Simposio
Nuove prospettive terapeutiche nella gestione del paziente diabetico anziano
30 Novembre 2017
La Terapia Insulinica
Vito Borzì
Outline
Introduzione: obiettivi della terapia insulinica nel paziente diabetico anziano
Associazione tra ipoglicemie, variabilità glicemica ed outcomes Importanza del controllo glicemico post-prandiale Approccio fisiopatologico alla PPG: insulina Faster Aspart Approccio fisiopatologico alla FPG: insulina Degludec Nuovi approcci terapeutici nel fallimento da BOT: IDegLira
Outline
Introduzione: obiettivi della terapia insulinica nel paziente diabetico anziano
Associazione tra ipoglicemie, variabilità glicemica ed outcomes Importanza del controllo glicemico post-prandiale Approccio fisiopatologico alla PPG: insulina Faster Aspart Approccio fisiopatologico alla FPG: insulina Degludec Nuovi approcci terapeutici nel fallimento da BOT:IDegLira
Il diabete in età geriatrica
Con il progredire dell’età si assiste ad un progressivo aumento del numero di persone affette da diabete di tipo 2.
Progressiva riduzione della secrezione insulinica e aumento dell’insulino-resistenza
Riduzione della massa magra
Aumento assoluto/relativo del tessuto adiposo
Riduzione dell’attività fisica (sedentarietà, disabilità)
Dieta povera in fibre e ricca di carboidrati e grassi
Cause iatrogene (Diuretici tiazidici, cortisonici)
Fattori neuro-ormonali
Osservatorio ARNO Diabete Anziani 2017
ipovedenza, sordità
comorbidità
polifarmacoterapia
Solitudine
istituzionalizzazione
disabilità
L’anziano diabetico
demenza
depressione
Gentle Giant – First Album - 1970
Outline
Introduzione: obiettivi della terapia insulinica nel paziente diabetico anziano
Associazione tra ipoglicemie, variabilità glicemica ed outcomes Importanza del controllo glicemico post-prandiale Approccio fisiopatologico alla PPG: insulina Faster Aspart Approccio fisiopatologico alla FPG: insulina Degludec Nuovi approcci terapeutici nel fallimento da BOT: IDegLira
Diabetes Research and Clinical Practice 115; 2016; 24-30
According to multivariable logistic regression analysis, advanced age, cognitive dysfunction, and nephropathy were associated to occurrence of hypoglycemia
53 Italian Internal Medicine Units 3167 patients enrolled
IPOGLICEMIA nell’anziano
- Mortalità
- Ischemia
(miocardica e cerebrale)
- Aritmie
- Cadute
- Demenza
- Costi King Crimson – In the court of the Crimson King - 1969
Severe hypoglycaemia is associated with increased rates of MACE and
all-cause mortality across cardiovascular outcomes trials: VADT
ACCORD ADVANCE EXAMINE ORIGIN LEADER
Severe hypoglycaemia and outcomes
MACE, major adverse cardiovascular events ACCORD Study Group. N Engl J Med 2008;358:2545–59; Zinman et al. Diabetes 2017;66(Suppl. 1):A95; Duckworth et al. J Diabetes Complications 2011;25:355–61; Duckworth et al. N Engl J Med 2009;360:129–39; Goto et al. BMJ 2013;347:f4533; Bonds et al. BMJ 2010;340:b4909; Zoungas et al. N Engl J Med 2010;363:1410–8, for the ADVANCE Collaborative Group; Mellbin et al. Eur Heart J 2013;34:3137–44, for the ORIGIN Trial Investigators
No Hypo Hypo No Hypo Hypo
53 Italian Internal Medicine Units 3167 patients enrolled Diabetes Research and Clinical Practice 115; 2016; 24-30
