Insulin Initiation and Intensification

When Current Therapy Alone No Longer Provides

Adequate Glycaemic Control

<Speaker Name, Credentials, and Title>

@ 2015 Eli Lilly and Company

Conflict of Interest Disclaimer

Use this slide to communicate the speakers disclosure statement.
Some examples are as follows:
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companies: _______.

Objectives
Identify both the clinical factors and the individualised needs of your
patient to determine the appropriate insulin therapy regimen

Apply the clinical evidence supporting the use of insulin analogue

mixes to your current practice

Clinical Challenge
Person with Type 2 Diabetes on Oral Therapies but HbA1c Is 9.4%*
Case Presentation:
Age: 52 years
Duration of type 2 diabetes: 7 years
Review of patient logbook shows FPG
of 9.9-16.3 mmol/L (178.2-293.4
mg/dL) over the past 2 months
Weight: 209 lbs (95 kg)
BMI: 31.8 kg/m2
Blood pressure: 135/85 mmHg
Current treatment: glipizide 10 mg
QD, metformin 1000 mg BID
No reported hypoglycaemia

Lab Results:
FPG: 10.4 mmol/L (187.2 mg/dL)
2-hour PPG: 14.7 mmol/L (264.6 mg/dL)
Total cholesterol: 4.7 mmol/L
(181.5 mg/dL)
Triglycerides: 1.9 mmol/L (168.1 mg/dL)
AST: 15 IU/L
ALT: 19 IU/L
HbA1c: 9.4%
Urine microalbumin: 18 mg/24 hr

Patient Perspective:
Wants to improve glycaemic control and is willing to add an injectable therapy
but wants to minimise the number of injections
Has a fairly predictable daily routine, including meal composition

What therapeutic decisions would you make to

help this patient reach his or her HbA1c goal?
*Hypothetical patient case.
ALT = alanine transaminase; AST = aspartate transaminase; BID = two times per day; BMI = body mass index; FPG = fasting
plasma glucose; PPG = postprandial plasma glucose; QD = once per day.

ARS Question
What would be the next step in therapy for this patient?
a) No change to therapy monitor HbA1c again in 3 months

b)
c)
d)
e)
f)

Add an additional oral agent (eg, TZD, DPP-4 inhibitor)

Add a basal insulin at bedtime
Stop glipizide, begin a premixed insulin analogue therapy
Stop orals and start basal/bolus insulin therapy
Add a GLP-1 receptor agonist

ARS = audience response system; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; TZD = thiazolidinedione.

ARS Question
When evaluating treatment choices at this stage,
what do you think may be your patients primary
concern?
a) Stigma associated with injectable therapies
b) Fear of weight gain or hypoglycaemia
c) Disease progression
d) Treatment management
e) Insulin therapy

Natural History of Type 2 Diabetes

Glucose (mg/dL)

350

Prediabetes
Metabolic syndrome

300

Post-meal glucose

Diabetes
diagnosis

250

Fasting glucose

200
150
100

Relative Function

50
250

Insulin resistance

200
150

Incretin effect

100
50

Insulin level

-cell function

-15

-10

-5

0
Onset of
diabetes

Kendall DM, et al. Am J Med. 2009;122(Suppl 6):S37-S50.

10

15

20

25

30

Years

Initiating Insulin Therapy

Addressing the Needs for Fasting and
Postprandial Glucose Control

@ 2015 Eli Lilly and Company

Sequential Insulin Strategies in

Type 2 Diabetes
Non-insulin
regimens

Number
Number
of
of
injection
injection
s
s

Regimen
Regimen
complexi
complexi
ty
low

Basal insulin
only

(usually with oral

agents)

Basal insulin +
1
(mealtime)
rapid-acting
insulin
injection
Basal insulin +
2
(mealtime)
rapid-acting
insulin
More
injections
More flexible
flexible

Premixed
insulin twice
daily

3+

flexible
flexible

Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379.

Less
Less

mo
d.

hig
h

Flexibilit
y

11

Treatment Strategies
Glucose Triad
Treatment strategy should target all 3 components
HbA1c

FPG

Ceriello A, Colagiuri S. Diabet Med. 2008;25(10):1151-1156.

