
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
Impact of Intensive Glycemic

Therapy
Summary of Major Clinical Trials
Initial trial
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
Relative Risk (95% CI)
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.
ACCORD Eye: Microvascular Relative

Risk Reduction With Intensive Therapy
ACCORD Eye Glycemia Arm
Duration of
follow-up
Baseline A1C
A1C at 1
yeara
Retinopathy
a
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)
Significant between-group difference was maintained throughout the study
ACCORD=Action to Control Cardiovascular Risk in Diabetes
ACCORD Study Group and ACCORD Eye Study Group. N Engl J Med.
Legacy of Bad Metabolic

Memory
Before entering VADT
After entering VADT
intensive treatment arm
Drives
Drives risk
risk of
of
complications
complications
Generation
Generation of
of aa
bad
bad glycemic
glycemic
legacy
legacy
9.5
9.0
intensive treatment arm
Modelling the prior

history of patients
recruited in VADT
illustrates the
drawbacks of late
intervention
8.5
HbA1c (%)
8.0
7.5
7.0
6.5
6.0
1
10 11 12 13 14 15 16 17
Time since diagnosis (years)
Solid line: changes in HbA1c in response to intensive treatment in VADT
Upper broken line: theoretical reconstruction of prior diabetes progression based on UKPDS
Lower broken line: the ideal time course of glycemic control
Del Prato S, et al. Int J Clin Pract 2010;64:295304.
Implications of ACCORD,
ADVANCE, and VADT for
Microvascular Risk
Microvascular disease
Lowering A1C to 7.0% reduces

microvascular and neuropathic
complications in type 2 diabetes
If achievable without causing significant

hypoglycemia or other adverse events,
even lower A1C goals may be suggested for
selected individuals having:
Short duration of diabetes

Long life expectancy
No significant CVD
Skyler JS et al. Diabetes Care. 2009;32:187-192.
Implications of ACCORD, ADVANCE,

and VADT for Macrovascular Risk
Macrovascular disease
Intensive glycemic control that exceeds an A1C

goal of < 7.0% yields no significant reduction in
CVD outcomes compared to standard glycemic
control
Lowering A1C to a goal of 7.0% is a

reasonable glycemic goal until more evidence
becomes available
Long-term follow-up of the DCCT and UKPDS

cohorts suggests that treating to an A1C goal
below or near 7.0% yields long-term reductions
in the risk of macrovascular disease if it is
instituted in the years soon after diagnosis of
diabetes
Skyler
JS et al. Diabetes Care. 2009;32:187-192.
UKPDS: Intensive Insulin/SU Therapy

Reduces Risk of Outcomes in NewlyDiagnosedAny
T2DM
diabetes-related end point
Hazard ratio
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
man RR, et al. N Engl J Med 2008;359:157789.
Long-term Effects of Intensive Glucose

in Newly Diagnosed T2DM patients
Intensive (SU/Ins) vs. Conventional glucose control
HR (95%CI)
HR (95%CI)
Intensive (metformin) vs. Conventional glucose control
HR (95%CI)
Holman RR, et al. N Engl J Med 2008;358:254559.
HR (95%CI)
Early Addition of Insulin Significantly

Improves Metabolic Control (UKPDS 57)
Conventional policy
Insulin alone
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.
Clinical Inertia in Response to

Inadequate Glycemic Control
Shah BR, et al. Diabetes Care 2005;28:6006.
Time to Insulin Initiation and

Incidence
of Complications are Increasing
Median duration until
insulin initiation
(years)
Patients with at least 1

macrovascular event before
initiation (%)
Kostev K, et al. Diabetologia 2011;54(Suppl.1):3
CREDIT: Insulin is Started Late and in

Patients with a High Prevalence of CV
Disease and Risk Factors
Worldwide registry on insulin initiation in T2DM and follow up
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
Macrovascular disease (%)
34
36
33
33
Hypertension (%)
69
71
69
66
LDL >160 mg/dL
11
11
15
TG > 150 mg/dL
47
43
47
51
Obesity (BMI >30 Kg/m)
41
42
40
40
Freemantle N, et al. Diabetes 2009;58(Suppl.1):A474.
Greater Likelihood of Achieving

HbA1c <7% when Baseline is
Lower
Pooled analysis of 2193 patients with

24 weeks titrated glargine added to OAD
HbA1c change from baseline
< 8.0 8.0-8.4 8.5-8.9 9.0-9.49.5

Baseline HbA1c
No difference in hypoglycemia rates
% of patients attaining < 7% HbA1c
< 8.0 8.0-8.4 8.5-8.9 9.0-9.49.5

Baseline HbA1c
Riddle MC, et al. Diabetes 2009;58(Suppl.1):A125.
Greater Likelihood of Achieving

HbA1c <7% when Baseline is
Analysis ofLower
electronic medical records of 13,494 people
with T2DM initiating insulin* between 2005 and 2010
HbA1c change from baseline at 1 year
6.5
6.5 to <77 to <8 8 to <9 9
Baseline HbA1c
% attaining < 7% HbA1c at 1 year
6.5
6.5 to <77 to <8 8 to <9 9
Baseline HbA1c
*88.3% insulin glargine or detemir (0.7% both), 11% NPH insulin

Aagren M, et al. Diabetologia 2011;54(Suppl.1):1027.
Glycemic Changes with Insulin

Glargine
by Baseline OAD Use
8.7
2 OADs
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
Fonseca V, et al. Diabetes Obes Metab 2011;13:81422.
Hypoglycemia and Weight with Insulin

Glargine
by Baseline OAD Use: Pooled Analysis
Significantly lower hypoglycemia
in MET only patients
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
Change in body weight (kg)
p = 0.9547
Fonseca V, et al. Diabetes Obes Metab 2011;13:81422.
0/1
p = 0.1830
2
Met
OAD OAD only
SU
only
MET
+ SU
Increase in Body Weight After

Treatment Correlates with Baseline
HbA
Pooled data
from1c
9 RCTs (24 weeks) in adults with T2DM treated
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
Baseline HbA1c (%)
Leahy JL, et al. Diabetes 2011;60(Suppl.1):2308.
Overall
Effect of Age and bBseline

HbA1c on Body Weight Change
Pooled data from 9 RCTs (24 weeks) in adults with T2DM treated with
insulin glargine or comparator (63% other insulins, 32% OADs, 6%
dietary)
Insulin glargine, r = -0.163, p < 0.001
<50
50 to <65 65
Baseline age (years)
HbA1c <7% (% patients)
Insulin glargine, p = 0.055*
Comparator, r = -0.122, p < 0.001
<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
Diabetes Remission After

Intensive Insulin Therapy in New
Onset T2DM
Patients in remission (%)
100
CSII
MDI
OHA
80
p = 0.0012
60
51.1%
44.9%
40
26.7%
20
0
0
90
180
270
360
450
382 patients with newly

diagnosed type 2 DM
CSII, MDI, or OHA until
reversal of
hyperglycemia. Treat for
2 weeks
Remission defined as
FBG > 126 mg/dL or
2-hr PP > 180 mg/dL
Initial HbA1c 9.5%-9.8%
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.
Acute insulin response