Pathophysiological cardiovascular consequences of hypoglycaemia
CRP, C-reactive protein; IL-6, interleukin 6; VEGF, vascular endothelial growth factor; Adapted from Desouza et al. Diabetes Care 2010;33:1389; Frier et al. Diabetes Care 2011;34 (Suppl. 2):S132; 1. Wright et al. Diabetes Care 2010;33:1591; 2. Chow et al. Diabetologia 2013;56 (Suppl. 1):S243
VEGF IL-6 CRP
Neutrophil
activation
Platelet
activation Factor VIII
Blood
coagulation
abnormalities
Sympathoadrenal response
Epinephrine
Inflammation
Endothelial
dysfunction
Vasodilatation
Heart rate
variability
Rhythm
abnormalities
Haemodynamic changes
Heart workload
Contractility
Output
HYPOGLYCAEMIA
Persists for up to 48 hours1 Effects last up to 7 days2
• Abnormalities in: • Atrioventricular conduction
• Ventricular repolarisation
• Catecholamine release leads to: • K+
• R-wave amplification
• T-wave flattening
• Depression of ST segment
• Prolongation of QT interval
• Risk of cardiac arrhythmia
Hypoglycaemia is associated with ECG abnormalities
ECG, electrocardiogram Laitinen et al. Ann Noninvasive Electrocardiol 2008;13:97–1051
P
R
S
Q
ECG
(m
V)
Time (seconds)
3
2
1
0
–0.25 0.00 0.25 0.50 0.75
Baseline
Hypoglycaemic hyperinsulinaemia
T
Chow et al. Diabetes 2014;63:1738–47
Incidence rate of arrhythmias during hypoglycaemia vs euglycaemia
Day Night
IRR 95%
CI p IRR
95% CI
p
Bradycardia N/A N/A N/A 8.42 1.40-51.0
0.02
Atrial ectopic 1.35 0.92-1.98
0.13 3.98 1.10-14.40
0.04
VPB 1.31 1.10-1.57
<0.01 3.06 2.11-4.44
<0.01
Complex VPB
1.13 0.78-1.65
0.52 0.79 0.22-2.86
0.72
Table 2 Analysed using generalised estimated equations IRR, incident rate ratio; VPB, ventricular premature beat
Hypoglycaemia is associated with ECG abnormalities
Frier, B. M. Nat. Rev. Endocrinol. 10, 711–722 (2014)
Rachel A. Whitmer JAMA. 2009;301(15):1565-1572
A longitudinal cohort study from 1980-2007 of 16 667 patients with a mean age of 65 years and type 2 diabetes
Association between glycaemic variability, hypoglycaemia and outcomes
Desouza et al. Diabetes Care 2010;33:1389–94; Driesen et al. J Neurosci Res 2007;85:575–82; Mooradian. Brain Res Brain Res Rev 1997;23:210–8; Sanon et al. Clin Cardiol 2014;37:499–504; Dhalla et al. J Hypertens 2000;18:655–73
Presented at the 53rd Annual Meeting of the European Association for the Study of Diabetes (EASD), Session 33. 15 September 2017, Lisbon, Portugal
Outcomes Glycaemic variability
Hypoglycaemia
Hyperglycaemia
Glycaemic control: variability
BG, blood glucose Image adapted from Penckofer et al. Diabetes Technol Ther 2012;14:303–10; Vora & Heise. Diabetes Obes Metab 2013;15:701–12
Hypoglycaemia
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 23 24
0
6
2
4
10
12
14
16
18
22 Time (hours)
BG
(m
mol/
L)
Patient A
36
72
108
144
180
216
252
288
324
BG
(mg/d
L)
Mean BG ≈ HbA1c 7.8%
(61.7 mmol/mol)
Patient B
Low variability
High variability
8
0
Hyperglycaemia
Glycaemic control: similar HbA1c, different profile
Image adapted from Penckofer et al. Diabetes Technol Ther 2012;14:303–10; Vora & Heise. Diabetes Obes Metab 2013;15:701–12
Hypoglycaemia
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 23 24 22 Time (hours)
Mean BG ≈ HbA1c 7.8%
(61.7 mmol/mol)
Low variability
High variability
36
72
108
