Ueda2015 lilly.the art of insulin dr.mesbah sayed

The Art and Science of Insulin

Role of Modern Basal/Prandial Insulins

inType 2DM

Mesbah Sayed KamelMD

Disclosures

• I have provided services ( speaker, advisor, consultant

and investigator in clinical trials ) for the following

companies:

Novo Nordisk, MSD,Sanofi Aventis, Novartis

,Lilly,Astra Zenica&Merck Sorono.

• For these activities I received appropriate honoraria

and/or grant support.

2

Clinical ChallengePerson 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

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.

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

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

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

c) Add a basal insulin at bedtime

d) Stop glipizide, begin a premixed insulin analogue therapy

e) Stop orals and start basal/bolus insulin therapy

f) Add a GLP-1 receptor agonist

UKPDS A 1% Decrease in HbA1c Is Associated with a Large

Reduction in Complications

Stratton IM, et al. BMJ. 2000;321(7258):405-412.

12% Stroke

Microvascular

complications (eg, kidney

disease and blindness) 37%

Amputation or fatal

peripheral blood vessel

disease43%

Deaths related to diabetes21%

Heart attack14%

HbA1c

1%

Recommended Glycaemic Treatment Targets* A Global Standard?

American Diabetes

Association1 IDF2 AACE3

HbA1c (%) <7.0 <7.0 ≤6.5

FPG mmol/L

(mg/dL)

<3.9-7.2

(70-130)

<6.5

(<115)

<6.1

(<110)

PPG mmol/L

(mg/dL)

<10

(<180)†

<9.0

(<160)†

7.8

(<140)‡

*Treatment targets for non-pregnant adults; †Measured at 1-2 hours following a meal; ‡Measured at 2 hours following a meal.

AACE = American Association of Clinical Endocrinologists; IDF = International Diabetes Federation.

1. American Diabetes Association. Diabetes Care. 2013;36(Suppl 1):S11-S66. 2.IDF. Available at:

http://www.idf.org/sites/default/files/IDF%20T2DM%20Guideline.pdf. Accessed 29 August 2013. 3. Handelsman Y, et al. EndocrPract. 2011;17(Suppl 2):1-53.

A Combination of FBG and PPG contribute

to HbA1c

• The relative contribution of PPG and FBG varies with HbA1c

Monnier L, et al. Diabetes Care. 2003;26(3):881-885.

HbA1c Range (%)

Co

ntr

ibu

tio

n (

%)

PPG

FBG

<7.3 7.3-8.4 8.5-9.2 9.3-10.2 >10.20

20

40

60

80

100

Postprandial, Not Fasting, Glucose Is

Associated with MI and Mortality Risk

Blood Glucose (mmol/L)

300

200

100

0

Incid

en

ce R

ate

per

10

00

Pati

en

ts

n=994

FPG PPG

4.4-6.1 ≤7.8 >7.8 4.4-8.0 ≤10.0 >10.0

MI = myocardial infarction.

Hanefeld M, et al. Diabetologia. 1996;39(12):1577-1583.

Diabetes Intervention Study: 11-year Follow-upMI

Mortality

300

200

100

0

P<.05

P<.05

• What are the treatment options from guideline to practice ?

9

IDF Treatment Algorithm for People

with Type 2 Diabetes

DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; TZD = thiazolidinedione.

DF. Available at: http://www.idf.org/sites/default/files/IDF%20T2DM%20Guideline.pdf. Accessed 29 August 2013

Then, at each step, if not to target (generally HbA1c <7.0%)

Consider first line

Basal +mealtime

insulin

Consider second line

Consider third line

Consider fourth line

Basal insulin, or

premixed insulin

(later basal + mealtime)

or

Basal insulinor

Premixed insulinor

AGI or DPP-4 inhibitor or

TZD

GLP-1 receptor

agonist

orMetformin

(if not first time)AGI or DPP-4 inhibitor or

TZDSulfonylurea

MetforminSulfonylurea

or

AGI

Usual approach

Alternative approach

Lifestyles measures

American Diabetes Association/EASD Joint Position Statement

General Therapy Recommendations in Type 2 Diabetes

DPP-4i = DPP-4 inhibitor; GI = gastrointestinal; RA = receptor agonist; HF = heart failure; SU = sulphonylurea.

