ideal basal insulin: degludeg

Addressing Barriers in Achieving Optimal Glycemic Target with Ideal Basal Insulin,

Degludeg & its Clinical Experience in Glycemic Control

1

Dr Shahjada SelimAssistant Professor

Department of EndocrinologyBSMMU

Objectives

• To obtain insights on the existing insulin therapy barriers and to understand the need for a better insulin

• To learn about the new ultra-long-acting basal insulin - the molecule of Insulin Degludec

• Pharmacokinetics/Pharmacodynamics• Clinical efficacy and safety• Flexibility in dosing• Clinical use, dosing and titration

What are problems encountered…

3

Canada7.36–8.7%11

Latin America 7.6%1 US 7.2%7

China 9.5%11

India 8.7–9.6%9,11

Japan 7.05–9.6%11

Korea 7.9–8.7%4

Russia 9.6%11

Spain 9.2%8

Sweden 8.7%3

Turkey 10.6%3

UK 8.510–9.8%2

Germany 8.42–9.2%8

Greece 8.911–9.7%3,8

Italy 8.4%11

Poland 9.0%11

Portugal 9.7%3

Romania 9.9%3

1. Lopez Stewart et al. Rev Panam Salud Publica 2007;22:12–20; 2. Kostev & Rathmann Primary Care Diabetes 2013;7:229–33; 3. Oguz et al. Curr Med Res Opin 2013;29:911–20; 4. Ko et al. Diabet Med 2007;24:55–62; 5. Arai et al. Diabetes Res Clin Prac 2009;83:397–401; 6. Harris et al. Diabetes Res Clin Pract 2005;70:90–7; 7. Hoerger et.al. Diabetes Care 2008;31:81–6; 8. Liebl et al. Diabetes Ther 2012;3:e1–10; 9. Shah et al. Adv Ther 2009;26:325–35; 10. Blak et al. Diabet Med 2012;29:e13–20; 11. Valensi et al. Int J Clin Pract 2008;62:1809–19

Poor glycemic control: A worldwide problemReported mean HbA1c in T2D patients exceeds local targets in nearly all countries

But why are we not getting to goal?

5

The glucose targets are known…

Patients have poor blood glucose control

Patients struggle to remain fully compliant with their insulin regimens

Patients and physicians are concerned about hypoglycemia

User friendly insulin regimens would help empower patients and physicians

Insulin doses are being missed or not taken as prescribed

Treatments are needed that respond to the functional and emotional needs of people with diabetes. The need for treatment options that could help improve compliance and ultimately long term health outcomes.

Key global findings from the Survey

Barriers to achieving optimal glycemic control

• Risk of Hypoglycemia • Suboptimal dosing &

titration• Glucose Variability

Hypoglycemia

• Fear of Hypoglycemia• Complexity of Regimen• Lack of Flexibility

Adherence to Treatment

Limitations with current basal insulin therapy

• Basal insulins must be administered at the same time every day1

• Variability of glucose lowering effect of current insulins (inter-patient and intra-patient)2

• Currently available long-acting insulin analogues do not always last 24 hours2

• Reducing variability and extending duration of action could simplify titration and reduce the incidence of hypoglycemia2

1. Joshi et al. SA Fam Pract 2009;51:97–102; 2. Evans et al. Diab Obesity Metab 2011;13:677–684

9

Longer duration of action

Controls fasting blood

glucose with 1

injection per day in

all individuals

Flat time-action profile

Lower risk of hypoglycemi

a

Less day-to-day

variability

Lower hypo- and

hyperglycemia

Ideal Basal

Insulin

Clinical Benefit

Development of an ideal basal insulin to meet these challenges

Novel agent to address insulin barriers

10

Optimal Glycemic Control

Optimal dosing & titration

Greater flexibility for better adherence

Lower hypoglycemi

a risk

Hypoglycaemia Risk and Glucose Variability

BARRIER

11

Hypoglycemia continues to be a problem with current basal insulin analogues

12

1 of 4 patients on basal-only therapy had a self-treated hypoglycemic event in the past 30 days

Brod M, Rana A, Barnett AH. Impact of self-treated hypoglycemia in type 2 diabetes: a multinational survey in patients and physicians. Current Medical Research and Opinion. 2012;28(12):1947-1958.