(pmol/L per min)
-cell Function After Intensive

Insulin Therapy in New Onset T2DM
1400
CSII in the remission group

MDI in the remission group
OHA in the remission group
Non-remission group
p < 0.0001
1200
p = 0.006
1000
800
600
400
200
0
-200
Before therapy
After therapy
At 1 year
* p < 0.05 vs each intervention in the

remssion group (after treatment)
Weng J, et al. Lancet 2008;371:175360.
Effect of Insulin Glargine

on -cell Function
First-phase (t = 0 to 10 min minus basal levels) and second-phase insulin
secretion
(t = 10 to 120 min minus basal levels) in response to IV glucose administration
in T2DM (n = 14) before and after 8 weeks of insulin glargine treatment
1.4
1.2
Second-phase insulin response

Insulin Secretion
(mU/kg per min)
Insulin Secretion
(mU/kg per min)
First-phase insulin response

p = 0.0071
1.0
0.8
0.6
0.4
0.2
0.0
Before
glargine
After 8 weeks
of glargine
Pennartz C, et al. Diabetes Care 2011;34:204853.
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)
Short-term Intensive Therapy in

Newly Diagnosed T2DM Improves
-cell Function
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.
The Role of Insulin-Based

Management within The
Framework of ADA/EASD
Guidelines for Type 2 Diabetes
A Patient-Centered Approach Based on
Individualizing and Integrating Insulin Within a
VIVIAN A. Multimodal
FONSECA, MD,
FRCP - Program
Chair
Treatment
Plan
Barriers to Insulin Therapy

Initiation Attitudes in the DAWN Study
Survey of 2681 Physicians and 2061 Patients
Most physicians
Prefer to delay insulin until absolutely

necessary
Admit they use insulin as a threat with
patients
Most patients
Believe that needing insulin means they

DAWN = failed
Diabetes
Wishes, and Needs
toAttitudes,
follow treatment
Korytkowski M. Int J Obes. 2002;26(suppl 3):S18-S24.
recommendations
Peyrot M, et
al. Diabetes Care. 2005;28:2673-2679.
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
The Quest for a Better Basal Insulin
Insulin Initiation and Optimization in

Type 2 DM
Key Factors Assessing Insulin

Strategies
Absolute A1c reduction!
% Achieving target
<7%!
Insulin titration and
doses!
Amount of
Addition of Basal Insulin vs a Third

Oral Agent to Combination Oral
Therapy
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
*P<0.05 for glargine vs rosiglitazone

Rosenstock J, et al. Diabetes Care.
2006;29:554-559.
0.5%
1.0%
1.5%
2.0%
2.5%
3.0%
3.5%
A1C
7.0%
6.5%
8%
*
Glargine
Rosiglitazone
Addition of Basal Insulin to Oral

Therapy
Treat-to-Target Trial
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
756 Patients with Type 2 Diabetes on 1 or 2 Oral Agents
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
96 120 144 168
Time (days)
The Quest for a Better Basal Insulin
A Qualified A1c by
Hypoglycaemia
Hypoglycaemia
The impact of hypoglycaemia on A1c
~ 0.40.6% ?
NPH
Glargine
A1c
Insulin Analogues Are Associated With

Lower Hypoglycemia Rates Than Human
Insulin in T1DM
Prandial Insulins
Basal Insulins
Rate of Hypoglycemia,
events/100 patient-years
3500
N = 56 patients with T1DM2,a
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
Frequency of Mild Hypoglycemia,

episodes/patient-month
N = 1899 patients with T1DM1
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
Minimizing Hypoglycemia in Treatment

Regimens Containing Insulin for Patients with
T2DM
Increasing Rates
of Hypoglycemia
Most
frequenta
Prandial Human insulin

and
Analogue insulins
mixtures
Mixture (70/30)
More
frequentb
Basal +
Basal plus 2 to 3 prandial

Basal plus one prandial
NPH
Less
frequentc
Basal Analogue basal (glargine, detemir)

only Newer basal analogues (degludec)
Most frequent, 3.5% to 6.0% events/year; b more frequent,

2.0% to 4.5% events/year; c less frequent, 1.5% to 3.5%
events/year.
a
Moghissi E, et al. Endocr Pract. 2013;19:526-535.
Analogue insulin better

insulin better
Human
Insulin Analogues May Offset the Risk of

Hypoglycemia Often Observed With Insulin
Initiation in T2DM
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.
Pontiroli AE, et al. Diabetes Obes Metab. 2012;14:433-446.
Severe Hypoglycemia Increases the

Risk of Mortality in Patients With
T2DM and CVD
Deathany cause,
standard therapy group
2.93 (1.86-4.63)
Deathany cause,
intensive therapy group
1.79 (1.32-2.44)
Macrovascular events
1.77 (1.39-2.25); P < .001
Deathany cause
2.05 (1.65-2.55); P < .001
DeathCV cause
2.02 (1.52-2.69); P < .001
Deatharrhythmia
2.14 (1.43-3.18); P < .001
ACCORD1
ORIGIN2
Odds Ratio (95% CI)
Unadjusted rates; data shown

are hazard ratios.
1. Bonds DE, et al. BMJ. 2010;340:b4909.

2. The ORIGIN Trial Investigators. Eur Heart J. 2013 Sep 2. [Epub ahead of print].
Combining Insulin Therapy

With Metformin Minimizes
Weight Gain
Yki-Jrvinen1
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
Yki-Jrvinen H, et al. Ann Intern Med. 1999;130:389-396.

2
Avils-Santa L, et al. Ann Intern Med. 1999;131:182-188.
3
Bergenstal RM, et al. Diabetes. 1998;47(suppl 1):A89. Abstract 347.
1
Insulin Therapy
Arguments for Basal and Prandial Options
Basal treatment
Controls glucose production between meals

and overnight
Nearly constant levels
Prandial treatment
Limits hyperglycemia after meals

Immediate rise and sharp peak at 1 hour
postmeal
For ideal insulin replacement therapy, each

component should come from a different
insulin
Relative Changes over 3 Years and

Mean1SD
Hypoglycaemia
Tailoring Insulin Therapy to Meet

Patient Goals and Lifestyle
Insulin
regimen should be
adjusted to meals and activity
level, not vice versa
Basal insulin dose adjusted to

provide adequate coverage of
fasting glucose
Timing and dosage of prandial

insulin adjusted according to
carbohydrate intake at each meal
Education and training from diabetes

educator recommended
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
Initiate insulin with a single

injection of a basal insulin,
such as insulin glargine
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
Continue regimen and

check HbA1c every 3 months
FBG = Fasting blood glucose
Nathan DM, et al. Diabetes Care
Insulin Dosages (units/kg)

from Published Studies
Study
Final
doses
Treat to
Target1
0.48 U/kg (Glar)

0.42 U/kg (NPH)
INSIGHT2 LANMET3 INITIATE4
0.41 U/kg
(Glar)
1. Riddle MC, et al. Diabetes Care. 2003;26(11):3080-3086.

2. Gerstein HC, et al. Diabetic Med. 2006;23(7):736-742.
3. Yki-Jrvinen H, et al. Diabetologia. 2006;49(3):442-451.
4. Yki-Jrvinen H, et al. Diabetes Care. 2007;30(6):1364-1369.
0.69 U/kg
(Glar)
0.66 U/kg
(NPH)
0.60 to 0.64
U/kg (Glar)
Stepwise Insulin Initiation in

BBT
T2DM
Stepwise strategy
adds insulin doses
one at a time
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
A1C < 8%: 0.1-0.2 U/kg

A1C > 8%: 0.2-0.3 U/kg
Not specified,
but low
2 U every 3 d
1-4 U every 2-3 d
2 U every 3 d
4U
TDD: 0.3-0.5 U/kg

50% basal analogue
50% prandial analogue
Not specified,
but low
2 U every 3 d
If premeal BG > 180 mg/dL, add 10% at next meal

If 2-h postmeal BG > 180 mg/dL, add 10% at that meal
2 U every 3 d
Basal algorithms
Initial dose
Titration
Prandial algorithms
Initial dose
Titration
1. Nathan DM, et al. Diabetes Care. 2009;32:193-203.