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


American Diabetes Association/EASD Joint Position Statement

Key Points1

Glycaemic targets and blood-glucose-lowering therapies must be

individualised

Diet, exercise, and education: foundation of any type 2 diabetes therapy

program

Unless contraindicated, metformin is the optimal 1st-line drug

After metformin, data are limited. Combination therapy with an additional 1

to 2 oral or injectable agents is reasonable, but aim to minimise side effects

Insulin therapy alone or in combination with other agents may be necessary

for many patients

Treatment decisions should be made from a patient-centred approach

Cardiovascular risk reduction must be an important focus of therapy

Mean reduction in A1c

mod. from Nathan D et al. Diabetologia 2008; 51:8-11

drug Route of

administration

Introduction/

FDA-approval

Mean reduction in A1c

(monotherapy)

Insulin sc 1921 ≥ 2,5

Sulfonylureas oral 1946 1,5

Metformin oral 1995 1,5

Alpha-Glucosidase

inhibitors

oral 1995 0,5 – 0,8

Glitazones oral 1997- 1999 0,8 – 1,0

GLP-1-agonist sc 2005 0,6

DPP-IV Inhibitors oral 2006 0,5 – 0,9

However over time,

most type 2 diabetics will also need

both basal and mealtime insulin

to control glucose

6-

19

When Oral Medications Are Not Enough

• Watch for the following signs

– Increasing BG levels

– Elevated A1C

– Unexplained weight loss

– Traces of ketonuria

– Poor energy level

– Sleep disturbances

– Polydipsia

• Next steps

– Make a decision to start insulin

– Offer patient encouragement, not blame

Remind the patient of disease progression…

Typical Diagnosis of Diabetes

Severity of Glucose Intolerance

Years

to

Decade

s

Normal Blood

Glucose

NATURAL HISTORY OF TYPE 2 DIABETES

Risk of Macrovascular Complications

Insulin Resistance

IGT

Insulin Secretion

Postprandial Glucose

Risk of Microvascular Complications

Frank

Diabetes

NGT

Worsens with Time

• The risk for hypoglycemia in type 2 diabetes

is low, and newer insulin analogs have

demonstrated even lower rates of

hypoglycemia than older insulin products.

• Although weight gain can be expected with

insulin (similar to that seen with

secretagogues), the benefits of glycemic

control clearly exceed the small increases in

body weight.17

• Of note, insulin has been shown to reduce

mortality postmyocardial infarction,and more

than 10 years of follow-up in the United Kingdom

Prospective Diabetes Study (UKPDS) have

clearly shown no increase in cardiovascular risk.

• Finally, although multiple daily injections may be

required for patients with advanced, uncontrolled

diabetes, simpler insulin regimens are often

highly effective if initiated earlier in the course of

diabetes18

Premix vs. Basal-Bolus: It’s all about life styleFactor Premix Regimen Basal Bolus Regimen

Injection frequency Prefers fewer injections No problem with more injections

SMBG Unwilling to self monitor Willing to self monitor

Daily routine Fixed Variable

Ability to follow regimen Limited cognitive functionMotivated with good cognitive

function

Support-education and

emotionalEssential Extremely essential

Adapted from: Liebl, et al. Int J Clin Pract, 2009;63(Suppl 164):1-5.

Patient centered approach

The INSTIGATE study reported on treatment patterns for insulin initiation in major European countries.

• The most common first insulin in Germany was rapid acting insulin only (34%)

• UK and Greece mixtures were the most common first insulin (48%).

• In France and Spain, basal insulin was the most common initial insulin.

In the recently published CREED Study involving countries from Middle East, North Africa and Western Pacific,

• 50% of patients were treated with twice daily insulin regimens

20Leibl A et al. - Current Medical Research & Opinion Vol. 27, No. 5, 2011, 887–895

• Premixed Vs basal insulin in type 2 DM :

21

22

Study Design

• Primary objective: HbA1c

• Secondary objectives: 2-hr postprandial blood glucose (BG), other BG values,

insulin dose, and hypoglycemia rate

• 32 week, multicenter, randomized, open-label crossover study

• Patients: 105 insulin-naïve adults with type 2 diabetes

• Treatments: Humalog Mix25 BID plus Met (1500-2550 mg/d) or Lantus at

bedtime plus Met (1500-2550 mg/d) for 16 weeks

Humalog® Mix25™ (BID) Plus Metformin (Met) vs Lantus® Once Daily Plus Met in Pts New to Insulin

Malone JK et al. Clin Ther 2004;26:2034-2044.