Percentage of patients who reported having at least one self-treated hypoglycemic event in the past 30 days

All Basalonly

Basal+bolus

36% 45%25%

Fear of hypoglycemia is a concern for patients taking basal insulin analogues

15

Percentage of patients worried about experiencing self-treated nocturnal hypoglycemia

Brod M, Rana A, Barnett AH. Impact of self-treated hypoglycemia in type 2 diabetes: a multinational survey in patients and physicians. Current Medical Research and Opinion. 2012;28(12):1947-1958.

42%

57% of patients reported being concerned about the potential negative impact of nocturnal

hypoglycemic events on their long-term health

Risk of hypoglycemia affects dose of insulin initiated by HCPs

16Brod M, Rana A, Barnett AH. Impact of self-treated hypoglycemia in type 2 diabetes: a multinational survey in patients and physicians. Current Medical Research and Opinion. 2012;28(12):1947-1958.

Percentage of HCPs who adjust initial dose of insulin due to risk of hypoglycemia

56%

42%56%

Initiated patients on a lower insulin dose than recommended due to risk of hypoglycemic events

Glucose variability (GV) predicts hypoglycemia risk before starting and during insulin therapy

Qu et al. Diab Tech Therapeutics 2012;14:1008–12

Numbers next to bars are p values

GV is therefore likely to be a significant player in overall treatment success

Variability of FPG and cardiovascular mortality10-year survival

Group 1 (8.5%)

Group 2 (14.8%)Group 3 (27.7%)

1.0

0.7

0.6

0.5

0.00 2 4 6 8 10

Time (years)

0.8

0.9

Surv

ival

pr

obab

ility

Mean CV of FPG*

Variability in blood glucose is an independent risk factor for mortality

*Significant differences in the CV of FPG (p<0.001)Muggeo et al. Diabetes Care 2000;23:45–50

19

BARRIERS


Hypoglycemia Risk and Glucose

Variability

GOAL

Need for an ideal basal insulinWhat is Insulin Degludec?

20

Degludec:Multi-hexamer formation key to protraction mechanism

Degludec molecules form hexamers

The side chain (linker) forms an accurate fit between Degludec hexamers to form multi-hexamers

Degludec association Proposed steps from injection to absorption

Degludec multi-hexamers

Degludec monomers

-Zn2+

Degludec di-hexamers

-Phenol

Injected formulation

S.C. depot formation

Absorption

Capillary membrane

Subcutaneous tissue

Insulin degludec in blood Albumin binding

Monomers

Cell membrane

Capillary blood

Insulin receptors

Multi-hexamers

Degludec:Mode of action

PK/PD in T1DM: Half-life greater than 25 hours

24

2x longer half-life vs insulin glargine (25.4 hours vs 12.5 hours)

Heise T, Hövelmann U, Nosek L, Bøttcher S, Granhall C, Haahr H. Insulin degludec has a two-fold longer half-life and a more consistent pharmacokinetic profile than insulin glargine. Poster presented at: 71st Scientific Sessions of the American Diabetes Association; 24-28 June 2011; San Diego, California, USA.

PK/PD in T1DM: Four times less variability in glucose-lowering effect over 24 hours vs insulin glargine

25Heise T, Hermanski L, Nosek L, Feldman A, Rasmussen S, Haahr H. Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes. Diabetes, Obesity and Metabolism. 2012;14(9):859-864.

GIR=glucose infusion rate; AUC GIR (GIR in subscript) =Area under the curve for glucose infusion rate; CV%= coeffecient of variation

Insulin degludec provides four times lower day-to-day variability vs insulin glargineMean within-subject variability at steady state*

Heise T, Hermanski L, Nosek L, Feldman A, Rasmussen S, Haahr H. Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes. Diabetes, Obesity and Metabolism. 2012;14(9):859-864.

4x less variability with insulin degludec vs insulin glargine

PK/PD in Type 2 DM: A flat, stable glucose-lowering effect

27Insulin degludec [summary of product characteristics]. Bagsværd, Denmark: Novo Nordisk A/S; 2012.