2. Garber AJ, et al. Endocr Pract. 2013;19:327-336.
3. International Diabetes Federation Clinical Guidelines Taskforce. Brussels, Belgium: International Diabetes Federation; 2012.
Overview of Stepwise Basal and Prandial

Insulin
(SwBBT) Trials in T2DM
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].
Stepwise Insulin Initiation Results in Less

Hypoglycemia Than Initial BBT
A1C
BBT
Sw SU
Sw + SU
BL
8.5
8.4
8.3
EOT
7.7
7.9
7.9
Similarly low hypoglycemia rates were observed across categories in the

stepwise study arms of other trials:
STEP-Wise (range, 0.01-9.7 episodes per year) 2

All-to-Target (range, 0.1-14.5 events per patient-year) 3
FullSTEP (rate ratio, SwBBT vs BBT: 0.58; P < .001) 4
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].
Insulin Initiation and Titration in

T2DM
Pearls for Practice

Stepwise insulin initiation and titration are
associated with improved control with low rates
of severe hypoglycemia
However, fewer than 50% of patients with

T2DM treated with any insulin + oral
antidiabetic regimen attain A1C < 7%
Consider discontinuing insulin secretagogues

when prandial insulin is initiated
Performing 6- or 7-point SMBG for 3 days before

medical appointments provides useful
information for glycemic pattern management in
T2DM
Even more frequent glucose monitoring (eg,
Insulin Pen Usage By

Geographical Region
ROW
94%
86%
56%
47%
Period, mo/y
ROW = rest of world.

Clarke A et al. Expert Opin Drug Deliv. 2007;4:165-174.
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
Medication Adherence and

Hypoglycemic Events After Switching to
an Insulin Pen (cont)
Medication Possession Ratio (MPR)
P<0.01
Percent of Adherent Patients (MPR

80%)
P<0.01
Pen use resulted in 60% fewer hypoglycemic events requiring third-party

intervention (odds ratio: 0.40; 95% CI: 0.27-0.61; P<0.05)
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.
Total Costs, Second Year, $
Insulin Pens Associated With

Reduced
Health Care Costs vs Syringes
16,000
P<0.05
P<0.05
14,000
12,000
10,000
P<0.05
8000
6000
4000
2000
0
Data are mean.

OAD = oral antidiabetic drug.
Nonconcurrent, comparative, retrospective analysis of Medicaid-enrolled patients with T2DM. Total health
care costs, excluding prescription costs, were $14,857 for patients switching to pens and $31,765 for those
switching to syringes.
Pawaskar MD et al. Clin Ther. 2007;29:1294-1305.
Annual Treatment
costs Per Patient, $
Switching to Insulin Pens Lowers

All-Cause Treatment Costs
Savings = $1590/patient Savings = $1748/patient
P<0.01
P<0.01
16,000
14,000
12,000
10,000
8000
6000
4000
2000
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.
What Should We Expect in

the Future of Insulin?
Ultra - fast acting
Inhaled/ nasal/ oral
Ultra long acting ? 2-3 times per week
Combinations of basal insulin and GLP-1

RA fixed / variable dosing?
70%
National Trends in Ambulatory

Treatment of Type 2 Diabetes,
DipeptidylPeptidase-4 (DPP-4) Inhibitor
Biguanides
1997-2012
Glucagon-Like Peptide-1 (GLP-1) Agonist
Glitazones (Thiazolidinediones)
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%
National Trends in Ambulatory

Treatment of Type 2 Diabetes with
Insulins, 1997-2012
Regular Insulins
Short-Acting Insulins
Intermediate Insulins
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
Whenever needed to achieve A1C control

Avoid futile strategies
Are there benefits from early use ORIGIN?
Individualize therapy
Get patients to goal
Prevent complications
Which
All insulins are efficacious

Consider side effect profiles
Ultimately, choice depends on patient and
provider preferences
What is valued?

Clinical Case Study
Management of Early Type 2
Diabetes after Initial Monotherapy
Fails
VIVIAN A. FONSECA, MD, FRCP- Program Chair

Long-standing Type 2 DM
Case Study
Relevant Medical History
45-year-old male accountant
Diabetes diagnosed 1 year ago
Currently on lifestyle intervention and 2g/d

metformin;
A1C has increased from 6.8% to 7.8% in past 6

months
FPG has increased from 110 - 160 mg/dL over 6

months
Review of Hx with CDE reveals no significant

changes in life style or body weight.
Case Study
Physical Exam Remarkable For
Obese with weight 214 lbs for a height 5 10

(BMI 30.7)
BP 148/92 mm/Hg
Fundi show a few microaneurysms
CV exam unremarkable
Abdomen prominent with increased adipose
tissue
Waist circumference 102 cm
Pedal pulses palpable
Vibratory and DTRs normal
Case Study
Relevant Labs
FBG 162 mg/dl

A1C 7.8%
S.Creatinine 1.1 mg/dL; eGFR 81 mL/min/1.73 m2
U/A with no Proteinuria
Alb/Creat Ratio = 18 mcg/mg ( N: 0-20)
Lipid profile
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
Correlation of A1C with

Average Glucose (AG)
A1C (%)
6
7
8
9
10
11
12
Mean plasma glucose

mg/dL
mmol/L
126
154
183
212
240
269
298
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.
Current Goals of Treatment in

T2D
Glucose control, including FPG, PPG, and
A1c
Screen for status of complications
Compensate for diminished -cell function
Re-adjust pharmacotherapy and MNT
Eliminate symptoms
Blood pressure and lipid control
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
What are the

appropriate next steps
with this patient?
WHAT THERAPIES ARE SUPPORTED
BY THE NEW ADA/EASD and/or
AACE?
Antihyperglycemic Therapy in Type 2 Diabetes: General Recommendations
ADA/EASD Position Statement Diabetes Care Online April 19, 2012
Follow Up Treatment of T2D in

PC
Liraglutide is started and titrated to 1.8 mg
daily
Initial nausea had abated within 2 weeks
FPG decreased to < 120 mg/dl after 3
weeks
At 3 months A1C was 6.8 % and patient
had lost 5.5 lb
Follow Up Treatment of T2D in

PC
Glargine insulin 10 units at 10 PM was
initiated and titrated to an FPG 110 mg/dl
After 3 weeks, the FPG was 114 mg/dl on 22
units glargine insulin/ day
At the 3 month visit post lunch plasma
glucoses were 125 mg/dl, post dinner values
were 150 mg/dl.
At the 6 month visit , A1c was 7.0%, only
one mild hypo had occurred and the weight
had increased 1 kg.
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