PPG

12

Treatment Strategies
Insulins
Basal insulin: targets FPG > PPG
Benefit: Only 1-2 injections per day
Drawback: Patients may require prandial insulin to reach HbA1c targets

Prandial (mealtime) insulin: targets PPG > FPG

Benefit: Most physiologic; best at targeting PPG
Drawback: Most injections; requires addition of basal insulin to
target FPG

Premixed insulin: targets both FPG and PPG

Benefit: Fewer injections than prandial
Drawback: Unable to adjust components separately

Lasserson DS, et al. Diabetologia. 2009;52(10):1990-2000.

13

Basal vs Mealtime Hyperglycaemia

in Diabetes

Basal hyperglycaemia

Plasma Glucose (mmol/L)

13.9

Mealtime hyperglycaemia

11.1
Type 2 Diabetes

8.3
5.5
2.8

Healthy

0
0600

1200

1800

2400

0600

Time of Day
Change in AUC from healthy basal >104 mmol/Lhr (>1875 mg/dLhr);
estimated HbA1c >8.7%
Artist's rendering based on hypothetical glucose values.
AUC = area under the curve.
Riddle MC. Diabetes Care. 1990;13(6):676-686.

14

Basal vs Mealtime Hyperglycaemia

in Diabetes
When Only Basal Hyperglycemia Is Corrected
Basal hyperglycaemia

Plasma Glucose (mmol/L)

13.9

Mealtime hyperglycaemia

11.1
8.3
5.5
2.8

Healthy

0
0600

1200

1800

2400

0600

Time of Day
Change in AUC from healthy basal 49.9 mmol/Lhr (900 mg/dLhr);
estimated HbA1c = 7.2%
Artist's rendering based on hypothetical glucose values.
Riddle MC. Diabetes Care. 1990;13(6):676-686.

15

Basal vs Mealtime Hyperglycaemia

in Diabetes
When Only Mealtime Hyperglycaemia Is Corrected
Basal hyperglycaemia

Plasma Glucose (mmol/L)

13.9

Mealtime hyperglycaemia

11.1
8.3
5.5
2.8

Healthy

0
0600

1200

1800

2400

0600

Time of Day
Change in AUC from healthy basal 79.1 mmol/Lhr (1425 mg/dLhr);
estimated HbA1c = 6.4%
Artist's rendering based on hypothetical glucose values.
Riddle MC. Diabetes Care. 1990;13(6):676-686.

16

Basal vs Mealtime Hyperglycaemia

in Diabetes
When Both Basal and Mealtime Hyperglycaemia Are Corrected
Basal hyperglycaemia

Plasma Glucose (mmol/L)

13.9

Mealtime hyperglycaemia

11.1
8.3
5.5
2.8

Healthy

0
0600

1200

1800

2400

0600

Time of Day
Change in AUC from healthy basal 12.5 mmol/Lhr (225 mg/dLhr);
estimated HbA1c = 6.4%
Artist's rendering based on hypothetical glucose values.
Riddle MC. Diabetes Care. 1990;13(6):676-686.

17

Clinical Evidence Supporting the

Use of Insulin Analogue Mixtures

@ 2015 Eli Lilly and Company

Achieving HbA1c Goals

Comparison of Premixed Analogue Insulin with Basal
Insulin Alone
Achieving HbA1c Goal (%)

Hypoglycaemia: Betweengroup Comparison

Study

HbA1c
Goal

Analogue
Mix BID

Glargine

Pvalue

Overall

Nocturnal

PAIR-PI1
(Lilly)

7.0%

30%

12%

.002

No difference

Glargine>Mix

PAIR-IN2
(Lilly)

7.0%

42%

18%

<.001

Mix>Glargine

Mix>Glargine

INITIATE3
(Novo)

<7.0%

66%

40%

<.001

Mix>Glargine

Not reported

Janka*4
(Sanofi US)

7.0%

39%

49%

.0596

Mix>Glargine

Mix>Glargine

*Human insulin mix 70/30 vs glargine + OADs (SU and MET).

Met = metformin; Novo = Novo Nordisk; OAD = oral antidiabetes drug; su = sulphonylurea.
1. Malone JK, et al. Diabet Med. 2005;22(4):374-381. 2. Malone JK, et al. Clin Ther. 2004;26(12):2034-2044. 3. Raskin P, et al.
Diabetes Care. 2005;28(2):260-265. 4. Janka HU, et al. Diabetes Care. 2005;28(2):254-259.