Lantus + Met

0 16

Weeks

32-6 to -10

Lead-in

Humalog Mix25

(BID) + Met

Humalog Mix25

(BID) + Met

Lantus + Met

NPH + Met


Humalog® Mix25™ (BID) Plus Metformin (Met) vs Lantus® Once Daily Plus Met in Pts New to Insulin

-2

0

2

4

6

8

10

Lantus +

Met

Mix25 + Met

8.7 7.8

-

0.93

8.

77.4

-

1.32

p<0.001 p<0.001

*

†

Baseline (N=71 type

2 DM pts)

Endpoint (N=71)

Change from baseline

(N=67)

Mean

Hb

A1c

(%)

Daily insulin dose

(Mean ±SD)(U/kg) 0.57 ±0.37

**

0.62 ±0.37 **

p<0.001Data derived from Malone JK et al. Clin Ther 2004;26:2034-2044.

Mix25 + Met associated with lower mean HbA1c

and greater change in mean HbA1c compared with Lantus + Met

Higher percentage of patients treated with

Mix25 + Met attain treatment targets except

fasting blood glucose

Lantus + Met

0

10

20

30

40

50

60

70

80

90

HbA1c values

≤ 7.0%

FBG

≤ 7 mmol/L

AM pp BG*

≤ 10mmol/L

PM pp BG*

≤ 10mmol/L

Perc

en

tag

e o

f p

ati

en

ts

Mix25 + Met

p<0.001p=0.036

p=0.019

p<0.001

* postprandial blood glucose

Data derived from Malone JK et al. Clin Ther 2004;26:2034-2044.

Humalog® Mix25™ (BID) Plus Metformin (Met) vs Lantus® Once Daily Plus Met in Pts New to Insulin:

Overall and Nocturnal Hypoglycemia

Ep

iso

de

s/p

ati

en

t/3

0 d

ays

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

Lantus +

Met

Lantus +

Met

Mix25 +

Met

Mix25 +

Met

0

0.05

0.10

0.15

0.20

0.25p=0.041

p=NS

Overall hypoglycemia Nocturnal hypoglycemia

N=101 N=100 N=101 N=100

Data derived from Malone JK et al. Clin Ther 2004;26:2034-2044.

Humalog® Mix25™ (BID) Plus Metformin (Met) vs Lantus® Once Daily Plus Met in Pts New to Insulin: Summary

Mix25 BID + Met compared with Lantus + Met (patient

population with oral antidiabetic agent failure):

Associated with significantly greater HbA1c reduction at 32

weeks

Enabled a larger proportion of the treatment population to

attain HbA1c ≤7.0%, despite significantly higher fasting blood

glucose levels

Improved glycemic control after breakfast and dinner

Resulted in higher overall hypoglycemia rate but similar rate

of nocturnal hypoglycemia


A Study Comparing Insulin Lispro Mix 25 With

Glargine Plus Lispro Therapy in Patients With Type 2

Diabetes Who Have Inadequate Glycaemic Control

on Oral Antihyperglycaemic Medication:

Results of the PARADIGM Study

K. Bowering1, V. A. Reed2, J. Felicio3,

J. Landry4, L. Ji5 and J. Oliveira6

1University of Alberta, Division of Endocrinology and Metabolism in the Department of Medicine,

Edmonton, AB, Canada; 2Eli Lilly and Company, Asia-Pacific Medical Communications, Sydney,

NSW, Australia; 3Universidade Federal do Pará, Endocrinology Division, Belém, Brazil; 4Eli Lilly

Canada Inc., Toronto, ON, Canada; 5Peking University People’s Hospital, Department of

Endocrinology and Metabolism, Beijing, China; 6Eli Lilly and Company, Indianapolis, IN, USA