GIR, glucose infusion rate

PK/PD in T2DM: Concentration reaches steady state in 3 days

54320 1 6

Days since first dose

Seru

m ID

eg c

once

ntra

tion

Prop

ortio

n of

Day

6 le

vel (

%)

120

110

100

90

80

70

60

50

40

30

20

10

0

T2D

0 1 2 3 4

Seru

m ID

eg c

once

ntra

tion

Prop

ortio

n of

Day

4 le

vel (

%)

120

110

100

90

80

70

60

50

40

30

20

10

0

Days since first dose

T1D

T1D trial, n=66; T2D trial, n=49T1D trial, 0.4, 0.6 or 0.8 U/kg; T2D trial, 0.4, 0.6 or 0.8 U/kgEstimated ratios and 95% CIHeise et al. Diabetes 2012;61(Suppl. 1):A259

Reaching steady state with insulin degludec

Units added each day

Units remaining from prior injections(t1/2~24 h) Units absorbed into circulation

5 UDay 1 10 U

~9 U

7.5 U5 U

7.5 U

~9 U

10 U

10 U

15 U

17.5 U

19 U

20 U

10 U

10 UDay 5

Day 4

Day 3

Day 2

Insulin in s.c. depot

10 U

5050%

5050%

5050%

5050%

5050%

Insulin in circulationInjected insulinMaximum units present in 24h interval

10 U

10 U

10 U

10 U

Therefore there is no stacking

Figure adapted from Heise and Meneghini Endocr Pract 2014;20:75–83

Pharmacokinetics of insulin degludec in special populations Age

Hepatic functionRenal function

Geriatric (≥65)Younger adults (18–35)

The PK properties of insulin degludec are not affected by increasing age, renal impairment or hepatic impairment

0 4 8 12 16 20 240

2000

4000

6000

8000

10000 Normal

Mild

Moderate

Severe

Time since injection (hours)

IDeg

con

cent

ratio

n(p

mol

/L)

0 4 8 12 16 20 240

2000

4000

6000

8000

10000 Normal

Child-Pugh A

Child-Pugh B

Child-Pugh C

Time since injection (hours)

IDeg

con

cent

ratio

n(p

mol

/L)

0 4 8 12 16 20 24Time since injection (hours)

2000

4000

6000

8000

10000

IDeg

con

cent

ratio

n (p

mol

/L)

0

PK, pharmacokineticKupčová et al. Clin Drug Investig 2014;34:127–33; Kiss et al. Clin Pharmacokinet 2014;53:175–83; Korsatko et al. Drugs Aging 2014;31:47–53

31

Efficacy in reaching the target HbA1cHow well does IDeg achieve glycemic control for patients?

32

BEGIN™ phase 3 program

Investigating the efficacy and safety of Insulin Degludec in type 1 and type 2 diabetes

USA

Russia

France

Denmark Poland

Romania

Israel

Finland

India

Malaysia

Norway

Taiwan

Thailand

Spain Turkey

Austria

South Korea

South Africa

Japan

Hong Kong

Germany

Canada

Mexico

Brazil

Argentina

Greece

Macedonia

United Kingdom

Ireland

Italy

UkraineCzech Republic

SlovakiaHungary

Bulgaria

Serbia & Montenegro

BelgiumNetherlands

Multinational clinical trial program

33

Australia

China

Sweden

Croatia

Largest clinical trial program for any basal insulin

40 countries>11,000 subjects

Regulatory guidance recommends that insulin be tested in a treat-to-target design:

BEGIN™ program designed to meet noninferiority insulin trial standards

34Center for Drug Evaluation and Research. Guidance for industry: diabetes mellitus: developing drugs and therapeutic biologics for treatment and prevention (draft guidance). Rockville, MD: Food and Drug Administration, U.S. Dept of Health and Human Services; February 2008.

Summary of insulin degludec BEGIN™ phase 3 program

35

Heller S, Buse J, Fisher M, Garg S, Marre M, Merker L, Renard E, Russell-Jones D, Philotheou A, Ocampo Francisco AM, Pei H, Bode B. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825):1489-1497; Data on file NN1250-3770. Novo Nordisk A/S, Bagsværd, Denmark. Please contact Novo Nordisk for additional information; Zinman B, Philis-Tsimikas A, Cariou B, Handelsman Y, Rodbard HW, Johansen T, Endahl L, Mathieu C. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN™ Once Long). Diabetes Care. 2012;35(12):2464-2471; Data on file NN1250-3672. Novo Nordisk A/S, Bagsværd, Denmark. Please contact Novo Nordisk for additional information; Meneghini L, Atkin SL, Bain S, Gough S, Raz I, Blonde L, Begtrup K, Johansen T, Birkeland KI. Flexible once-daily dosing of insulin degludec does not compromise glycemic control or safety compared to insulin glargine given once daily at the same time each day in people with type 2 diabetes. Abstract presented at: 71st Scientific Sessions of the American Diabetes Association; 24-28 June 2011; San Diego, California, USA. Abstract 35-LB; Data on file NN1250-3668. Novo Nordisk A/S, Bagsværd, Denmark. Please contact Novo Nordisk for additional information; Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Muñoz-Torres M, Rosenstock J, Endahl LA, Ocampo Francisco AM, Hollander P. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes. Lancet. 2012;379(9825):1498-1507; Onishi Y, Park SW, Yoo SJ, Clauson P, Tamer SC, Iwamoto Y. Insulin degludec improves glycemic control in insulin-naïve patients with type 2 diabetes: results of a randomized pan-Asian trial. Poster presented at: 72nd Scientific Sessions of the American Diabetes Association; 8-12 June 2012; Philadelphia, Pennsylvania, USA. 1059-P.