19

For Patients Not Controlled on Orals:

Add Basal Insulin Plus 1-3 Injections
of Rapid Acting Insulin or Add 1-3
Injections of Premix?

@ 2015 Eli Lilly and Company

Humalog Mix25 (25% insulin lispro [rDNA origin]

injection, 75% insulin lispro protamine suspension)
In people without diabetes, insulin secretion increases1 and glucagon
levels are suppressed in response to a meal and BG is maintained in
a narrow range2

Humalog Mix25 in a twice-daily regimen provides both basal and

rapid-acting insulin, which restores first-phase insulin response in
type 2 diabetes and suppresses endogenous glucagon production 3,4

Premixed insulin targets both FPG and PPG concentrations to lower

HbA1c

Recent IDF guidelines on postprandial control reflect the emerging

importance of postprandial BG concentrations5

BG = blood glucose; IDF = International Diabetes Federation.

1. Polonsky KS, et al. N Engl J Med. 1988;318(19):1231-1239. 2. Unger RH. N Engl J Med. 1971;285(8):443-449. 3. Bruttomesso D, et al. Diabetes.
1999;48(1):99-105. 4. Roach P, Woodworth JR. Clin Pharmacokinet. 2002;41(13):1043-1057. 5. IDF. Available at:
http://www.idf.org/webdata/docs/Guideline_PMG_final.pdf. Accessed 23 August 2013.

21

Humalog Mix25 vs Basal-bolus Therapy (BBT)

PARADIGM Study Overview

Study objective:
Demonstrate noninferiority of Humalog Mix25 to BBT
Primary objective: change in HbA1c at endpoint

48-week, multicentre, randomised, open-label, active-controlled trial

426 patients with inadequate control (HbA 1c 7.0%-10.9%) on OADs
Randomized to Humalog Mix25 QD progressing to TID or insulin glargine
progressing to up to 3 additional Humalog (insulin lispro [rDNA origin]
injection) injections
Dose titrated and injections up to TID to reach a preprandial glucose
4.5-6.0 mmol/L
All additional injections of Humalog or Humalog Mix25 were added to regimen based
on investigators discretion when glycaemic targets were not achieved

Patients continued metformin plus pioglitazone and/or SU

(SU discontinued if taking Humalog)
Pioglitazone was discontinued 2 weeks before randomisation in countries where
concomitant use with insulin is contraindicated
QD = once daily; TID = three times daily.
Bowering K, et al. Diabet Med. 2012;29(9):e263-e272.

22

Humalog Mix25 vs BBT

HbA1c and Hypoglycaemia Results

n=177

LS Mean Change in HbA1c (%)

-1.79
-1.8

-1.8

-1.81
-1.82
-1.83
-1.84

-1.84

-1.85
Between-treatment
difference (95% CI):
-0.04% (-0.25, 0.17)
CI = confidence interval; LS = least squares.
Bowering K, et al. Diabetic Med. 2012;29(9):e263-e272.

BBT

2.5

-1.78
Rate of Hypoglycaemia
per 30 Days, Mean Change

n=184

2.0

Humalog Mix25

1.96
1.71

1.5
1.0

0.85
0.67

0.5
0.0
Overall
Hypoglycaemia

Nocturnal
Hypoglycaemia

Patients in both treatment groups

experience similar rates.
23

Insulin Dose and Number of Injections at Week 48

Treatment Groups
Humalog Mix25
n=177

BBT
n=184

Mean insulin dose, U/Kg (SD)

0.71 (0.45)

0.71 (0.47)

Mean number of daily injections (SD)

2.14 (0.75)

2.25 (1.20)

One

40 (22.6)

79 (42.9)

Two

74 (41.8)

20 (10.9)

Three

63 (35.6)

49 (26.6)

Injection regimen, patients, n (%)

Four

36 (19.6)

SD: standard deviation

Bowering et al. Diabet Med 2012;29(9):e263-72.