Primary Objective

A 48-week, randomized, open-label, active-controlled

study conducted to

Assess initiation and intensification with LM25 therapy

Determine if initiation and intensification with glargine plus insulin

lispro, in terms of glycaemic control are comparable (non-inferior),

as measured by change in HbA1c from baseline

In patients with T2D inadequately controlled with oral antihyperglycaemic

medications

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

Study Design

Randomization


• LM25: 25% insulin lispro, 75% insulin lispro protamine suspension once daily, progressing up to thrice

daily, G + L: insulin glargine once daily alone, progressing up to 3 additional insulin lispro injections

• QD: once daily, TID: thrice daily, G: insulin glargine, L: insulin lispro injection

Measures

Primary

Change in HbA1c from baseline to endpoint

Secondary

Percentage of patients achieving HbA1c targets of ≤48 mmol/mol (≤6.5%) and <53 mmol/mol (<7.0%) at endpoint

Postprandial blood glucose

Daily total insulin dose

7-point self-monitored blood glucose profiles

Lipid and cholesterol profiles

Exploratory

Patient evaluation of Qol (EQ-5D)

Patient evaluation of disease-specific Qol (DHP-18)

Safety

Events related to hypoglycaemia were assessed as to incidence, rate, and severity


LS Mean Change in HbA1C From Baseline to

Endpoint


• HbA1c: hemoglobin A1c, G: insulin glargine, L: insulin lispro injection

8.98

7.1

9.03

7.3

0

1

2

3

4

5

6

7

8

9

10

Baseline A1c Endpoint A1c

LS

Me

an

Ch

an

ge

in

Hb

Aic

(%

)

LM25

G + L

Insulin Dose and Number of Injections at

Week 48

Treatment Groups

LM25

n=177

G + L

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)

Injection regimen, patients, n (%)

One 40 (22.6) 79 (42.9)

Two 74 (41.8) 20 (10.9)

Three 63 (35.6) 49 (26.6)

Four 36 (19.6)


• LM25: insulin lispro mix 25, 25% lispro, 75% insulin lispro protamine suspension, G: insulin glargine,

L: insulin lispro injection, SD: standard deviation

Humalog Mix 25 flexible dosing regimen

35

(% of patients)


Similar hypoglycemia rates were observed

between treatment groups.

86.7

75.4

2.8

84.8

71.6

3.4

0

20

40

60

80

100

OverallHypoglycaemia

NocturnalHypoglycaemia

SevereHypoglycaemia

Inci

de

nce

of

Hyp

ogl

yca

em

ia (

%)

G + L, n=184

LM25, n=177

Oliveira et al. Diabetes. 2010;59(Suppl 1):A171-2 [628-P].

• LM25: insulin lispro mix 25, 25% lispro, 75% insulin lispro protamine suspension, G: insulin

glargine, L: insulin lispro injection

Key Findings

This is the first randomised controlled study to investigate treatment with LM25 initiated as a once-daily therapy and with the option to be intensified up to three times a day, in insulin-naїve patients with Type 2 diabetes

The results show that initiating and intensifying insulin therapy with LM25 was non-inferior to initiating and intensifying insulin treatment with glargine + insulin lispro, as measured by change in HbA1c from baseline to study end

Hypoglycaemia incidence was also not statistically different between the two groups


Case

• 65 year old male lawyer has had DM for 14 year, and hisrecent PPG after lunch is 354 mg/dl despite increasing thedose of basal insulin

• Patient is usually taking heavy carbohydrate meals

• Previous heart attack and is taking several cardiovascularand hypertensive medications

• BMI of 32

• Admits to feeling a little tired recently

• ↑ frequency of micturition for 2-3 times/week

Clinical Profile

Age: 65

BMI: 32

Blood Glucose

Last A1C: 10.2%

PPG after lunch: 354

mg/dL

Lipid Profile

Total: 153 mg/dL

LDL: 70 mg/dL

HDL: 41 mg/dL

Triglycerides: 225 mg/dL

Kidney Profile

Creatinine: 0.8 mg/dL

Microalbuminuria:

Negative

Liver Function

ALT: normal

AST: normal

Blood Pressure

Normal: 130/90 mmHg

Cardiovascular

condition Previous

myocardial infarction

Eye Exam

Normal

Foot Exam

Normal pulses and

sensation

Two questions that may be relevant

1. Add one injection of rapid acting insulin to

basal insulin or switch to premix?

2. How should I think about increasing dose

frequency?

• Does insulin Initiation Guarantee Good Glycaemic Control ?