OAD=oral anti-diabetic drug; MET=metformin; DPP-4=dipeptidyl peptidase-4 inhibitor; SU=sulphonylurea; TZD=thiazolidinedione.

36

BEGIN™ Once Long StudyEfficacy and Safety in Type 2 Diabetes

Insulin-naïve T2D: study designBEGIN ONCE LONG – 2 years

IDeg OD + metformin ± DPP-4 (n=773)

IGlar OD + metformin ± DPP-4 (n=257)

Insulin-naïve patients with

type 2 diabetes(n=1030)

Inclusion criteria• Type 2 diabetes ≥6 months• Insulin naïve, treated with

metformin ± SU, DPP-4 or acarbose for ≥3 months• HbA1c 7.0–10.0%• BMI ≤40 kg/m2

• Age ≥18 years

Randomised 3:1 (IDeg OD: IGlar OD)*1 week wash-out (week 52) to allow for antibody measurement, hence 105 weeks = 104 weeks’ exposure

Continue core phase treatment (n=551)

Continue core phase treatment (n=174)

Core phase – 52 weeks Extension phase – 52 weeks

105 weeks0 52* 53

OD, once dailyZinman et al. Diabetes Care 2012;35:2464–71; Rodbard et al. Diabet Med 2013;30:1298–304

Equivalent reductions in HbA1c vs insulin glargine

38Zinman B, Philis-Tsimikas A, Cariou B, Handelsman Y, Rodbard HW, Johansen T, Endahl L, Mathieu C. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN™ Once Long). Diabetes Care. 2012;35(12):2464-2471.

Significant reductions in FPG vs insulin glargine

39Zinman B, Philis-Tsimikas A, Cariou B, Handelsman Y, Rodbard HW, Johansen T, Endahl L, Mathieu C. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN™ Once Long). Diabetes Care. 2012;35(12):2464-2471.

Significantly lower risk of nocturnal hypoglycemia vs insulin glargine

40

• 36% lower risk of nocturnal confirmed hypoglycemia vs insulin glargine (P=0.038)• 86% lower risk of severe hypoglycemia vs insulin glargine (P=0.017)• 18% lower risk of overall confirmed hypoglycemia vs insulin glargine (P=NS)Zinman B, Philis-Tsimikas A, Cariou B, Handelsman Y, Rodbard HW, Johansen T, Endahl L, Mathieu C. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN™ Once Long). Diabetes Care. 2012;35(12):2464-2471.

Low Adherence to Treatment

BARRIER

41

Patients are not taking basal insulin as prescribed

42Brod M, Rana A, Barnett AH. Adherence patterns in patients with type 2 diabetes on basal insulin analogues: missed, mistimed and reduced doses. Current Medical Research and Opinion. 2012;28(12):1933-1946.

Percentage of patients reporting at least one basal insulin dosing irregularity in the past 30 days

Almost 1 of 4 patients have mistimed* at least one basal insulin dose in the past 30 days

22%

14%

24%

Misseda dose

Mistimeda dose

Reduceda dose

*by ±2 hours from prescribed time.