24

Humalog Mix25 vs Insulin Glargine

DURABLE 24-week Study Overview
Primary outcome assessed1: endpoint HbA1c
Secondary outcomes assesed1:

Change in HbA1c from baseline to endpoint

HbA1c at each visit
Percentage of patients with endpoint HbA1c <7% and 6.5%
7-point SMBG, body weight change from baseline, total daily insulin dose,
rate of hypoglycaemia

24-week initiation phase of DURABLE study1

Randomised, open-label, multicentre, multinational, parallel trial
Patients: 2091 insulin-nave patients with type 2 diabetes from 242 sites in
11 countries1
Post hoc analysis with 480 insulin-nave elderly patients 65 years
of age2
Treatment: Humalog Mix25 BID or insulin glargine QD with continued
OADs including a sulphonylurea in 92% of patients1
DURABLE = Assessing the DURAbility of Basal versus Lispro mix 25 insulin Efficacy; SMBG = self-monitored blood glucose.
1. Buse JB, et al. Diabetes Care. 2009;32(6):1007-1013. 2. Wolffenbuttel BHR, et al. Diabet Med. 2009;26(11):1147-1155.

25

Humalog Mix25 vs Insulin Glargine

Change in HbA1c at Endpoint (%)

DURABLE 24-week Results HbA1c

All patients1

Elderly subset2
Glargine QD + OAD

-0.4

Humalog Mix25 BID + OAD

-0.8
-1.2

-1.5
-1.7

-1.8
-1.6
-1.7
-2
*

Percent of
Patients with
HbA1c <7.0%

40.3

41.0

Glargine QD + OAD

47.5**

55.6*

Humalog Mix25 BID + OAD

*P=.005; **P <.001.

1. Buse JB, et al. Diabetes Care. 2009;32(6):1007-1013. 2. Wolffenbuttel BHR, et al. Diabet Med. 2009;26(11):1147-1155.

26

Humalog Mix25 vs Insulin Glargine

DURABLE 24-week Results Elderly Hypoglycaemia
Severe Hypoglycaemia Events*

Glargine QD+OAD

Humalog Mix25 BID+OAD

Weeks 1-12

Weeks 13-24

Consider lower starting dose (<10 U BID) in elderly or more

gradual titration of dose.

*Indicates the number of patients;By the 24-week endpoint incidence was not significant.
Wolffenbuttel BHR, et al. Diabet Med. 2009;26(11):1147-1155.

27

Humalog Mix25 vs Insulin Glargine

DURABLE 24-week Results Summary
Compared with insulin glargine QD, Humalog Mix25 BID in
combination with OADs demonstrated in all patients and the
elderly subset1,2:
Lower endpoint HbA1c

Greater percentage of patients with endpoint HbA1c <7.0%

Lower PPG after at least one meal
Higher FPG
Increased weight gain and insulin dose
Increased overall hypoglycaemia
In a large, ethnically diverse population with type 2 diabetes, noctural
hypoglycaemia rates were lower1
In the elderly population, nocturnal hypoglycaemia rates were similar2

1. Buse JB, et al. Diabetes Care. 2009;32(6):1007-1013. 2. Wolffenbuttel BHR, et al. Diabet Med. 2009;26(11):1147-1155.

28

Humalog Mix25 in Insulin-nave Patients with

Type 2 Diabetes
Summary of BID Dosing

In patients with type 2 diabetes not previously treated with insulin,

Humalog Mix25 BID resulted in the following:
Improved overall glycaemic control vs basal-only insulin regimens1-3
Improved mealtime glycaemic control vs basal insulin1-3

Recommended starting dose is 10 U BID in general3

Consider decreasing starting dose in elderly population3
Avoid continuing sulphonylurea with insulin mixtures or prandial
insulin to decrease risk of hypoglycaemia4

Humalog Mix25 provides an effective insulin regimen

for starting insulin in patients with type 2 diabetes.
1. Malone JK, et al. Clin Ther. 2004;26(12):2034-2044. 2. Buse JB, et al. Diabetes Care. 2009;32(6):1007-1013.
3. Wolffenbuttel BHR, et al. Diabet Med. 2009;26(11):1147-1155. 4. Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379.