Insulin initiation does not necessarily result in HbA1c reduction.

UK: 73% of patients maintained an HbA1c ≥7.5%, 6-months post insulin

initiation1

Insulin treatment does not necessarily result in achieving goal HbA1c.

The INITIATE study, a 28-week parallel designed, randomized study,

showed that 40% of patients on basal therapy and 66% of patients on

premix achieved the target HbA1c of <7%2

The Treat to Target trial (4T) reported that 42% of patients adding basal

insulin to oral therapy did not reach an HbA1c ≤7%3

The International Diabetes Management Practice Study (IDMPS), listed

attainment of HbA1c goal (<7%) in patients with type 2 diabetes to be

37% (Asia), 36% (Eastern Europe), and 36% (Latin America) among

patients treated with insulin4

Insulin Initiation Does Not Guarantee Good GlycaemicControl

INITIATE = Initiate Insulin by Aggressive Titration and Education.

1. Calvert MJ, et al. Br J Gen Pract. 2007;57(539):455-460. 2. Raskin P, et al. Diabetes Care. 2005;28(2):260-265. 3. Riddle MC,

et al. Diabetes Care. 2003;26(11):3080-3086. 4. Chan JC, et al. Diabetes Care. 2009;32(2):227-233.

Basal insulin only(usually with oral agents)

Non-insulin regimens

Basal insulin + 1

(mealtime) rapid-

acting insulin

injection

Premixed insulin

twice daily

Basal insulin + ≥2

(mealtime) rapid-

acting insulin

injections

low

mod.

high

1

2

3+

Number of

injections

Regimen

complexity

More flexible Less flexible Flexibility

Therapy following Basal Only Insulin


If Basal insulin

fails, what is the

next best

approach?

IDF Treatment Algorithm for People

with Type 2 Diabetes

DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; TZD = thiazolidinedione.

DF. Available at: http://www.idf.org/sites/default/files/IDF%20T2DM%20Guideline.pdf. Accessed 29 August 2013

Then, at each step, if not to target (generally HbA1c <7.0%)

Consider first line

Basal +mealtime

insulin

Consider second line

Consider third line

Consider fourth line

Basal insulin, or

premixed insulin

(later basal + mealtime)

or

Basal insulinor

Premixed insulinor

AGI or DPP-4 inhibitor or

TZD

GLP-1 receptor

agonist

orMetformin

(if not first time)AGI or DPP-4 inhibitor or

TZDSulfonylurea

MetforminSulfonylurea

or

AGI

Usual approach

Alternative approach

Lifestyles measures

If Basal insulin

fails, what is the

next best

approach?

Second-line insulin choices in type 2

diabetes: patient factors

Basal-bolus Premix Basal plus

Patient preference for fewest injections + +

Variable meal pattern + +

Variable daily routine +Limited capability (eg, cognitive

function, dexterity) +

Better postprandial control required + +Unwilling to self-monitor several times

daily +Limited support (family, general

practitioner) + +

Reference:

Modified from Barnett A et al. Int J Clin Pract. 2008; 62:1647-1653

• Humalog Mix50 – mimics physiological insulin secretion to provide tighter

PPG control

In Non-diabetic Individuals, Basal Secretion Represents Approximately 50% Total Daily Insulin

Data from Polonsky KS et al. J Clin Invest 1988; 81:442-48

Normal

Obese

Extrapolated Basal Secretion

50.1±3.1% Normal subjects

45.2±2.2% Obese subjects

0

100

200

300

400

500

600

Perc

ent

Basal In

sulin

Secre

tion

0600 1000 1400 1800 2200 0200 0600

Clock Hours

* After a test meal.Data derived from: Schwartz S, et al. Clin Ther. 2006;28:1649-1657. Schwartz S, et al. Diabetologia 2003;46(suppl 2):A267.

Humalog® Mix50™ Tight Mealtime Control

Increasing the proportion of rapid-acting insulin improves PPG*

• PPG decreased as proportion of rapid-acting insulin increased

• Basal-only insulin was associated with highest PPG of the 4 regimens

2-h

r P

PG

(m

mo

l/L

)

Each regimen resulted in

PPG significantly different from all other

regimens (pairwise comparison). P<0.05.