144
180
216
252
288
324
BG
(mg/d
L)
0 0
6
2
4
10
12
14
16
18
BG
(m
mol/
L)
8
Patient A Patient B
The relationship between glycaemic variability and hypoglycaemia is established
Bode et al. Diabetologia 2013;56(Suppl. 1):S423
Outline
Introduzione: obiettivi della terapia insulinica nel paziente diabetico anziano
Associazione tra ipoglicemie, variabilità glicemica ed outcomes Importanza del controllo glicemico post-prandiale Approccio fisiopatologico alla PPG: insulina Faster Aspart Approccio fisiopatologico alla FPG: insulina Degludec Nuovi approcci terapeutici nel fallimento da BOT: IDegLira
Postprandial spikes in glucose are part of the normal physiological process…
PPG, postprandial glucose Schematic representation. Adapted from Monnier L & Colette C. Diabetes Metab 2015;41:179–182
Breakfast Lunch Dinner
Glycaemia (mmol/L; mg/dL)
Prep
ran
dia
l g
lycaem
ia F
PG
Postprandial glycaemia
Normal
4 h 4 h 4 h
Prep
ran
dia
l g
lycaem
ia
Prep
ran
dia
l g
lycaem
ia
Physiological exposure
…BUT in diabetes are greater and of longer duration
PPG, postprandial glucose Schematic representation. Adapted from Monnier L & Colette C. Diabetes Metab 2015;41:179–182
Breakfast Lunch Dinner
Glycaemia (mmol/L; mg/dL)
Postprandial glycaemia
Diabetes
Normal
4 h 4 h 4 h
Prep
ran
dia
l g
lycaem
ia
Prep
ran
dia
l g
lycaem
ia
Physiological exposure
Overall glucose exposure in people with diabetes • Basal hyperglycaemia • Postprandial
hyperglycaemia
Postprandial hyperglycaemia
PPG increment: PPG peak–preprandial glycaemia
Prep
ran
dia
l g
lycaem
ia F
PG
Basal hyperglycaemia
The association between postprandial blood glucose and cardiovascular mortality
CVD, cardiovascular disease; PPG, postprandial blood glucose 1. DECODE Study Group. Lancet 1999;354:617–621; 2. Cavalot F et al. J Clin Endocrinol Metabol 2006;91:813–819; 3. Shaw JE et al. Diabetologia 1999;42:1050–1054; 4. Tominaga M et al. Diabetes Care 1999;22:920–924; 5. Balkau B et al. Diabetes Care 1998;21:360–367; 6. Hanefeld M et al. Diabetologia 1996;39:1577–1583; 7. Barrett-Connor E et al. Diabetes Care 1998;21:1236–1239; 8. Donahue RP et al. Diabetes 1987;36:689–692
DECODE 19991
Pacific and Indian Ocean
19993
Funagata Diabetes Study
19994
Whitehall, Paris and
Helsinki Study 19985
Diabetes Intervention Study 19966
The Rancho-Bernardo
Study 19987
PPG
Honolulu Heart Program
19878
CVD death
San Luigi Gonzaga
Study 20062
1. Cavalot F et al. J Clin Endocrinol Metabol 2006;91:813–819; 2. Cavalot F et al. Diabetes Care 2011;34:2237–2243
• 529 (284 men and 245 women) consecutive type 2 diabetic patients1
• 77 events over 5 years1
• Multivariate analysis including HbA1c, pre- and postprandial glucose showed only post-lunch glucose to be predictive1
• Long-term follow up (14 years) confirms this evidence2
aMay lead to diabetic complications; bMay predispose to future CV events CV, cardiovascular; OGTT, oral glucose tolerance test; PPG, postprandial plasma glucose Ceriello A. Diabetes Technol Ther 2017 DOI: 10.1089/dia.2017.0135
“Recent evidences, however, suggest that the value of glycaemia at 1 h during an OGTT
is a stronger predictor for developing diabetes than the value at 2 h and that it is an
independent risk factor for CV disease.”
