Geremia B. Bolli Department of Medicine Perugia University Medical School, Italy, EUROPE 31st Panhellenic Annual Congress of the Hellenic Association for the Study & Education of Diabetes Mellitus Thessaloniki, 9 November 2017 THE PIVOTAL ROLE OF BASAL INSULIN REPLACEMENT IN THE TREATMENT OF DIABETES MELLITUS
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THE PIVOTAL ROLE OF BASAL INSULIN REPLACEMENT IN THE ... · Initiation of basal insulin is usually delayed Freemantle et al. DOM 2012;14:901-909; Zilov AV, et al. Diabetes 2011;60
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Geremia B. BolliDepartment of Medicine
Perugia University Medical School, Italy, EUROPE
31st Panhellenic Annual Congress of the Hellenic Association
for the Study & Education of Diabetes Mellitus
Thessaloniki, 9 November 2017
THE PIVOTAL ROLE OF BASAL INSULIN REPLACEMENT
IN THE TREATMENT OF DIABETES MELLITUS
Geremia B.Bolli
CONFLICT OF INTERESTover past two years
Sanofi
Eli Lilly
Menarini
agenda
➢Fasting and inter-prandial plasma glucose
concentration as major determinant of mean daily
glycaemia and A1C
➢Role of basal insulin
➢Type 2 diabetes as endocrine disease with insulin
deficiency
➢How to replace and titrate basal insulin as early as
possible
➢Insulin preparations
3
Glu
co
se
(m
mo
l/l) 9.0
5.0
160
0
7.0
320
480
Ins
ulin
(p
mo
l/l)
Mean ± 2SD
0700 1200 1800 2400 0600 hrs
Normal SubjectsMeals
Ciofetta M. et al., DIabetes Care 22:795-800, 1999
Physiology of Glucose Homeostasis known only since 1980
4 h 5 h 9 h total 18 hPG controlby basalinsulin
ADA-EASD 2015
\
???
Natural history of Type 2 DM
NGT IGT/IFG T2D
Diet OHGAs OHGAs
+ Insulin
Insulin sensitivity remains low
Time (years)IFG: Impaired fasting glucose; IGT: Impaired glucose tolerance;
NGT: Normal glucose tolerance; OHGA: Oral hypoglycaemic agent.
Initiation of basal insulin is usually delayed
Freemantle et al. DOM 2012;14:901-909;
Zilov AV, et al. Diabetes 2011;60 (Suppl.1):2485
Use of insulin is delayed until 7–15 years from diagnosis,when HbA1c is 9.0–10.3%
0 4 8 16 years
Japan
Eastern Europe
Southern Europe
Canada
South Asia
East Asia
China
Middle East
North Africa
Latin America
Northern Europe
N=511
N=252
N=1032
N=1073
N=460
N=735
N=3623
N=11971
N=21107
N=9062
N=9493
9.9%
9.3%
9.0%
9.3%
9.1%
9.7%
9.6%
9.5%
10.3%
9.5%
9.5%
A1c
6.7
7.9
10.2
9.0
8.0
12.0
12.0
11.4
15.5
11.0
12
12.5
Start of therapy with basal Insulins
Caratteristiche Media±ds
o %
Età (anni) 62.1±11.2
Maschi (%) 53.4%
Durata diabete (anni) 10.9±8.3
BMI (Kg/m2) 29.3±5.4
HbA1c (%) 8.9±1.6
HbA1c <=7% (%) 11.5%
HbA1c >8% (%) 68.6%
Pressione sistolica (mmHg) 140±20
Pressione diastolica (mmHg) 79±10
Colesterolo totale (mg/dl) 186±43
Colesterolo HDL (mg/dl) 48±13
Colesterolo LDL (mg/dl) 106±35
Trigliceridi (mg/dl) 166±129
Caratteristiche dei pazienti per cui è stata avviata una terapia con analoghi lenti dell’insulina.
Combinazioni di farmaci Tutti
(%)
HbA1c
<=7.0%
(%)
HbA1c
>7.0%
(%)
Insulina+Metformina+SU 47.9 28.6 52.2
Insulina+Glinidi 12.5 16.6 10.7
Insulina+Metformina 11.2 17.2 9.5
Insulina+Metformina+Glinidi 6.9 6.0 7.0
Insulina+SU 6.6 6.8 6.6
Insulina 5.2 16.7 3.7
Insulina+Metformina+SU+Glinidi 1.6 1.5 1.7
Insulina+Metformina+SU+Acarbose 1.6 0.8 1.8
Insulina+Metformina+SU+DPP-IV 1.1 1.1 1.1
Pattern terapeutici più utilizzati al momento dell’avvio della terapia con analoghi lenti dell’insulina.
• Durante l’intero periodo di osservazione 2004-2011, un totale di 57.920 pazienti precedentemente in terapia con ipoglicemizzanti orali hanno avuto un cambiamento della terapia ed inizio di insulina.