33.2% of patients reported insulin omission ⁄ non-adherence at least 1

day in the last month, with an

average of 3.3 days

73%

27%

67%

33%

73% of physicians reported that their typical patient

does not take their insulin as prescribed

Insulin doses are being missed or not taken as prescribed

Too busy18.9%

Travelling16.2%

Challenging to take at same time each day

9.4%

Forgot7.4%

Regimen too complicated

3.8%

Peyrot et al. Diabet Med 2012;29:682–9

GAPP™• A global internet

survey of patient and physician beliefs regarding insulin therapy

• n=1250 physicians

46

BARRIERS


Complex Regimens & Low

Treatment Adherence/user

friendly

GOAL

Fixed administration time for basal insulin is difficult for patients

1. Peyrot et al. Diabetic Medicine 2012;29:682–9; 2. Peyrot et al. Diabetes Care 2010;33:240–5

22% of patients said they planned their daily activities around insulin injections2

28% of patients said they find it difficult to take insulin at the prescribed time daily or with meals every day1

2-in-5 patients had missed a dose of basal insulin within the last 30 days

Basal insulin

Missed, mis-timed (by more than 2 hours)and reduced doses of basal insulin

Data on file.

Insulin analogue patients

44% I had skipped a meal39% I had exercised recently

81% I had exercised recently71% I had skipped a meal

37% I had exercised recently31% I had skipped a meal

On the last occasion that patients had missed, mis-timed or reduced their basal insulin dose, 37%, 21% and 68% (respectively) had done so intentionally

Proportion of patients intentionally missing, mistiming or reducing a dose of basal insulin the last time they did this

TOP 2 reasons for intentionally missing, mistiming or reducing a dose of basal insulin the last time they did this

Basal insulin

Insulin analogue patients

Data on file.

Better FlexibilityHow can IDeg improve treatment adherence of patients?

50

Insulin degludec and flexibility in day-to-day dosing time

On occasions when administration at the same time of the day is not possible, insulin degludec allows for flexibility in the timing of insulin administration. A minimum of 8 hours between injections should always be ensured.

Patients who forget a dose are advised to take it upon discovery and then resume their usual once-daily dosing schedule.

Insulin degludec [summary of product characteristics]. Bagsværd, Denmark: Novo Nordisk A/S; 2012. 51

52

BEGIN™ Flex T2 StudyFlexibility in Type 1 and Type 2 Diabetes

Flexible vs Fixed dosing in T2D: study designBEGIN FLEX T2D

Inclusion criteria• Type 2 diabetes ≥6 months• Previously treated with OADs

and/or basal insulin• HbA1c:

OADs only 7–11%Basal insulin ± OADs 7–10%• BMI ≤40 kg/m2

• Age ≥18 years

Patients with type 2 diabetes

(n=687)

0 26 weeks

Open label

IGlar OD ± OADs (n=230)(metformin/SU/pioglitazone)

IDeg Fixed OD ± OADs (n=228)(metformin/SU/pioglitazone)

IDeg Flexible OD ± OADs (n=229) (metformin/SU/pioglitazone)

Meneghini et al. Diabetes Care 2013;36:858–64

Flexible dosing time

Mon Tue Wed Thu Fri Sat Sun

MorningMorning Morning

Evening Evening Evening Evening

40 h 40 h 40 h

8 h 8 h

24 h

Insulin degludec: Varied daily dosing intervals (between 8 to 40 hours)

Insulin glargine: Dosed once daily at the same time each day, per insulin

glargine label

Insulin degludec’s ultra-long duration of action and steady-state profile allows for a forced flexible dosing interval in patients with diabetes

55Meneghini L, Atkin SL, Bain S, Gough S, Raz I, Blonde L, Begtrup K, Johansen T, Birkeland KI. Flexible once-daily dosing of insulin degludec does not compromise glycemic control or safety compared to insulin glargine given once daily at the same time each day in people with type 2 diabetes. Abstract presented at: 71st Scientific Sessions of the American Diabetes Association; 24-28 June 2011; San Diego, California, USA. Abstract 35-LB.

Summary of insulin degludec flexible day-to-day dosing time

• Insulin degludec administered at flexible dosing times provided:– Effective glycemic control with noninferior HbA1c reductions

compared to insulin glargine, with less nocturnal hypoglycemia– FPG reductions greater than insulin glargine in patients with

type 2 diabetes

56Meneghini L, Atkin SL, Bain S, Gough S, Raz I, Blonde L, Begtrup K, Johansen T, Birkeland KI. Flexible once-daily dosing of insulin degludec does not compromise glycemic control or safety compared to insulin glargine given once daily at the same time each day in people with type 2 diabetes. Abstract presented at: 71st Scientific Sessions of the American Diabetes Association; 24-28 June 2011; San Diego, California, USA. Abstract 35-LB.