Outline
Introduzione: obiettivi della terapia insulinica nel paziente diabetico anziano
Associazione tra ipoglicemie, variabilità glicemica ed outcomes Importanza del controllo glicemico post-prandiale Approccio fisiopatologico alla PPG: insulina Faster Aspart Approccio fisiopatologico alla FPG: insulina Degludec Nuovi approcci terapeutici nel fallimento da BOT: IDegLira
Approaching the physiological insulin profile could improve PPG control
Promoted signal
+
-
Stimulatory
Inhibitory
Suppressed signal
Postprandial state
Rate of glucose
appearance
Rate of glucose
disappearance
PG
Endogenous insulin
Glucagon
+
-
-
+
Fat Muscle
Tissues
Liver
Glucose is primarily derived from the gut
Gut
Time (h)
Insulin a
ction (
at
mealtim
e)*
Exogenous insulin
-
Under-insulinisation of hepatic tissue results in insufficient
suppression of EGP
Fast-acting insulin
From the normal pancreas
‘Ultra-fast’ insulin
Regular human insulin
Ultra-fast insulin should:
• Better approach physiological insulin secretion
• Provide greater early suppression of EGP
Less suppression of EGP
EGP, endogenous glucose production; PG, plasma glucose; PPG, postprandial plasma glucose Adapted from: Aronoff et al. Diabetes Spectr 2004;17:183–90; Gerich et al. Diabet Med 2010;27:136–42; Home. Diabetes Obes Metab 2015;17:1011–20
La prima insulina Ultra-fast: Faster Aspart
*also known as nicotinamide – the amide form of vitamin B3 Adapted from Brange J et al. Diabetes Care 1990;13:923–954
Asp
Asp
Niacinamide*: modificatore dell’assorbimento
Responsabile dell’assorbimento più veloce
Arginina: potenziatore di stabilità
Aumenta la stabilità molecolare
Faster aspart vs. insulin aspart via sc injection
Twice as fast onset of appearance in the bloodstream
Two-fold higher insulin exposure within the first 30 min
74% greater insulin action within the first 30 min
Compared with insulin aspart, faster aspart has:
Pooled analysis of NN1218 trials 3887, 3888, 3889, 3891, 3921, 3978. Faster aspart, fast-acting insulin aspart; GIR, glucose infusion rate; IAsp, insulin aspart; sc, subcutaneous
Faster aspart Insulin aspart
0 30 60 Time (min)
0
50
100
150
200
250
300
IAsp s
eru
m c
onc.
(pm
ol/
L)
9 4
0 30 60
GIR
(m
g/k
g/m
in)
0
2
4
6
8
Time (min) Heise et al. Clin Pharmacokinet 2017;56:551–9
PPG control with mealtime faster aspart Standardised meal test: mealtime comparison
Faster aspart (mealtime) Insulin aspart (mealtime)
*p<0.0001; P-values are 2-sided. ETD represents PPG changes from baseline estimates. Changes from baseline in PPG increments were analysed based on an ANOVA model.
0
18
36
54
72
90
108
126
0
1
2
3
4
5
6
7
0
Week 26
PPG
incre
ment
(mg/d
L)
Time (min) Bolus dose 0.1 U/kg
PPG
incre
ment
(mm
ol/
L)
0 60 120 180 240
108
126
72
90
36
54
18
0
6
7
4
5
2
3
1
0
PPG
incre
ment (m
g/d
L)
2-h ETD**: –0.67 mmol/L [95% CI: –1.29; –0.04] –12.0 mg/dL [95% CI: –23.3; –0.7]
**
1-h ETD*: –1.18 mmol/L [95% CI: –1.65; –0.71] –21.2 mg/dL [95% CI –29.7; –12.8]
*
**p=0.0375.
aCompared with mealtime insulin aspart. ANOVA, analysis of variance; CI, confidence interval; ETD, estimated treatment difference (faster aspart–insulin aspart); PPG, postprandial plasma glucose
Error bars: ± standard error (mean). *p<0.0001; **p=0.0375.