Glargine Human Insulin

30/70

Humalog®

Mix25™

Humalog®

Mix50™

Patients

without diabetes

Humalog Mix50 injected three times daily comparison with human insulin 30/70

Metabolic control in patients with type 2 diabetes using Humalog Mix50

injected three times daily: crossover comparison with human insulin

30/70

• Objectives

– This study was designed to compare metabolic control with three

daily injections of Humalog Mix50 or premixed human insulin 30/70

(30% regular/70% NPH) twice daily in accordance with normal

prescription practice

• Patients and methods

– The study cohort of 40 patients with type 2 diabetes used a two-

way, crossover design. Patients were randomized to either Mix50 at

each main meal or human insulin 30/70 at breakfast and dinner for

3 months, followed by the alternate treatment for 3 months

– Blood glucose was measured by the patients at baseline and at the

end of each treatment sequence

– No significant carryover effects were observed, so treatment

sequences were combined and data analyzed by unpaired t-tests

Schernthaner G et al. Horm Metab Res. 2004; 36: 188-193.

LM50 TID vs. Humulin 30/70 BID:

endpoint A1C

LM50=50% insulin lispro/50% insulin lispro protamine suspension; Humulin 30/70=30% regular human insulin/70% human insulin isophane suspension.

Mean A

1C

(%

)

6.0

7.0

8.0

9.0

LM50 TIDHumulin 30/70Baseline

p<0.001

8.4%

8.1%

7.6%

p=0.021p=0.034

6.5

7.5

8.5


2-hour postprandial reductions in postprandial glucose were significantly greater

with LM50 TID than those observed in Humulin 30/70 treatment (p0.001)

*p<0.001 compared to baseline and Humulin 30/70. N=35 patients with type 2 diabetes mellitus. 24-week crossover. LM50=50% insulin lispro/50% insulin lispro protamine suspension; Humulin 30/70=30% regular human insulin/70% human insulin isophane suspension.

Postp

randia

l blo

od

glu

cose (

mm

ol/L)

6

8

10

12

After dinnerAfter lunchAfter breakfast

LM50 TID

Humulin 30/70

Baseline

**


Metabolic control in patients with type 2 diabetes using

Humalog Mix50 injected three times daily: crossover

comparison with human insulin 30/70

Study summary and conclusions

– The decrease from baseline in A1C was significantly greater with

Mix50 than with 30/70 insulin

– There were no significant differences between treatments

regarding incidence of hypoglycemia or adverse events

– In patients with type 2 diabetes, a regimen of Humalog Mix50

administered three times daily before meals maintains glucose

control more effectively than premixed human insulin 30/70

administered before breakfast and dinner


Two questions that may be relevant

1. Add one injection of rapid acting insulin to basal

insulin or switch to premix?

2. How should I think about increasing

dose frequency?

Basal insulin only(usually with oral agents)

Non-insulin regimens

Basal insulin + 1

(mealtime) rapid-

acting insulin

injection

Premixed insulin

twice daily

Basal insulin + ≥2

(mealtime) rapid-

acting insulin

injections

low

mod.

high

1

2

3+

Number of

injections

Regimen

complexity

More flexible Less flexible Flexibility

Therapy following Basal Only Insulin


How can you

add prandial

insulin?

AUTONOMY: The First Randomized Trial Comparing

Two Patient-driven Approaches to Initiate and Titrate

Prandial Insulin Lispro in

Type 2 Diabetes

Steve V. Edelman,1 Rong Liu,2 Jennal Johnson,2 Leonard C. Glass2

1University of California, San Diego Department of Medicine; 2Eli Lilly and Company, Indianapolis, IN, USA

Edelman et al. Diabetes Care 2014;(Ahead of print).