29

Humalog Mix25 Twice Daily vs Basal

Insulin Glargine Once Daily and Humalog
Once Daily in Patients with Type 2
Diabetes Requiring Insulin Intensification:
A Randomised Phase IV Trial

@ 2015 Eli Lilly and Company

30

Humalog Mix25 BID vs Basal Insulin Glargine Once Daily + Humalog

Once Daily
Study Overview

Study objective: to compare the efficacy and safety of Humalog Mix25 BID
vs basal insulin glargine once-daily and Humalog once-daily (BBT) in patients
with inadequate glycaemic control on once-daily basal insulin glargine plus
metformin and/or pioglitazone
Primary objective: to assess noninferiority and then superiority of
Humalog Mix25 BID vs BBT according to change in HbA1c at 24 weeks
Noninferiority margin 0.4%, two-sided significance level 0.05

24-week, multicentre, randomised, open-label, parallel arm, non-inferiority,

phase IV trial in 476 adults with type 2 diabetes with inadequate glycaemic
control on once-daily basal insulin glargine plus metformin and/or pioglitazone

Tinahones et al. Diabetes Obes and Metab 2014;(Ahead of print).

31

Humalog Mix25 BID vs Basal Insulin Glargine Once Daily +

Humalog Once Daily
Primary Objective: Change in HbA1c

Significant reductions in HbA1c in both treatment arms

Noninferiority was shown between Humalog Mix25 BID and BBT:

treatment difference (95% CI): -0.21 (-0.38, -0.04)

Significantly greater reduction in HbA1c for Humalog Mix25 BID (based on
gated superiority assessment) as compared with BBT: (95% CI): -0.22
(-0.39, -0.05)
9

8.65

8.6

8.5
8
7.5

7.35

7
HbA1c

6.5

Tinahones et al. Diabetes Obes and Metab 2014;(Ahead of print).

7.52

HbA1c at baseline
HbA1c at end of study

32

Humalog Mix25 BID vs Basal Insulin Glargine Once Daily +

Humalog Once Daily
Safety and Tolerability
Adverse Events

TEAE
rate (%)
Serious TEAE
rate (%)

Humalog
Mix25
BID
(N =
236)

BBT
(N =
240)

Pvalue

48.3

39.2

.052

4.7

3.3

.492

AE
Discontinuati
on

LSM
[95% CI]
bodyweight
increase (kg)

1.13
[0.75,
1.52]

0.50
[0.11,
0.89]

Reported
Hypoglycaemia
Humalog
Mix25

LSM (95%) difference

BID
(N = 236)

0.018
*

Hypoglycaemi
a
Overall
hypoglycaemia
(3.9 mmol/L)
Documented
symptomatic
(3.9 mmol/L;
70 mg/dl)
Asymptomatic
(3.9 mmol/L;
70 mg/dl)

BBT
(N = 240)

No. of
No. of
Patients Episodes Patients Episodes
with
per
with
per
1
Patient1
PatientEpisode
year
Episode year Mean
n (%) Mean (SD) n (%)
(SD)
144

13.07

150

16.51

(61.0)

(22.03)

(62.5)

(26.44)

109
(46.2)

7.21
(14.55)

110
(45.8)a

7.72
(15.67)

97
(41.1)

5.18
(12.62)

109
(45.4)

8.34
(18.00)

50
1.54
52
(21.2)
(4.58)
(21.7)
a
One patient discontinued btreatment
0.04because of
Severe
2 (0.8)
0 (0.0)
hypoglycaemia
(0.45)
b
Neither of these 2 patients required treatment
discontinuation
Nocturnal

TEAE = treatment-emergent adverse event.

Tinahones et al. Diabetes Obes and Metab 2014;(Ahead of print).

1.82
(5.25)
0.00
(0.00)
33

Humalog Mix25 BID vs Basal Insulin Glargine Once Daily

+ Humalog Once Daily
Summary
Noninferiority (PP population), and then superiority (ITT population), of Humalog Mix25
BID vs. BBT was shown in terms of change in HbA 1c at 24 weeks

Mean blood glucose, glycaemic variability, overall tolerability, and hypoglycaemic

episodes per patient-year did not show significant differences between treatments
during the study

Total daily insulin doses for each regimen were not found to be significantly different
at end of study

No significant differences in the frequency of hypoglycaemic episodes and health

outcomes were observed between the two regimens

No statistically significant between-treatment differences were seen in

ITSQ domain and total scores at last visit
PAM-D21 questionnaire domain scores at last visit
Changes in these scores from baseline to last visit

ITSQ = Insulin Treatment Satisfaction Questionnaire; PAM-D21= Perceptions About Diabetes-Medications 21.
Tinahones et al. Diabetes Obes and Metab 2014;(Ahead of print).