Russell-Jones et al. Diabetes Care 2017;doi:10.2337/dc16-1771
0
10
20
30
40
50
60
70
80
Week 26 Week 52
Severe
or
BG
-confirm
ed h
ypogly
caem
ic
epis
odes p
er
patient-
year
of exposure
NS
NS
Week 261 Week 522
Estimated ratio
95% CI Estimated
ratio 95% CI
Faster aspart (mealtime)/ insulin aspart (mealtime)
1.01 0.88;1.15 1.01 0.88;1.15
Faster aspart (post-meal)/ insulin aspart (mealtime)
0.92 0.81;1.06 n/a n/a
The analysis was based on a negative binomial regression model. Treatment-emergent was defined as an event that has onset up to 1 day after last day of randomised treatment and excluding the events occurring in the run-in period. Estimated treatment ratios (faster aspart/insulin aspart) are presented with 95% CIs BG-confirmed: PG value <3.1 mmol/L (56 mg/dL) BG, blood glucose; CI, confidence interval; faster aspart, fast-acting insulin aspart; PG, plasma glucose; NS, non-significant
Treatment-emergent hypoglycaemia
Faster aspart (mealtime)
Insulin aspart (mealtime)
Faster aspart (post-meal)
1. Russell-Jones et al. Diabetes Care 2017;doi:10.2337/dc16-1771; 2. Mathieu et al. ADA 2017. Poster 992-P
NS
No difference in the overall rates of severe or BG-confirmed hypoglycaemia between treatment arms
SCHEDA TECNICA
Si può somministrare da 2 minuti prima del pasto a 20 minuti dopo
36
Early exposure glucose-lowering effect
Randomised, double-blind, two-period crossover
trial, 30 elderly (>65 years) and 37 younger adults
(18–35 years) with T1DM received single subcutaneous
faster aspart or IAsp dosing (0.2 U/kg) and underwent an
euglycaemic clamp (target 5.5 mmol/L) for up to 12 h
Faster aspart
Faster aspart, fast-acting insulin aspart; PPG, postprandial plasma glucose; T1D, type 1 diabetes
Effectively improved glycaemic control
No statistically significant difference in the overall rate of hypoglycaemia
Similar overall safety profiles, and as expected for insulin aspart
Has the potential to improve postprandial glucose control over current rapid-acting insulin analogues in elderly patients with diabetes
Russell-Jones et al. Diabetes Care 2017;doi:10.2337/dc16-1771; Mathieu et al. ADA 2017. Poster 992-P
Outline
Introduzione: obiettivi della terapia insulinica nel paziente diabetico anziano
Associazione tra ipoglicemie, variabilità glicemica ed outcomes Importanza del controllo glicemico post-prandiale Approccio fisiopatologico alla PPG: insulina Faster Aspart Approccio fisiopatologico alla FPG: insulina Degludec Nuovi approcci terapeutici nel fallimento da BOT: IDegLira
Terapia insulinica basale
Borzì V, Il giornale AMD 2013: 16; 287-293
Insulin degludec IGlar U100
Type of insulin New-generation long-acting basal insulin analogue
First-generation basal insulin analogue
Mode of protraction
Forms soluble multihexamers Precipitates as microcrystals
Half-life ~25 hours ~12 hours
Day-to-day variability (AUCGIR,0–24h)
Coefficient of variation 20% Coefficient of variation 80%
AUCGIR, area under the curve for glucose infusion rate; IGlar U100, insulin glargine U100 Insulin glargine image data on file; Jonassen et al. Pharm Res 2012;29:2104–14; Heise et al. Expert Opin Drug Metab Toxicol 2015;11:1193–201; Heise et al. Diabetes Obes Metab 2012;14:859–64
Insulin degludec injected
Long multi-hexamers assemble
[ Phenol; Zn2+]
Insulin degludec from injection to depot
Phenol from the vehicle diffuses quickly, and degludec links up via
single side-chain contacts
L’insulina degludec un nuovo analogo, realizzato mediante la delezione del residuo Thr30