Flexibility in day-to-day dosing time

57

Establishing a routine is important, but it is not always possible to inject at the same time each day…

On occasions when administration at the same time of day is not possible, insulin degludec allows for flexibility in the timing of insulin administration

Who could benefit from flexibility in day-to-day dosing time?

Juggles a busyfamily life Travels Needs help

injectingHas unpredictable work hours

58

59

Ideal Basal

Insulin

Longer duration of action

Controls fasting blood glucose

with 1 injection per day in all individuals

Has a long duration of action (at least 42 hours) & a half-life twice as long as that of insulin glargine

Flat time-action profile

Lower risk of hypoglycemia

Provides a flat and stable

glucose-lowering effect, equally

distributed over 24 hours

Less day-to-day

variability

Lower hypo- and hyperglycemia

Has 4 times lower variability in

glucose-lowering effect compared

with insulin glargine

Ideal Basal

Insulin

Clinical Benefit

Insulin Degludec

Improved Adherence & Overall Glycemic Control

60

Controls fasting blood glucose with 1 injection per day

in all individuals

Has a long duration of action (at least 42 hours) & a half-life twice as long as

that of insulin glargine

Lower risk of hypoglycemia

Provides a flat and stable glucose-lowering effect,

equally distributed over 24 hours

Lower hypo- and hyperglycemia

Has 4 times lower variability in

glucose-lowering effect compared

with insulin glargine

Clinical Benefit

Insulin Degludec

Improved Adherence & Overall Glycemic Control

Lower risk of complications Improve

Quality of Life

Establishing Safety How does IDeg address the fear of hypoglycemia?

61

PG <3.1 mmol/La

(56 mg/dL)

Yes

Hypoglycemia classification – consistent and stringent in phase 3

Suspected hypoglycemia or routine PG measurement

Patient able to treat self? No

Severe hypoglycemia

Not classified as confirmed hypoglycemia

Yes

Confirmed hypoglycemia(including night time)

No

a: With or without symptomsA nocturnal episode is any confirmed episode with time of onset between 00:01 am and 05:59 am, inclusive.

0.25 2.5

Pre-specified meta-analyses: overall confirmed hypoglycemia

In favour of IDeg In favour of IGlar

1.10 [0.96;1.26] Not significant

0.91 [0.83;0.99] Significant*

0.83 [0.70;0.98] Significant*

0.83 [0.74;0.94] Significant*

T2D

LOW VOLUME

BB

FLEX T2D

ONCE ASIA

ONCE LONG

Pooled T2D

FLEX T1D

BB T1D LONGT1D

Pooled T1D

Pooled T1D & T2D

52

26

26

26

52

52

26

Pooled insulin-naïve T2D

Weeks

Adjusted for trial, type of diabetes, anti-diabetes therapy at screening, sex, region and age. Flexible arm not included in analysis. *Significantly lower risk based on 95% CIRatner et al. Diabetes Obes Metab 2013;15:175–84

0.04 0.4 4

Pre-specified meta-analyses: nocturnal confirmed hypoglycemia

0.83 [0.69;1.00] Not significant

0.74 [0.65;0.85] Significant*

0.64 [0.48;0.86] Significant*

0.68 [0.57;0.82] Significant*

T2D

LOW VOLUME

BB

FLEX T2D

ONCE ASIA

ONCE LONG

Pooled T2D

FLEX T1D

BB T1D LONGT1D

Pooled T1D

Pooled T1D & T2D

26

26

26

52

52

26

Pooled insulin-naïve T2D


52

Weeks


Meta-analyses: severe hypoglycemia in type 1 and type 2 diabetes

0.03125 0.3125 3.125

Significant*0.14 [0.03;0.70]

Not significant0.81 [0.42;1.56]




T2D

Pooled T2D

T1D Pooled T1D

Pooled T1D & T2D

Pooled insulin -naïve T2D


Nocturnal confirmed hypoglycemiaDefinition

0.0 0.2 0.4 0.6 0.8 1 1.2 1.4

T2D Insulin-naïve

0.64 [0.48; 0.86]*

0.56 [0.39; 0.80]*

0.73 [0.56; 0.97]*

Nocturnal confirmed hypoglycemia(original definition) (0:01–5:59)

Nocturnal confirmed symptomatichypoglycemia (0:01–5:59)