Insulin Therapy in Type 2 Diabetes
When and How Do We Start? When Do We Add?
How Do The Guidelines Guide Us?
Charles F. Shaefer, Jr., MD, FACP

Senior Partner
University Medical Group Primary Care
University Health Systems
Assistant Clinical Professor of Medicine
Medical College of Georgia at Georgia Regents University
Augusta, Georgia
Diabetes Care 2012;35:13641379

Diabetologia 2012;55:15771596
7%
DiabetesCare,Diabetologia.19April2012[Epubaheadofprint]
(Adaptedwithpermissionfrom:IsmailBeigiF,etal.AnnInternMed2011;154:554)
Diabetes Care 2012;35:13641379

Diabetologia 2012;55:15771596
Sequential Insulin Strategies in

Patients With T2DM
Non-insulin regimen
Basal insulin only
(usually with oral
agents)
Basal insulin + 1
(mealtime) rapid-acting
insulin injection
Basal insulin + 2
(mealtime) rapid-acting
insulin injection
More Flexible
Less Flexible
Premixed insulin twice

daily
Number Complexit
of
y of
injectio regimen
ns
Low
Mod
3+
High
Inzucchi S, et al. Diabetes Care. 2012;35:1364-1379.
How to Start Insulin Therapy when

Oral Antidiabetic Drugs Fail in
Patients with T2D
Basal Insulin
Therapy
Combination of 2 or 3 OADs
Lifestyle changes plus metformin
Currently Available Basal

Insulins
Lucidi D, et al. Diabetes Care. 2011;34:1312-1314.

Niswender K, et al. Clin Diabetes. 2009;27:60-68.
Time-Action Profiles Illustrate

Variability in NPH Insulin vs Basal
Insulin Analogues
Long-acting insulin analogues are

preferred over NPH insulin because
they:
Do not exhibit a pronounced peak in

activity
Have more predictable time-action
profiles and less within/between patient
variability
Are associated with less nocturnal
hypoglycemia
apsed Time (hours)

odbard H et al. Endocr Pract. 2009;15:541-559
Insulin Glargine vs NPH Insulin

Added to Oral Therapy: FPG and HbA1c
756 patients previously treated with 12 OHAs and
HbA1c >7.5%
Mean daily insulin dose
Insulin glargine: 47 units
NPH: 42 units
10
7
6
0
1
2
Time (weeks)
1
6
Riddle M, et al. Diabetes Care 2003;26:30806.
2
0
2
4
HbA1c (%)
FPG (mmol/l)
Insulin glargine
NPH
1
Time (weeks)2
1
6
2
0
2
4
Treat to Target Trial

Frequency of Hypoglycemia
Basal Insulin Added to OADs

Improves Glycemic Control
in A1C, from baseline, %
24 week non-inferiority trial of 973 insulin-nave

T2DM patients inadequately controlled on OADs
Similar hypoglycemia
rates (<30%
symptomatic)
Change in body weight
(kg):
Insulin glargine: 1.4

Insulin detemir: 0.6
(P<.001)
Final insulin doses

(U/day):
nen S, et al. Diabetes Care. 2010;33:1176-1178
Insulin glargine: 43.5

Insulin detemir: 76.5
(P<.001)
Initiating Basal Insulin Therapy

Start with 10 U or 0.1 to 0.2 U/kg once dailya
Administer in AM if nocturnal hypoglycemia is
a significant concern
Better 24-hour coverage has been observed
with FPG
0.4 U/kg
once daily
Monitor
to determine
dosage adjustments
If cost is an issue, use NPH (0.1 U/kg twice
Increase
daily)dose by 2 U every 3 days until FPG is 70 to
130 mg/dL
If hypoglycemia occurs
or FPG < 70: reduce
dose by 4 U or 10% TDD
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
Hamaty M. Cleve Clin J Med. 2011;78:332-342.

Nathan DM, et al. Diabetes Care. 2009;32:193-203.
Hinnen D, et al. Combating clinical inertia through pattern management and
intensifying therapy. In: Mensing C, et al, eds. The Art and Science of Diabetes
Self-Management Desk Reference. 2011:531-576.
Indications That It May Be Time

to Stop Titrating Basal Insulin
Based on individualized glucose

target (eg, fasting AM glucose < 100
mg/dL or fasting glucose 100-130
mg/dL)
When total insulin dose exceeds 0.5

units/kg/day
Large glucose drops overnight or

between meals (possible overbasalization)
Nocturnal hypoglycemia
When Is It Time to Initiate

Prandial Insulin Therapy in T2DM?
The individual is not meeting glycemic

targets on basal insulin
A1C still not at goal with 0.5 U/kg/day of

daily basal insulin
Elevated A1C despite normal FPG (in the
absence of available PPG readings) with
basal insulin
FPG with basal insulin is within targeted
range, but PPG is persistently above goal
Further increases in basal insulin result in
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.
Davidson MB, et al. Endocr Pract. 2011;17:395-403.
Which Agent Should We

Choose
If Basal Insulin Fails?
Postprandial Hyperglycemia
Persists
Basal
Therapy
164 patientsAfter
with baseline
A1c
7.5% on diet, oral agents, or insulin
Mealtime hyperglycemia persists after 3 months of intensive treatmen

220
200
180
Gluco
se
mg/dL
A1C >7% (n=44)
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
Relative Contribution of Fasting and Postprandial

Hyperglycemia to HbA1C - I
On OADs, postprandial hyperglycemia
(PPHG) becomes dominant as HbA1C
approaches goal
Total
Hyperglycemia
(%)
HbA1C
Monnier L et al. Diabetes Care. 2003;26:881-885.
FPG (BHG) = fasting plasma glucose (basal hyperglycemia)
Relative Contribution of Fasting and

Postprandial Hyperglycemia to HbA1C - II
After treatment intensification with basal
insulin, postprandial hyperglycemia (PPHG)
contributes >50% of overall hyperglycemic
burden despite HbA1c category
Total
Hyperglycemi
a
(%)
HbA1C
Riddle M, et al. Diabetes Care. 2011;34:2508-2514.
FPG (BHG) = fasting plasma glucose (basal hyperglycemia)
When Basal Insulin is Not Enough

What Strategy?
In clinical practice
Premix insulins
Basal plus (stepwise basal-bolus)
Basal-bolus
Insulin in combination with other

therapies (GLP-1 RAs, DPP-4 Is, SGLT2-Is,
etc.)
AIC (%)
Premixed Insulin Added to Any Combination of OADs

Improves Glycemic Control in Insulin-Nave Patients
with T2DM
DURABLE Study
OADs kept at baseline dose(s) throughout the study

A1C goals were maintained a median of 16.8 months with
lispro 75/25 and 14.4 months with glargine (P=0.4)
e JB, et al. Diabetes Care. 2009;32:1007-1013

e JB, et al. Diabetes Care. 2011;34:249-55
Hypoglycemia
Episodes per Patient Year
Documented Hypoglycemic Episodes (<56

mg/dL)
Raskin P. Diabetes Care 2005;28:260-265.
P<0.05
HbA1c(%)
N=371 insulin-nave
patients.
Insulin glargine + OADs vs
twice-daily human NPH
insulin (70/30)
Follow-up: 24 weeks
Janka H, et al. Diabetes Care
Hypoglycemia*(events/patient year)
Insulin Glargine vs 70/30 Premixed