34

Initiating Therapy with Humalog Mix25

Start with low dose and increase gradually 1
Insulin-nave patients

Start as 10 U subcutaneously (SC) before breakfast

and evening meals1

Patients already on once-daily insulin

Calculate total daily dose

Total daily dose 2
Give SC before breakfast and SC before evening meal

OAD recommendation:

Maintain at least metformin 1-1.5 g/day in divided doses

Stop sulphonylurea

BG measurements:

Monitor pre-breakfast (fasting) and pre-evening meal BG

every 3-4 days

*OADs to be used in accordance with the locally approved package insert. Some OADs may be contraindicated. Physicians and
patients should decide if additional BG measurements may be needed.
1. Hirsch IB, et al. Clin Diabetes 2005;23(2):78-86. 2. IDF task force for clinical guidelines. Available athttp://www.idf.org/sites/
default/files/IDF-Guideline-for-Type-2-Diabetes.pdf. Accessed 23 August 2013.

35

Patients with Type 2 Diabetes on Intensive Insulin

Therapy Achieve Glycaemic Control Using 50%
Basal and 50% Bolus (Preprandial) Insulin
diabetes, endogenous
basal insulin secretion
accounts for
approximately 50% of
total daily insulin1

Patients with type 2

diabetes on intensive
insulin therapy
regimens can achieve
glycaemic control using
50% basal and 50%
bolus insulin2

100
Mean Total Daily
Insulin Dose (units)

In individuals without

Insulin Dose at Endpoint2

P=.63

50

51

54

P=.83
57

55

0
Basal Dose

Bolus Dose

Continuous subcutaneous insulin infusion

(n=51)
Multiple daily injections (n=54)

*Doses adjusted to achieve target preprandial and bedtime BG levels.

1. Polonsky KS, et al. J Clin Invest. 1988;81(2):442-448. 2. Herman WH, et al. Diabetes Care. 2005;28(7):15681573.

36

Humalog Mix50 (50% insulin lispro [rDNA

origin] injection, 50% insulin lispro protamine
suspension)
Provides premixed basal and prandial insulin in every
injection
Targets both FPG and PPG concentrations to lowerHbA1c1
Restores a more physiologic profile of prandial plasma insulin
and suppresses endogenous glucagon production in patients
with type 2 diabetes2

The total number of injections can be minimised by using

premixedinsulin

Contains both rapid- and intermediate-acting insulins in a single

dose1
Manages both FPG and PPG levels without juggling multiple
devices orproducts

Allows for convenient dosing immediately (up to 15 minutes)

beforemeals3

1. Roach P, Woodworth JR. Clin Pharmacokinet. 2002;41(13):1043-1057. 2.Bruttomesso D, et al.

Diabetes.1999;48(1):99-105.
3. Humalog Mix50/50 [Prescribing Information]. Eli Lilly and Company; 2009.

37

Humalog Premixed Insulins

An Acceptable Alternative to Regular Human Insulin
Mixtures for Twice Daily Insulin Use
Compared with regular human insulin mixtures, Humalog
premixed insulins in twice-daily regimens:
Improved PPG control
Reduced the number of nocturnal hypoglycaemic episodes
(among all patients) while maintaining similar HbA 1c levels

Provided the convenience of injecting immediately before a

meal, compared to injecting 30-45 minutes preprandially for
regular human insulin mixtures

Roach P, et al. Clin Ther. 1999;21(3):523-534.

38

Clinical Challenge
Person on Oral Therapies but HbA1c Is 9.4%
Case Presentation:
Age: 52 years
Duration of type 2 diabetes: 7 years
Review of patient logbook shows FPG of 9.916.3 mmol/L (178.2-293.4 mg/dL) over the
past 2 months
Weight: 209 lbs (95 kg)
BMI: 31.8 kg/m2
Blood pressure: 135/85 mmHg
Current treatment: glipizide 10 mg QD,
metformin 1000 mg BID
FPG: 10.4 mmol/L (187.2 mg/dL)
2-hour PPG: 14.7 mmol/L (264.6 mg/dL)
HbA1c: 9.4%
Patient Perspective:
Wants to improve glycaemic control and is willing to add an injectable
therapy
but wants to minimise the number of injections
Has a fairly predictable daily routine, including meal composition
39

Conclusions
Putting it into Practice
Consider both the clinical factors and the needs , concerns
and abilities of the patient when deciding on the most
appropriate insulin regimen option to meet the target
glycaemic goals
Evaluate the typical meal composition of the patient and
regularity of schedule when deciding on the premixed insulin
options
Attempt to match therapy to physiologic insulin secretion
patterns to best address a patients glycaemic needs
The Humalog portfolio provides options for achieving an
insulin response that mimics physiology to meet the varying
clinical and personal needs of your patients.