Nocturnal ADA documented symptomatichypoglycemia (0:01–5:59)


0.51 [0.36; 0.72]*

0.43 [0.28; 0.64]*

0.62 [0.45; 0.84]*

0.75 [0.58; 0.99]*

0.68 [0.51; 0.91]*

0.72 [0.55; 0.93]*

0.72 [0.51; 1.00]

0.65 [0.45; 0.93]*

0.70 [0.51; 0.96]*

0.0 0.2 0.4 0.6 0.8 1 1.2 1.4



Nocturnal confirmed symptomatichypoglycemia (0:01–5:59)

Nocturnal ADA documented symptomatichypoglycemia (0:01–5:59)

T2D Basal–bolus

Entire trial periodMaintenance period only

Heller et al. Diabetes 2014;63(Suppl. 1):A106

Nocturnal confirmed hypoglycemiaTime period

0.0 0.2 0.4 0.6 0.8 1 1.2 1.4

T2D Insulin-naïve

0.64 [0.48; 0.86]*

0.60 [0.45; 0.80]*

0.93 [0.75; 1.15]


Nocturnal confirmed hypoglycemia(21:59–5:59)



0.51 [0.36; 0.72]*

0.49 [0.35; 0.69]*

0.76 [0.59; 0.99]*

0.75 [0.58; 0.99]*

0.73 [0.59; 0.91]*

0.77 [0.60; 0.97]*

0.0 0.2 0.4 0.6 0.8 1 1.2 1.4





T2D Basal–bolus

0.72 [0.51; 1.00]

0.70 [0.54; 0.91]*

0.70 [0.53; 0.92]*

Entire trial periodMaintenance period only

Heller et al. Diabetes 2014;63(Suppl. 1):A106

Summary of efficacy and safety in type 2 diabetes

• In patients with type 2 diabetes, insulin degludec provides– Effective glycemic control with noninferior HbA1c reductions compared to insulin glargine,

with less hypoglycemia– FPG reductions greater than insulin glargine

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Zinman B, Philis-Tsimikas A, Cariou B, Handelsman Y, Rodbard HW, Johansen T, Endahl L, Mathieu C. Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes: a 1-year, randomized, treat-to-target trial (BEGIN™ Once Long). Diabetes Care. 2012;35(12):2464-2471; Data on file NN1250-3672. Novo Nordisk A/S, Bagsværd, Denmark. Please contact Novo Nordisk for additional information; Onishi Y, Park SW, Yoo SJ, Clauson P, Tamer SC, Iwamoto Y. Insulin degludec improves glycemic control in insulin-naïve patients with type 2 diabetes: results of a randomized pan-Asian trial. Poster presented at: 72nd Scientific Sessions of the American Diabetes Association; 8-12 June 2012; Philadelphia, Pennsylvania, USA. 1059-P; Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Muñoz-Torres M, Rosenstock J, Endahl LA, Ocampo Francisco AM, Hollander P. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes. Lancet. 2012;379(9825):1498-1507.

OAD=oral anti-diabetic drug; MET=metformin; DPP-4=dipetidyl peptidase-4 inhibitor; TZD=thiazolidinedione.

Non-inferior HBA1c reduction & Significant FPG reductions

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Significant reductions in hypoglycemia

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Comparable reductions in nocturnal hypoglycemia vs insulin glargine

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• 23% lower risk of nocturnal confirmed hypoglycemia vs insulin glargine (P=NS)• 3% higher risk of overall confirmed hypoglycemia vs insulin glargine (P=NS)

Meneghini L, Atkin SL, Bain S, Gough S, Raz I, Blonde L, Begtrup K, Johansen T, Birkeland KI. Flexible once-daily dosing of insulin degludec does not compromise glycemic control or safety compared to insulin glargine given once daily at the same time each day in people with type 2 diabetes. Abstract presented at: 71st Scientific Sessions of the American Diabetes Association; 24-28 June 2011; San Diego, California, USA. Abstract 35-LB.

Who could benefit from hypoglycemia risk reduction?

Reports hypoglycemic events

Admits to lowering dose to avoid hypoglycemia

Is afraid of hypoglycemia

Has higher fasting target due to hypoglycemia risk

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Clinical use, dosing and deviceHow can we use IDeg in practice?

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Clinical Indications• With intensified glucose monitoring and the insulin

dose adjusted on an individual basis, Insulin Degludec can be used in:

Renal and Hepatic Impairment Elderly (>65 years old)

• Safety and efficacy have not been established in children and adolescents below 18 years of age.