Insulin in OHA Failures
P=0.0009
*Confirmed symptomatic
hypoglycemia (blood glucose <60
mg/dL [<3.3 mmol/l]
Pharmacokinetics of Available Prandial

Insulins:
Rapid-Acting Analogues vs Regular Human
Rapid-acting analogue
Regular human insulin
Insulin
Insulin Aspart
70
60
50
40
30
20
10
0
0
60 120 180 240 300 360 420 480
Time, min
80
60
40
20
0
0
60
120 180 240 300 360
Insulin Glulisine
Insulin Concentration, IU/mL
80
Insulin Concentration, mU/L
Insulin Concentration, mU/L
Insulin Lispro
140
120
100
80
60
40
20
0
0
Time, min
60
120 180 240 300 360
Time, min
Rapid-acting analogues have more rapid

onset and shorter time to peak than regular
human insulin
US FDA. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA.
American Diabetes Association. Practical Insulin: A Handbook for Prescribing Providers. 3rd ed. 2011:1-68.
Timing of Prandial Insulin Injections

Insulin Lispro1
Mean Blood Glucose,

mg/dL
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
Injecting 15 to 20 minutes before meal may reduce PPG more than

injecting at mealtime
1. Rassam
By contrast,
regular human insulin needs to be injected 30 to 45
AG, et al. Diabetes Care. 1999;22:133-136; 2. Cobry E, et al. Diabetes Technol Ther. 2010;12:173-177;
4,5
3. Luijf
YM, et al. before
Diabetes Care.
2010;33:2152-2155;
4. American Diabetes Association. Practical Insulin: A Handbook for
minutes
meals
Prescribing Providers. 3rd ed. 2011:1-68; 5. Skyler JS. In: Lebovitz HE, ed. Therapy for Diabetes Mellitus and Related
Disorders.
Biphasic Aspart vs Basal-Plus vs Basal

and Stepwise Prandial Insulin in T2DM:
Study Design
Patient Baseline
Characteristics
Mean A1C = 9.4%

(after run-in)
Age 54 y
Diabetes duration 9 y
BMI 33.2 kg/m2
4-wk run-in
on 2-3 OADs
Glycemic Target:
Endpoints:
Fasting and preprandial

BG < 100 mg/dL
A1C, FPG, weight,

hypo
BIASP 70/30 (n = 192)
GLAR + 1 GLU (n =
189)
GLAR + stepwise addition of 0-3 GLU
(n = 191)
A1C =
9.4%
60 weeks
Rosenstock J. Diabetes. 2011;60(suppl 1):A20 [abstr 73-OR].

and Stepwise Prandial Insulin in T2DM
Over 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 + 0-3 GLU (n = 191)
GLAR + 1 GLU (n =
189
BIASP (n = 192)
Total Insulin Dose
BL 6 12
24
36
Weeks
48
60

and Stepwise Prandial Insulin in T2DM
Over 60 Weeks
BIASP (n =
192)
GLAR + 1 GLU (n
= 189)
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Change in Body Weight

8
Weight (kg)
Rate (EPY)
Hypoglycemia (BG < 50 mg/dL +

Symptoms)
0.8
GLAR + 0-3 GLU (n

= 191)
BL
P < .05 vs BIASP.
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
A1C Change From Baseline to

Week 24
Following 14-week run-in with insulin glargine
Mean A1C decreased from >10.0% to ~8.0%
288 patients achieved A1C 7.0%
Final dose was 0.55 U/kg regardless of reaching target
mITT = modified intent to treat.

Davidson MB et al. Endocr Pract 2011
Basal Bolus Insulin

Percent of Patients with HbA1c < 7%
12 trials, with
2114 patients
HbA1c < 7% was
achieved in
53.9% (95% CI,
43.564)
Hypoglycemic
events
(mean/patient/30
Escalation
days):
0.88 from
(0.35-basal to basal-bolus increases
success rate in an additional ~12% to 14% of
1.3)
patients
Weight
gain
- HbA1c
< 7% is achieve in ~54% of patients
~2.75 kg (1.8-3.7)
Giugliano et al. Diabetes Research & Clinical Practice 92 (2011) 110
Insulin-Based Therapy
Case Studies
Charles F Shaefer, Jr, MD, FACP

University Physicians Primary Care
Medical College of Georgia
Georgia Regents University
Augusta, GA
Case 1
38-year-old male construction

supervisor presents with a random 2
hour post-prandial sugar of 208
mg/dl. He is asymptomatic and is in
the office for a new job physical. At
33 he had acute pancreatitis. His
father is overweight and has T2D.
Height = 510 Weight = 196 lb

BMI = 28.1
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
ADA Standards of Care

Diagnosis of diabetes
Condition
Criteria
Impaired fasting
glucose
IFG
Fasting and glucose = 100125 mg/dl
Impaired glucose
Tolerance
IGT
2 h post-prandial and glucose

= 140-199 mg/dl
Prediabetes
IFG or IGT or A1C 5.8-6.4%
Diabetes
2 or more of the following:

FBS 126 mg/dl
2 h post-prandial glucose
200 mg/dl
A1C 6.5% (done in a lab
using reference standard)
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
Reminder on Initial Dual Therapy
ADA suggests this option if

treatment naive with A1C > 9%
AACE:
Case 1
After 24 weeks on metformin and

SGLT2 inhibitor therapy his A1C is
reduced to 6.4%. His weight
decreases to 189 lb. He has no
hypoglycemia.
He has return visits at 4-6 month

intervals with his A1C <7% but
gradually increasing.
At age 42 his evaluation shows his

weight = 184, A1C = 8.1%, BP =
128/78 and TC = 148, TG = 124,
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)
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
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
How to Titrate Basal Analog Insulin
1-1-100 titration1
3-2-1 titration2
From Predictive 303 Study

Average sugars over previous 3 days and add 3 units
until morning sugar is 100 mg/dl
2-4-6-8 titration4
1.
2.
3.
4.
From ATLANTUS Study

Average sugars over the previous 3 days and add 2 units
until morning sugar is 100 mg/dl
3-0-3 titration3
From Canadian Insight Study

Add 1 unit each day until morning sugar is 100 mg/dl
Fairly complex
Used in initial Treat to Target Study
Gerstein HC, et al. Diabetes Med 2006; 23:736-42

Davies M, et al. Diabetes Care. 2005; 28:1282-8
Meneghini L, et al. Diabetes Obes Metab. 2007;9:902-13
Riddle M, et al. Diabetes Care. 2003; 26:3080-6
Reminder: When Is It Time to Initiate

Prandial Insulin Therapy in T2DM?
The individual is not meeting glycemic

targets on basal insulin
A1C still not at goal with 0.5 U/kg/day of

daily basal insulin
Elevated A1C despite normal FPG (in the

absence of available PPG readings) with
basal insulin
FPG with basal insulin is within targeted

range, but PPG is persistently above goal
Further increases in basal insulin result in