41

Backup

@ 2015 Eli Lilly and Company

42

Clinical Evidence Supporting the

Use of Insulin Analogue Mixtures
(Additional Slides)

@ 2015 Eli Lilly and Company

Premixed Insulin Analogues vs

Basal Insulin Analogues
Change in HbA1c at Endpoint in 4 RCTs
Insulin
Glargine,
BIAsp1
Change in HbA1c (%)

0.0

Insulin
Detemir
,
BIAsp2

Insulin
Glargine,
Humalog
Mix253

Insulin
Glargine,
Humalog
Mix254

-0.5
-1.0

**
**

-1.5

*
Basal insulin

-2.0

Premixed insulin

-2.5
-3.0

Premixed Insulin: 25-30% rapid-acting analogue; Insulin-experienced patients. *P<.01; **P<.001.

BIAsp = biphasic insulin aspart 70/30; RCT = randomised controlled trial.
Derived from 1. Raskin P, et al. Diabetes Care. 2005;28(2):260-265. 2. Holman RR, et al. N Engl J Med. 2007;357(17):1716-1730.
3. Malone JK, et al. Clin Ther. 2004;26(12):2034-2044. 4. Malone JK, et al. Diabet Med. 2005;22(4):374-381.

44

Premixed Insulin Analogues vs

Basal Insulin Analogues
Percent Reaching HbA1c 7% in 4 RCTs
Insulin
Glargine,
BIAsp1

Subjects Reaching
HbA1C 7% (%)

70

Insulin
Insulin
Insulin
Glargine,
Glargine,
Detemir,
3
2
Humalog Mix25Humalog Mix254
BIAsp

**
Basal insulin
Premixed insulin

60
50
40
30

**

**
*

20
10
0

Premixed Insulin: 25-30% rapid-acting analogue; Insulin-experienced patients. *P=.002; **P<.001; Target HbA1c <7% rather
than 7%.
Derived from 1. Raskin P, et al. Diabetes Care. 2005;28(2):260-265. 2. Holman RR, et al. N Engl J Med. 2007;357(17):1716-1730.

45

Effect of Premixed Insulin Analogues vs Basal Insulin

Analogues in Controlling PPG and HbA1c Levels
Postprandial control

Mean Difference of
Change in PPG Level
(95% CI), mmol/L

Long-acting insulin analogue

vs:
All premixed insulin analogues
Insulin aspart 30/70
Humalog Mix25
Humalog Mix50

-1.6
-1.3
-1.3
-1.8

-70 -60

HbA1c control

-50 -40 -30 -20 -10

Favors Premixed
Analogue

(-1.9
(-1.8
(-1.7
(-2.7

to
to
to
to

-1.2)
-0.7)
-0.9)
-1.0)

-0.39
-0.48
-0.33
-0.40

Error bars represent 95% CI.

CI = confidence interval; ILPS = insulin lispro protamine suspension.
Qayyum R, et al. Ann Intern Med. 2008;149(8):549-559.

(1957)
(936)
(609)
(530)

10

Mean Difference of
Change in HbA1c Level
(95% CI), %

Favors Premixed
Analogue

9
3
5
3

Favors
Comparator

Long-acting insulin analogue

vs:
All premixed insulin analogues
Insulin aspart 30/70
Humalog Mix25
Humalog Mix50
-1.2 -1.1 -0.8 -0.6 -0.4 -0.2

Studies
(Participants), n

0.2

(-0.50
(-0.61
(-0.48
(-0.65

to
to
to
to

Studies
(Participants), n

-0.28)
-0.34)
-0.17)
-0.15)

11 (3108)
4 (976)
5 (1720)
3 (530)

0.4

Favors
Comparator

46