AUTONOMY: Study Objective

• To compare efficacy and safety of 2 patient-based

self-titration algorithms for initiation and titration of prandial insulin

lispro in patients with type 2 diabetes inadequately controlled on

basal insulin plus OADs in endocrine and generalist settings

• Monitoring was done every day or every 3 days

– Approximately 44% of trial sites were in primary care settings

• 1st comparison of 2 self-titration insulin algorithms for escalation of

prandial insulin lispro therapy in a large, multicountry, randomized,

controlled trial


AUTONOMY: Study Design

Discontinue

HbA1c ≤7.0%

(≤53.0 mmol/mol)

Randomize

Enrollment

Add insulin lispro 1-2-3

with adjustments

(Q1D)

Add insulin lispro 1-2-3

with adjustments

(Q3D)

NO

6 Weeks 24 Weeks

Visit: 1 (screening) 2a 3a 4a,b 5a,b 6a 7a 8b 9b 10 11b 12 13b 14b 15 16b 17 18b 19

Week: -1 0 1 2 4 6 7 8 9 10 12 14 16 18 19 23 27 29 31

a6-week GLA optimization lead-in only required for subjects who had to be converted to GLA from insulin NPH, ILPS, or detemir; required conversion from GLA twice daily to once daily; or those on once-daily GLA at study entry with HbA1c >7.0% (>53.0 mmol/mol) and fasting blood glucose >120 mg/dL (>6.7 mmol/L). Subjects who did not require GLA optimization were randomized at Visit 2, forewent Visits 3 to 7 and instead proceeded to the randomized treatment period beginning with Visit 8 activities, 1 week after Visit 2; bTelephone visits

Optional: Insulin

Glargine (GLA)

Optimization

Lead-ina

YES


AUTONOMY: Primary and Secondary Outcome Measures

• Primary efficacy outcome:

– Compare change in HbA1c from baseline to endpoint (Week 24 after randomization) for Q1D and Q3D algorithms

• Secondary outcomes:

– Incidence and annualized rate of self-reported total, severe, and nocturnal hypoglycemia

– Proportion of subjects achieving target values HbA1c ≤7.0%

– Change in FBG, 7-point SMBG profile, and weight from baseline

– Change in dose of basal (GLA) and prandial (lispro) insulin at end of study

– Change in 1,5-anhydroglucitol (a marker of hyperglycemia)

• Assessments in subjects ≥65 years of age:

– Change in HbA1c, hypoglycemia (incidence and rate), FBG, and proportion of subjects achieving target

• Safety was monitored throughout the study (hypoglycemia was considered an AE with severe hypoglycemia recorded as an SAE)


AUTONOMY: Proportion Achieving HbA1c

≤7.0%

*p<0.05 for Q3D vs. Q1D; p-values were computed based upon a logistic regression model with effects for treatment

algorithms and strata

Study A (N=528) Study B (N=578)

p=0.015p=0.162p=0.701p=0.128

*

Edelman SV. Diabetes Care 37:2132-40, 2014

AUTONOMY: Change From Baseline

Weight

*p<0.05 for Q3D vs. Q1D; data were reported as LSM ± SE of the mean based upon from a MMRM that included baseline

weight, strata, treatment algorithm, visit, and treatment algorithm by visit

We

igh

t (k

g)

Ch

an

ge

fro

m B

ase

line

(LS

M ±

SE

)

p=0.014 p=0.108

*

Edelman SV. Diabetes Care 37:2132-40, 2014

AUTONOMY: Discussion (Slide 1 of 2)

• Both algorithms (Q1D, Q3D) demonstrated statistically significant

and clinically equivalent reductions in HbA1c, significant increases

in 1,5-AG, and improved 7-point SMBG profiles in Studies A and B

• ~50% of subjects who had previously failed to reach goal HbA1c of

≤7.0% (53.0 mmol/mol) with basal insulin optimization plus OADs

achieved the ADA goals for glycemic control with less glucose

variability

• Sequential addition of prandial insulin lispro injections resulted

in ~61% of subjects only requiring ≤2 doses rather than a full

basal-bolus regimen (ie, simplifies treatment, could enhance

therapy compliance)

• Subjects gained 2-3 kg of weight, regardless of treatment algorithm,

with the initiation of prandial insulin


• Results show basal-bolus therapy can be initiated in the elderly

without increased risk of hypoglycemia

• Regardless of titration algorithm, improved metabolic control was

accomplished with low incidences and rates of nocturnal and severe

hypoglycemia in both the overall study population and the elderly

subgroup (≥65 years of age) with initiation and escalation of lispro

AUTONOMY: Discussion (Slide 2 of 2)


Conclusions

Putting it into Practice

• Recognise that the challenges of diabetes management for

patients require a patient-centred approach

• Patient education in order to optimise the types of behavioural

modifications that support effective self-care habits

• Thank you

Date post:	17-Aug-2015
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