della catena B e l’aggiunta di una catena di acido grasso a 16 atomi di carbonio a livello di LysB29
Insulin degludec: slow release following injection
[Zn2+ ]
Insulin degludec
multi-hexamers
Zinc diffuses slowly causing individual hexamers to disassemble, releasing
monomers
Subcutaneous depot
Monomers are absorbed from the depot into the circulation
10
20
0
Gla-300 is a new long-acting basal insulin with a more even and prolonged PK/PD profile vs Gla-100®
Gla-300 Gla-100
Reduction of volume by 2/3
Reduction of depot surface by
1/2
Gla-300
Same amount of units
3
0
2
1
Gla-100
0 6 30 36
Insulin concentration, µU/mL
24 18 12
Gla-300
Gla-100
0 6 30 36
Glucose infusion rate (GIR), mg/kg/min
24 18 12
Gla-300
160
100
140
120
Gla-100
0 6 30 36
Time, h
Blood glucose, mg/dL
24 18 12
Gla-300
More even and prolonged
PK/PD profile
Gla-100
25
15
5
Steinstraesser A et al. Diabetes Obes Metab. 2014;16:873-6; Becker RHA et al. Diabetes Care. 2014 Aug 22. pii: DC_140006. [Epub ahead of print]
-75%
35% ipoglicemia grave
11% ipoglicemia totale
36% ipoglicemia notturna
46% ipoglicemia grave
30% ipoglicemia totale
42% ipoglicemia notturna
Ipoglicemia
51% nell’intero
periodo
RCP Degludec
46
7637 patients with type 2 diabetes
at high risk for cardiovascular events
Significant reduction of hypo and FPG with insulin degludec compared with IGlar U100
-40% -53%
-7.2 mg/dl
Impact of glycaemic variability on outcomes
in DEVOTE
Outcomes
Glycaemic variability
Hypoglycaemia
DEVOTE 2 Outcomes by variability tertile
0
1
2
3
4
5
6
Severe hypoglycaemia MACE All-cause mortality
Rate
(events
/100 P
YO
)
Zinman et al. Diabetologia 2017; doi:10.1007/s00125-017-4423-z
Low variability Medium variability High variability
DEVOTE 3 Explore the associations of severe hypoglycaemia with cardiovascular outcomes and mortality Risk of MACE and all-cause mortality following a severe hypoglycaemic event
Pieber et al. Diabetologia 2017; doi:10.1007/s00125-017-4422-0
Hazard ratio [95% CI]
Prior severe hypoglycaemia
No prior severe hypoglycaemia
N R N R
First 3-point MACE 1.38 [0.96; 1.96] 32 6.34 649 4.57
First 4-point MACE 1.37 [0.99; 1.91] 37 7.44 768 5.47
Individual components
Non-fatal myocardial infarction 0.74 [0.36; 1.49] 8 1.57 305 2.13
Non-fatal stroke 1.81 [0.92; 3.57] 9 1.76 141 0.97
Cardiovascular death (including unknown) 2.14 [1.37; 3.35] 21 4.05 257 1.76
Unstable angina requiring hospitalisation 1.34 [0.59; 3.04] 6 1.18 139 0.96
All-cause mortality 2.51 [1.79; 3.50] 38 7.32 385 2.64
Hazard ratio [95% CI]
Higher risk of MACE/all-cause mortality any time following severe hypoglycaemia
0,25 0,5 1 2 4
DEVOTE Conclusions:
• DEVOTE confirmed the cardiovascular safety of insulin degludec in comparison with insulin glargine (both U100)
• The rate of severe hypoglycaemia was significantly reduced with insulin degludec versus IGlar U100 in DEVOTE
• DEVOTE supports a clinical benefit of a basal insulin that has low day-to-day variability and therefore provides consistent fasting glycaemia
• DEVOTE is consistent with data demonstrating an association between severe hypoglycaemia and mortality
Marso et al. N Engl J Med 2017;377:723–32
N. Simioni. Diabetes Ther April 12, 2017
52 subjects (48.1% >75 years)
At discharge, 28.9% had BG at target(140-180 mg/dl), while
50.0% had lower levels (average 119.0 ± 14.4 mg/dl). The
incidence rate of hypoglycemia was 0.07 (0.05; 0.11) episodes
per person-day; 1 out of 27 episodes occurred during the night.
