ideal basal insulin: degludeg
TRANSCRIPT
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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
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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
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What are problems encountered…
3
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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
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But why are we not getting to goal?
5
The glucose targets are known…
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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
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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
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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
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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
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Novel agent to address insulin barriers
10
Optimal Glycemic Control
Optimal dosing & titration
Greater flexibility for better adherence
Lower hypoglycemi
a risk
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Hypoglycaemia Risk and Glucose Variability
BARRIER
11
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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%
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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
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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
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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
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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
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19
BARRIERS
Optimal Glycemic Control
Hypoglycemia Risk and Glucose
Variability
GOAL
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Need for an ideal basal insulinWhat is Insulin Degludec?
20
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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
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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
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Capillary membrane
Subcutaneous tissue
Insulin degludec in blood Albumin binding
Monomers
Cell membrane
Capillary blood
Insulin receptors
Multi-hexamers
Degludec:Mode of action
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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.
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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
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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
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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
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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
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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
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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
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31
Efficacy in reaching the target HbA1cHow well does IDeg achieve glycemic control for patients?
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BEGIN™ phase 3 program
Investigating the efficacy and safety of Insulin Degludec in type 1 and type 2 diabetes
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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
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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.
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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.
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BEGIN™ Once Long StudyEfficacy and Safety in Type 2 Diabetes
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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
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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.
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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.
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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.
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Low Adherence to Treatment
BARRIER
41
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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.
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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
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46
BARRIERS
Optimal Glycemic Control
Complex Regimens & Low
Treatment Adherence/user
friendly
GOAL
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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
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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
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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.
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Better FlexibilityHow can IDeg improve treatment adherence of patients?
50
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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
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52
BEGIN™ Flex T2 StudyFlexibility in Type 1 and Type 2 Diabetes
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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
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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.
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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.
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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
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Who could benefit from flexibility in day-to-day dosing time?
Juggles a busyfamily life Travels Needs help
injectingHas unpredictable work hours
58
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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
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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
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Establishing Safety How does IDeg address the fear of hypoglycemia?
61
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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.
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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
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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
In favour of IDeg In favour of IGlar
52
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
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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]
Not significant1.12 [0.68;1.86]
Not significant0.97 [0.66;1.44]
In favour of IDeg In favour of IGlar
T2D
Pooled T2D
T1D Pooled T1D
Pooled T1D & T2D
Pooled insulin -naïve T2D
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
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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)
In favour of IDeg In favour of IGlar
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
In favour of IDeg In favour of IGlar
Nocturnal confirmed hypoglycemia(original definition) (0:01–5:59)
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
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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(original definition) (0:01–5:59)
Nocturnal confirmed hypoglycemia(21:59–5:59)
Nocturnal confirmed hypoglycemia(0:01–7:59)
In favour of IDeg In favour of IGlar
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
In favour of IDeg In favour of IGlar
Nocturnal confirmed hypoglycemia(original definition) (0:01–5:59)
Nocturnal confirmed hypoglycemia(21:59–5:59)
Nocturnal confirmed hypoglycemia(0:01–7:59)
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
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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
68
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.
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Non-inferior HBA1c reduction & Significant FPG reductions
69
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.
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Significant reductions in hypoglycemia
70
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.
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Comparable reductions in nocturnal hypoglycemia vs insulin glargine
71
• 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.
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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
72
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Clinical use, dosing and deviceHow can we use IDeg in practice?
73
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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.
74
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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
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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
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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
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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
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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
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