Вы находитесь на странице: 1из 197

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

A Road Map for Clinical Success

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
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

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
Change in body weight (kg)

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)

Change in body weight (kg)

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.

A Road Map for Clinical Success

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
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

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?

A Road Map for Clinical Success


Clinical Case Study
Management of Early Type 2
Diabetes after Initial Monotherapy
Fails

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

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.

Long-standing Type 2 DM
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

Long-standing Type 2 DM
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

Please Enter Your Response On Your Keypad

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

A Road Map for Clinical Success


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

A Road Map for Clinical Success

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

Inzucchi S, et al. Diabetes Care. 2012;35:1364-1379.

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.
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.

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].

Biphasic Aspart vs Basal-Plus vs Basal


and Stepwise Prandial Insulin in T2DM
Over 60 Weeks

BIASP (n =
192)
GLAR
+ 1 GLU (n = 189)
GLAR + 0-3 GLU (n
= 191)

Rosenstock J. Diabetes. 2011;60(suppl 1):A20 [abstr 73-OR].

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

Biphasic Aspart vs Basal-Plus vs Basal


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

Rosenstock J. Diabetes. 2011;60(suppl 1):A20 [abstr 73-OR].

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

A Road Map for Clinical Success

Insulin-Based Therapy
Case Studies

Charles F Shaefer, Jr, MD, FACP


University Physicians Primary Care
Assistant Clinical Professor of Medicine
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
Please Enter Your Response On Your Keypad

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)
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

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.
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

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
Please Enter Your Response On Your Keypad

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
Please Enter Your Response On Your Keypad
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

A Road Map for Clinical Success

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
Assistant Clinical Professor of Medicine
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

A Road Map for Clinical Success

Interactive Case Study


Effective Use of Insulin Pens in Type 2 Diabetes

Juan Pablo Frias, MD


President, National Research Institute, Los Angeles, CA
Assistant Clinical Professor of Medicine
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


Please Enter Your Response On Your Keypad

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

Please Enter Your Response On Your Keypad

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


Please Enter Your Response On Your Keypad

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

A Road Map for Clinical Success

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