Outline
Introduzione: obiettivi della terapia insulinica nel paziente diabetico anziano
Associazione tra ipoglicemie, variabilità glicemica ed outcomes Importanza del controllo glicemico post-prandiale Approccio fisiopatologico alla PPG: insulina Faster Aspart Approccio fisiopatologico alla FPG: insulina Degludec Nuovi approcci terapeutici nel fallimento da BOT: IDegLira
ADA 2017 Guidelines
EMA e IDegLira
AIFA e IDeGlira
Categoria farmacoterapeutica: farmaci usati per il diabete.
Insuline e analoghi per iniezione, ad azione prolungata.
Codice ATC: A10AE56.
Combining therapies offers opportunities to enhance efficacy and diminish side effects
HbA1c FPG PPG Weight Hypoglycaemia
Basal insulin GLP-1 RA monotherapy
0
+
–
GLP-1 RA/insulin combined
Nausea
For illustrative purposes only, not drawn to scale FPG, fasting plasma glucose; PPG, postprandial glucose
• Subcutaneous injection
• 3-mL pre-filled pen
• Fixed ratio of insulin degludec (100 U/mL) and liraglutide (3.6 mg/mL)
1 U insulin degludec + 0.036 mg liraglutide
1 dose step
10 U insulin degludec + 0.36 mg liraglutide
10 dose steps
50 U insulin degludec + 1.8 mg liraglutide
50 dose steps
Insulin titration to achieve glycaemic control
One product with multiple mode of action or two products in one
Uncontrolled on basal insulin
IDegLira clinical development programme
• ext., extension; GLP-1 RA, glucagon-like peptide-1 receptor agonist; IDeg, insulin degludec; IDegLira, insulin degludec/liraglutide; IGlar U100, insulin glargine U100; OAD, oral antidiabetic drug; SU, sulphonylurea; SGLT2i, sodium glucose co-transporter-2 inhibitor
• www.clinicaltrials.gov. Last accessed April 2017
Uncontrolled on OADs Uncontrolled on GLP-1 RA
DUAL VIII Durability of IDegLira vs. IGlar U100 as add-on to OAD
Completed trials
DUAL II
IDegLira compared with IDeg in patients previously treated with basal insulin
DUAL V IDegLira vs. basal insulin optimisation
DUAL IX IDegLira add-on to SGLT2i vs. IGlar U100
DUAL I and ext.
IDegLira compared with its mono- components, added on to OAD(s)
DUAL IV IDegLira add-on to SU vs. placebo
DUAL III Switch to IDegLira from (daily) GLP-1 RA therapy vs. unchanged therapy
DUAL VI Easy titration Once- vs. twice-weekly titration
DUAL VII IDegLira vs. basal–bolus
Ongoing
The DUAL clinical programme Summary of key clinical findings
Across all seven studies, IDegLira decreased mean HbA1c to below 7% (6.0–6.9%)
IDegLira resulted in weight loss after basal insulin and was either weight neutral (±0.5 kg) or resulted in weight loss after OAD(s)
IDegLira resulted in a low risk of hypoglycaemia (0.16–3.5 events/PYE)
These results were achieved with once daily injection of IDegLira
IDegLira, insulin degludec/liraglutide; OAD, oral antidiabetic drug; PYE, patient-year of exposure Gough S et al. Diabetes Obes Metab 2015;17:965–73; Buse J et al. Diabetes Care 2014;37:2926–33. Linjawi et al. Diabetes Ther 2017;8:101-114. Rodbard HW et al. Diabet Med. 2017 Feb;34(2):189-196. Lingvay et al. JAMA 2016;315:898-907. Harris et al. Diabetes Obes Metab. 2017 Jun;19(6):858-865. Billings et al. ADA 2017;136-OR
HbA1c