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.
Davidson MB, et al. Endocr Pract. 2011;17:395-403.
Case 1
He titrates up to 38 units of glargine

daily plus metformin and an SGLT2
inhibitor.
His weight increases to 192 lb.
His A1C = 6.7% He is having no

hypoglycemia.
He continues follow up every 4-6

months, continuing lifestyle change
and self-monitoring.
Case 2
Mary is a 58-year-old teacher and presents

with a 12 year history of T2D. She has been
treated with metformin (2000 mg daily)
initially and later with a GLP-1 RA but she
could not tolerate the addition of this
treatment due to nausea. She faithfully
follows her lifestyle modifications.
An SU (glipizide) was added and her A1C was

6.7-7.1% for several years. She had
occasional weak feelings.
When her A1C increased to 7.9% her clinician

added glargine and has been titrating for the
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
Assessing When to Add Prandial Therapy After

Optimizing Basal Insulin: Pooled Analysis of
Insulin Glargine Studies
Glargine was titrated by patients according to a

specified algorithm and supervised by a
clinician
FBS target was 100-130 mg/dl
A1C target was 7%
After 24 weeks of conscientious titration of

glargine in patients with A1C > 7% :
PPG was > 50% of the overall glycemic

contribution
More hypoglycemia and weight gain seen in
those with FBS > 130 mg/dl who continued
Shaefer C,
Reid T, DiGenio
A, Vlajnic A, Zhou R, Riddle M, Poster Presentation, ADA
glargine
titration
Scientific Sessions June 2013.
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
3) Add 2 mealtime
insulin injections to the
A1C Change From Baseline to

Week 24
Following 14-week run-in with insulin glargine
Mean A1C decreased from >10.0% to ~8.0%
288 patients achieved A1C 7.0%
Final dose was 0.55 U/kg regardless of reaching target
mITT = modified intent to treat.

Davidson MB et al. Endocr Pract 2011
Case 2
Rapid acting analog insulin glulisine

is added to the basal insulin (42u
qd) at the largest meal of the day
(evening) and titrated to 6 units of
glulisine at dinner.
Her SU is stopped
A1C is now 6.8%
Weight has increased 2.3 lb
She is having no symptomatic

hypoglycemia
How to Initiate and Titrate Prandial

Insulin
Initiate
10% basal insulin dose as rapid acting analog insulin at

largest meal of the day
OR
4 units rapid acting analog insulin
And titrate upward
Titrate
+2 units every 3 days until glucose is in range ( 180 mg/dl)

50 concept?
ADA, Diabetes Care 2011: 34 (suppl 1): S11-S61
Summary
Summary
Insulin is what is missing, be quick to

consider restoring it
Prevent hypoglycemia as a
cornerstone of diabetes care
In T2D basal+1 achieves about the

same result as basal+3 with fewer
side effects
Avoid the common mistake of overbasaling
Know when to shift from basal to
Devices and Delivery Systems for

Insulin
Technological Advances
in Insulin
Administration
and Glucose Monitoring
Juan Pablo Frias, MD

President, National Research Institute, Los Angeles, CA
University of California, San Diego
Diabetes Device Evolution
Insulin Delivery Devices

Vial/Syringe, Pen and Pump
Vial and
Syringe
Insulin
Pen
Insulin
Pump
Live demonstration of
vial/syringe and pen
Advantages and Disadvantages

Insulin Pen (vs.
Vial/Syringe)
Advantages
Disadvantages
Greater accuracy
Higher prescription cost
Lower rates of
hypoglycemia after
switch
Patients are unable to mix

their own insulin
formulations
Reduction in complexity
(ease-of-use)
Improved convenience
Less fear of injection
Greater treatment
satisfaction
Improved quality-of-life
Cuddihy R, et al. Am J Ther. 2011 July 15 [EAP]

Magwire ML. Am J Ther. 2011;18:392-402
Selam J-L. J Diabetes Sci Technol. 2010;4:505-13
Improved Dosing Accuracy with

Insulin Pens vs. Vial/Syringe
HCPs/Caregivers
Patients
*
*
Mean absolute bias (U)
Mean absolute bias (U)
P<0.05
Pfutzner A, et al. Current Medical Research and Opinion 2013;29(5), 475-481
Similar Dosing Accuracy of

Currently Available Insulin Pens
5 U dose
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
Krzywon, et al. Diabetes Technol Therr 2012;14(2):804-9.
57.87
NGFP
58.30
KP
SR, SoloSTAR
FP, FlexPen
NGFP, Next Generation FlexPen
KP, KwikPen
Patient and HCP Preference,

Efficacy and Safety of Pen vs.
Vial/Syringe
Ahmann A, et al. Diabetes Techol Ther 2014;16(2), 76-83
Patients Preferred
Insulin Pen Over
Vial/Syringe
Overall
Preference
Overcome Insulin
Resistance
Ahmann A, et al. Diabetes Techol Ther 2014;16(2), 76-83
Glucose
Control
Long-term Use
Some Studies Have Shown

Favorable Hypoglycemia Data with
Insulin Pen Use
Lee, et al. examined patients who switched
from vial/syringe therapy to a prefilled insulin
pen
Likelihood of experiencing a hypoglycemic

event decreased significantly (P<0.05)
There were decreases in hypoglycemiaattributable ER visits (P<0.05)
There were decreases in hypoglycemiaattributable physician visits (P<0.05)
WC, et al. Clin Ther. 2006;28:1712-25
Improved Insulin Adherence when

Switched from Needle/Syringe to
Pen
Lee, et al.
1,156 patients with type 2 diabetes

Medication adherence improved from
62% to 69% when patients switched
from vial/syringe to prefilled insulin
pen (p<0.01)
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
Cobden D, et al. Pharmacotherapy 2007;27:948-62
Economics of Insulin Pen Use

Higher Prescription but Lower Overall
Cost
Total mean all-cause annual treatment costs

were reduced by $1,590 per patient (P <
0.01)
Annual hypoglycemia-attributable costs were

reduced by $788 per patient (P < 0.01)
Annual diabetes-attributable costs were

reduced by $600 per patient (P < 0.01)
Lee WC, et al. Clin Ther 2006;28:1712-25.
Practical Issues With Pen Use
Training aids
Storage conditions and handling
Where on the body to inject
Pen needle disposal
Do not share pen (even with new needle)
Reimbursement and
Patient Assistance
Programs
Third party coverage of insulin pens
Patient Assistance Programs

- Novo Nordisk
- Sanofi
- Lilly
Insulin Pump Therapy in Patients

with
Type
2 Diabetes
Failing
16-week,
uncontrolled,
multicenter
study MDI
Therapy
21 patients
not reaching A1C targets with MDI
therapy (OAD)
Age 57 yr; Total daily insulin 100 U; A1C 8.4%

Initiated insulin pump therapy (Animas 2020)
Best possible control with the simplest possible
dosing regimen
Frias JP, et al. J Diabetes Sci Technol 2011;5(4):887-893
*P<0.01, **P<0.001 compared to Baseline
V-Go: Disposable Insulin Delivery

Device
Predefined basal dose

- 20, 30 and 40 Units/24 hrs
Bolus delivery
- 2 units per push
- Maximum 36 units/24 hrs
Max capacity 76 U/day
1-day use (fully disposable)
No electronics, no batteries, no
tubing
No programming required
Glucose Monitoring:
Episodic and
Continuous
Episodic Glucose
Monitoring
Continuous Glucose
Monitoring
Self-Monitoring of Blood Glucose