• No clinical experience in pregnant women. Animal reproduction studies have not revealed any difference between Insulin Degludec and Human Insulin regarding embryotoxicity and teratogenicity.

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Dosing of Insulin Degludec

Initiation

Type 2 diabetes• 10 units starting dose1

• Individual dose adjustments1

Type 1 diabetes• Combination with

mealtime insulin1

• Individual dose adjustment1

Transfer from other basal insulin

Type 2 diabetes• Unit-to-unit switch from

prior basal insulin/component1

Type 1 diabetes• OD therapy: unit-to-unit

switch1

• BID basal insulin or HbA1c <8.0%: dose determined on an individual basis1

BID, twice daily1. Tresiba® SmPC, Novo Nordisk, May 2013 75

How to adjust Insulin Degludec dose once a week1

1. Get to steady state – typically 2–3 days after first dose2. Titrate once-weekly based on average of 2 preceding FPG

measurements*

• ADA/EASD recommended FPG goal is 3.9 to 7.7 mmol/L (70 to 130 mg/dL) for many adult patients with diabetes2

22FPG, fasting plasma glucose; ADA, American Diabetes Association; EASD, European Association for the Study of Diabetes

If above goal, +2 units

If below goal, -2 units

If at goal, maintain dose

1. Tresiba® SmPC, Novo Nordisk, May 2013

*Fasting plasma glucose (FPG) measurements must be from 2 preceding days

Insulin NPH (Not truly basal) Glargine Detemir Degludec

Structure Crystalline suspension of human insulin with protamine and zinc

Addition of two and substitution of one amino acid

Addition of accylated fatty acid chain at B

Deletion of B30, addition of glutamic acid spacer and diacylated fatty acid chain at B29

Number of amino acids

51 53 51 50

Carbon in side chain

0 0 14 16

Mechanism of protraction

Less solubility in the extracellular fluid leads to slower absorption and a prolonged effect

Precipitation at acidic pH

Binding to albumin Multihexamer chain formation

Terminal half life Variable 12.5 hrs 12.5 hrs 25.1-25.4 hrs

Duration of action 13-20 hrs Upto 24 hrs Upto 18-23 hrs Upto 42 hrs

Intra-patient glycemic variability

High High Low Lowest

Exposure ratio: first 12 hrs to second 12 hrs after injection

60:40 50:50 50:50

Timing of administration

Once or twice or thrice daily

At the same time everyday

Once or twice daily At any time, every day

Comparison of various basal insulins

Insulin NPH Glargine Detemir Degludec

Risk of hypoglycemia Present Low Low Least

Risk of nocturnal hypoglycemia Present Low Low Least

Risk of severe hypoglycemia Present Low Low Least

Injection site reactions Lesser than glargine Possible, because of acidic pH

Rare Rare

Weight gain Yes Yes No Yes

Binding of IGF-1R (human insulin 100)

641+51 18+2 2

Binding affinity to insulin receptor (human insulin 100)

86+3 16+1 13-15

Use in renal impairment Dose needs to be adjusted Safe Safe Safe

Use in hepatic impairment Dose needs to be adjusted Safe Safe Safe

Miscibility with regular/rapid acting insulin

Can be mixed with soluble insulin without affecting absorption kinetics of either insulin

No No Yes

Miscibility with Glucagon like peptide – 1 receptor agonists

Yes No Yes

Comparison of various basal insulins-2

Clinical summary of Insulin Degludec

Successful non-inferior HbA1c reductions in type 1 or type 2 diabetes, based on treat-to-target trial designs1-3

Significantly lower risk of nocturnal hypoglycemia versus insulin glargine1–4

Flexibility in day-to-day dosing time when needed, delivered in a once-daily dose4–7

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1. Zinman et al. Diabetes Care 2012;35:2464–71; 2. Garber et al. Lancet 2012;379:1498–1507; 3. Heller. Lancet 2012;379:1489–97; 4.Keating. Drugs 2013;73:575–93; 5. Meneghini et al. Diabetes Care 2013;36:858–64; 6. Mathieu et al. J Clin Endocrinol Metab 2013;98:1154–62; 7. Tresiba® SmPC, Novo Nordisk, May 2013

Thank you or your kind attention!

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ideal basal insulin: degludeg

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