(SMBG)
American Diabetes Association Guidelines
Patients using multiple insulin injections or insulin

pump therapy should do SMBG at least prior to
meals and snacks, occasionally postprandially, at
bedtime, prior to exercise, when they suspect low
blood glucose, after treating low blood glucose
until they are normoglycemic, and prior to critical
tasks such as driving.
For patients using less-frequent insulin injections,

SMBG may be useful as a guide to management.
When prescribed as part of a broader educational

context, SMBG results may be helpful to guide
treatment decisions and/or patient selfAmerican
Diabetes Association. Standards
Medical Care in Diabetes-2013.
Diabetes Care
2013; 36 (Suppl. 1)
management
forofpatients
using less
frequent
Convergence of Technologies
Pathway to Artificial Pancreas
Summary
Significant advances in insulin delivery and

glucose monitoring devices have been made over
the past 2 decades
Insulin pens offer a safe, efficacious and costeffective method of insulin delivery
Numerous studies have shown improved patient

satisfaction and preference with insulin pens
compared to vial/syringe
Patch insulin pumps tailored specifically to

patents with type 2 diabetes are available and
effective
Glucose monitoring is an important component of

diabetes therapy, particularly in insulin-treated
Interactive Case Study

Effective Use of Insulin Pens in Type 2 Diabetes
Juan Pablo Frias, MD

President, National Research Institute, Los Angeles, CA
University of California, San Diego
Case Study: Susana
56-year-old Latino female
Type 2 diabetes diagnosed 12 years ago
PMH: HTN, dyslipidemia, obesity and

osteoarthritis
Social history: Waitress at breakfast

restaurant, no health insurance
Case Study: Susana
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
Case Study: Susana
Height 54; weight 205 lbs (BMI=35 kg/m2)
BP=124/82
A1C=9.1% (goal <7.0%; 6 months ago

9.2%)
Fasting glucose in 160-190 mg/dL range

past 2 weeks; no hypoglycemia
Total cholesterol=194 mg/dL; LDL-C=120

mg/dL, HDL-C=42 mg/dL, TG=162 mg/dL
(non-HDL-C=152)
Normal renal and liver function
Question #1
How would you treat Susana to improve her
A1C?
1.
Add pioglitazone
2.
Add an SGLT-2 inhibitor
3.
Add a DPP-4 inhibitor
4.
Discontinue 70/30 inusulin and start an analog

basal insulin (insulin glargine or detemir)
5.
Add a GLP-1 receptor agonist

Question #2
What else would you consider during Susanas
visit?
1.
Discuss medication adherence
2.
Discuss nutrition and physical activity
4.
Consider aspirin therapy
5.
Consider increasing atorvastatin dose
6.
All of the above
Case Study: Susana
Insulin glargine was obtained via the

Sanofi Patient Assistance Program
(Solostar pen)
70/30 insulin was discontinued
Patient received training on the insulin

pen, as well as a refresher on use of
glucose meter and symptoms and
treatment of hypoglycemia
Glargine initiated at 25 U daily (at

bedtime)
Case Study: Susana
Given instructions to text glucose to nurse

for insulin dose titrations and to follow-up
in 1 week (fasting glucose target was 90120 mg/dL)
Metformin and glimepiride continued at

same doses
Atorvastatin increased to 20 mg daily
Initiated daily baby ASA
Case Study: Susana

Returns
Insulin
to your office in 2.5 months
glargine 45 U QHS
No
further issues with skipping insulin

doses
No
hypoglycemia
A1C
= 7.8%; 7-day average fasting

glucose ~105 mg/dl
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.
Add a DPP-4 inhibitor
2.
Increase glimepiride dose
3.
Add a GLP-1 receptor agonist
4.
Add prandial insulin with meals
5.
Add a SGLT-2 inhibitor

Case Study: Susana

Initiated
liraglutide at 0.6 mg QD and

increased to 1.8 mg QD over subsequent 8
weeks (Novo Nordisk Patient Assistance
Program)
Mild
nausea (no vomiting) during first 2

weeks which subsided
Glimepiride
discontinued and insulin dose

reduced by ~20% upon initiation of GLP-1
RA
Case Study: Susana

0.9% (to 6.9%) and body weight
~8 lbs over the next 3-4 months
A1C
A1C
stable over a 9 month period on

metformin 1000 mg BID, liraglutide 1.8
mg QD and insulin glargine 40 U QHS
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
I report the following potential

duality/dualities of interest in the field
covered by my lecture:
Honorarium Novo Nordisk, sanofiaventis, Boehringer-Ingelheim,

Halozyme
Research sanofi-aventis,
Boehringer-Ingelheim, Mannkind,
Pfizer
Luigi Meneghini
Outline
Importance and limitations of

insulin therapy
Goals & evolution of current

basal analogs
Longer acting basal analogs
Pharmaco -kinetics & -dynamics

Efficacy
Hypoglycemia
Other considerations
Exercise, stacking & flexibility
Importance of Insulin
Therapy and Glycemic
Control
Decrease in historical risk of

microvascular complications
DCCT/EDIC Study Group. JAMA 2003; 290: 2159-2167
Limitations of Insulin
Therapy
Medications most commonly associated

with emergency hospitalisation
35,000
35%
30,000
30%
25,000
25%
95% of all endocrine emergency hospitalisations

in people > 6520,000
years
are caused by hypoglycaemia
20%
Estimated number of hospitalisations
Percentage of estimated number of hospitalisations
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
Severe Hypoglycemia Based on

DM Type, Treatment & Duration
Amiel. Diabetic Medicine 2008; 25: 245-254 / UK Hypoglycemia Study Group. Diabetologia 2007;50: 1140
Diurnal distribution of
hypoglycemia in wellcontrolled elderly with T2DM
Hay LC et al. Diab Tech Ther 2003; 5(1): 19-26
Evolution of current basal

analogs
Desirable characteristics of
injectable basal insulin
Extended duration of action
24 hrs or longer
QD administration
Flat pharmacodynamic profile
minimal to no peak effect Low risk of nocturna
hypoglycemia
Reduced day-to-day variability
Predictable blood glucose response
Evolution of basal insulin

preparations
= glucose infusion rate.

e T, et al. Diabetes. 2004;53(6):1614-1620.
Insulin detemir
Longer acting basal
Less nocturnal hypoglycemia

with basal analogues vs NPH
*
*
*
et al. Diabetes Care. 2003;26:3080-3086. Philis-Tsimikas, et al. Clin Ther. 2006;28 (10).
Longer acting basal analogs:

PK/PD
Duration of Action
Molecular size [or depot surface]

can influence rate of absorption
and clearance
PEG-lispro
(~ 71-98 kDa)
Glargine U300
Di-Hexamer
(~ 72kDa)
Hexamer
(~36 kDa)
Monomer
(~6 kDa)
Molecular size
Multi-hexamers
> 5000 kDa
Serum concentration and halflife of insulin degludec and

insulin glargine
Deg 0.8 U/kg

Glar 0.8 U/kg
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)
LY2605541: Pegylated lispro

insulin
LY2605541
~26 kDa
Insulin
Lispro1
5.8 kDa
1.
2.
3.
4.
Polyethylene
Glycol Chain2
~20 kDa
Humalog, US prescribing information, 2011.

Hansen RJ, et al. ADA 2012 abstract 896-P
Sinha et al. ADA 2012 abstract 1063-P
Meloun B, et al. FEBS Lett. 1975;58:134-137.
Functional size2,3
7198 kDa
Large hydrodynamic size delays insulin absorption

and reduces clearance, resulting in prolonged
Pegylated Lispro SingleDose Pharmacodynamics
al. ADA 2012: Poster 106-P. Heise et al. ADA 2012: Poster 1000-P.
Insulin Glargine U300 is a 3x

concentrated preparation with a
smaller depot surface area
PK/PD values at steady state in subjects with type 1 diabetes

Serum insulin
mU/L
Glucose infusion rate

Mg/kg/min
t al. (Abstract 1033) and Jax T (Abstract 1029), et al. EASD September 2327 2013; Barcelona, Spain,.
Longer acting basal

analogs:
Efficacy
Basal insulin replacement in

insulin-nave T2DM over 2
years
Degludec
vs
Glargine
A1C
SMBG
FPG
d HW, et al. Diabet Med. 2013 Aug 19. doi: 10.1111/dme.12303. [Epub ahead of print]
PEG-Lispro: Similar A1C

reduction in Type 2 diabetes
on prior basal
PEG-Lispro
vs
Glargine
NS
enstal RM, et al. Diabetes Care 2012; 35: 21402147
NS
Similar glycemic control between

Glargine U300 vs. U100 in T2DM
on basal + OADs
ted at the 2013 International Diabetes Federation meetings in Melbourne, Australia
Longer acting basal analogs:

Hypoglycemia
Basal insulin replacement in insulinnave T2DM over 2 years

Degludec
vs
Glargine
Overall hypoglycemia
Nocturnal hypoglycemia
d HW, et al. Diabet Med. 2013 Aug 19. doi: 10.1111/dme.12303. [Epub ahead of print]
Nocturnal Hypoglycemia in Phase 3

Treat-to-Target RCTs: Degludec vs.
Glargine
a
P < .05.
B, basal; BBT, basal-bolus therapy; B+OADs, basal
plus OADs; FLEX, flexible basal degludec dosing, 8a
Russell-Jones DL, et al. Diabetes. 61(suppl

1): A603 [abstr 2395-PO].
Hypoglycemia Incidence during 12

Weeks of Treatment in Type 2
Diabetes on Prior Basal
P=0.16
Overall
hypoglycemia
genstal RM, et al. Diabetes Care 2012; 35: 21402147
PEG-Lispro
vs
Glargine
Nocturnal
hypoglycemia
P=0.13
Lower risk of confirmed or severe* nocturnal

hypoglycemia with Glargine U300 vs. U100 in
T2DM on basal + OADs
* Severe hypoglycemia (all)

occurred in 1.0% and 1.5% of
ted at the 2013 International Diabetes Federation meetings in Melbourne, Australia U300 vs. U100 subjects,
Exercise and hypoglycemia
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
Prandial dose adjustments for

planned aerobic activity
8 T1DM males (age 333) tested 90 after meal + insulin

25% VO22 max x 60, 50% VO22 max x 30 & 60, 75% VO22 max
asa-Lhoret, R. et al. Diabetes Care 2001; 24:625630
Supplementing CHO more effective than

reducing daily insulin dose to prevent
exercise-induced hypoglycemia
Carbohydrate
supplementation
Mean
daily
insuli
n
dose
reduc
tion
of 2025%
Group A
(n=18)
(n=18)
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
Grimm et al. Diabetes Metab 2004; 30: 465-70
Similar awareness & recovery from

induced hypoglycemia for degludec
vs glargine
Glucagon response
Epinephrine
response
ler G, et al. Diabetologia 2013; Sep 22 [Epub ahead of print]
Recovery from hypo
Symptom scores
Degludec
Glargine
Physiologic stacking of basal insulin

preparations
First order kinetics of basal

insulin
se T, Meneghini L, Endocrine Pract (in print for 2014)
Steady state insulin concentration

achieved within 3-4 days with glargine
U300
aesser A, et al. Diab Obesity & Metabolism 2014; Epub [ahead of print]. DOI: 10.1111/dom.12283
More forgiveness from longer-acting

basal insulin preparations
Dosing regimen: Forced

flexible
Mon
Tue
Wed
T2: A1C
Thu
Fri
Sat
Sun
T2: nocturnal hypo
IDeg OD flex
8h
morning
8h
morning
T1: A1C
morning
T1: nocturnal hypo
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
Steady state reached within 3-4 days

Weekly dose adjustments safe

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ACP Insulin SlideCAST 222

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Please Take A Moment to Complete the Pre-Program Clinical

Performance and Knowledge Gap Assessment Survey

A Road Map for Clinical Success

Welcome and Program

LUIGI F. MENEGHINI, MD,

Vivian Fonseca, MD Research Support (to

Honoraria for Consulting

Grants from Eli Lilly, Abbott, Reata,

Glaxo Smith Kline, Takeda, Novo

Sanofi-Aventis, Amylin, BI/Lilly, BMSAZ, Novartis

Luigi F. Meneghini, Grant/Research:

Biodel, Boehringer Ingelheim,

Novo Nordisk, Sanofi Diabetes

Amylin Pharmaceuticals LLC

A Road Map for Clinical Success

Evolving, Multimodal Approaches

Antihyperglycaemic Therapy in T2DM - ADA

Insulin (multiple daily doses)

Long-Term Benefits of Glycemic

Long-term benefits persist after intervention

Type 1 (EDIC): Intensive treatment reduces risk of

Long-term benefits not seen consistently

No reduction of microvascular complications* in

Results suggest a metabolic memory

or conversion from normo- to micro- or macroalbuminuria

t al. Diabetes Care. 2006;29(2):340-344.

Impact of Intensive Glycemic

Relative Risk (95% CI)

ACCORD Eye: Microvascular Relative

Significant between-group difference was maintained throughout the study

ACCORD=Action to Control Cardiovascular Risk in Diabetes

Legacy of Bad Metabolic

intensive treatment arm

Modelling the prior

Time since diagnosis (years)

Solid line: changes in HbA1c in response to intensive treatment in VADT

Lower broken line: the ideal time course of glycemic control

Del Prato S, et al. Int J Clin Pract 2010;64:295304.

Lowering A1C to 7.0% reduces

If achievable without causing significant

Short duration of diabetes

Skyler JS et al. Diabetes Care. 2009;32:187-192.

Implications of ACCORD, ADVANCE,

Intensive glycemic control that exceeds an A1C

Lowering A1C to a goal of 7.0% is a

Long-term follow-up of the DCCT and UKPDS

UKPDS: Intensive Insulin/SU Therapy

man RR, et al. N Engl J Med 2008;359:157789.

Long-term Effects of Intensive Glucose

Intensive (metformin) vs. Conventional glucose control

Holman RR, et al. N Engl J Med 2008;358:254559.

Early Addition of Insulin Significantly

Clinical Inertia in Response to

Shah BR, et al. Diabetes Care 2005;28:6006.

Time to Insulin Initiation and

Patients with at least 1

Kostev K, et al. Diabetologia 2011;54(Suppl.1):3

CREDIT: Insulin is Started Late and in

Macrovascular disease (%)

LDL >160 mg/dL

TG > 150 mg/dL

Obesity (BMI >30 Kg/m)

Freemantle N, et al. Diabetes 2009;58(Suppl.1):A474.

Greater Likelihood of Achieving