• i pazienti passati da terapia orale ad insulina basale sono relativamente giovani e con una durata media di malattia di 10.9 anni. È da notare che al cambio di terapia quasi il 70% dei pazienti presentava valori di HbA1c maggiori di 8.0%, mentre un decimo presentava valori <=7.0%.
• Il 53.8% presentava valori >8% un anno prima del cambio di terapia e il 47.3% già due anni prima.
• Anche dopo l’inizio della terapia insulinica la metformina e i farmaci secretagoghi rimangono i farmaci più utilizzati .
• L’analisi dei pattern prescrittivi mostra come in quasi la metà dei casi l’utilizzo di analoghi lenti avvenga in concomitanza con terapia dual oral (metformina + secretagogo), mentre più raramente si associa a tripla terapia orale
Le Monografie degli Annali AMD : focus su «Cambiamento delle terapie» Cimino et al.2013
24-Hour Plasma Glucose in failure to OHA
Time of Day
22.2
16.6
11.1
5.5
0
0600 06001000 1400 1800 2200 0200
courtesy of Jay Skyler
adapted from Polonsky et al, N Engl J Med 1988
Glucose
(mmol/L)
Diabetic
T2
Normal
Effect of treatment with basal insulin
6
7
8
9
0 4 8 12 16 20 24
Weeks of treatment
8.6 8.6
6.9, 6.9 %
Mean A1c%
58% ≤ 7%
Riddle MC et al. Diabetes Care 2003;26: 3080-86
NPH vs glargineThe Treat-to-Target Trial
Glargine NPH
Consistent achievement of A1C 7.0%
with basal insulin
1. Riddle M, et al. Diabetes Care 2003;26:3080–6. 2. Yki-Järvinen H, et al. Diabetes Care 2006;49:442–51.3. Bretzel RG, et al. Lancet 2008;371:1073−84. 4. Janka H, et al. Diabetes Care 2005;28:254−9.
5. Rosenstock J, et al. Diabetes Care 2006;29:554–9. 6. Yki-Järvinen H, et al. Diabetes Care 2007;30:1364–69.
NPH vs glargineHypoglycemia by time of day in the Treat-to-Target Trial
Confirmed events per patient-year
*
*
*
*
*
*
*
* p <0.05
Riddle MC et al. Diabetes Care 2003;26: 3080-86
Riddle MC et al. Diabetes Care 2003;26: 3080-86
Events per pt-yr confirmed < 4 mmol/L
NPH Glargine % lower
Anytime of day-night 12.9 9.2 29
Nocturnal 5.5 3.1 44
Events per pt-yr confirmed < 3.1 mmol/L
NPH Glargine % lower
Anytime of day-night 5.1 3.0 41
Nocturnal 2.5 1.3 48
NPH vs glargineThe Treat-to-Target Trial
basal insulin preparations
➢NPH
➢Gla-100 (and biosimilars, copies outside EU/USA)
➢Detemir
➢Degludec
➢Gla-300
31
questions
➢Why new basal insulins?
➢How do they work?
➢What benefit for the patient?
➢Which one is the best?
32
NH
O
OH
O NH
O
OH
OHexadecandioyl
L-γ-Glu
desB30 Insulin
Glutamic acid ‘spacer’
C16 Fatty diacid side chain
DesB30
Thr
Des(B30) LysB29(γ-Glu Nε-hexadecandioyl) human insulin
Insulin Degludec Molecular Structure
s
A1
B1
A21
s s
s
s
s
T YG EE CYCC NLQLSISQVI NC
PTYY FFF GGG REE CC VLLAVLHSLHQNV Lys
Jonassen I et al. Pharm Res 2012 (DOI 10.1007/s11095-012-0739-z)
B29
Insulin Degludec: Mode of Absorption
Jonassen I et al. Pharm Res 2012 (DOI 10.1007/s11095-012-0739-z)
Heise T et al, Expert Opin Drug Metab Toxicol 2015
PD of acylated insulin Degludec vs Gla-U100
Glargine Gla300
a new version of Gla100
Gla300Gla100
Reduction of volume by 2/3
Reduction of depot surface by 1/2
Gla300
Same amount of units
Gla100
32
*red3 2
preredprered ))(6.3
(36)(*36**)(
cF
tPkVkSAk
dt
tdP
Reinhard Becker
PK/PD of Gla-U300 vs Gla-U100
Becker RHA et al, Diabetes Care 2015
basal insulin preparations
➢NPH
➢Gla-100 (and biosimilars, copies outside EU/USA)
➢Detemir
➢Degludec
➢Gla-300
38
IDeg and Gla-300, when compared to Gla-100, both:• Are non-inferior (A1C lowering)• Reduce the risk for hypoglycemia (primarily nocturnal) because of flatter action profile
Hypoglycemia with degludec and glargine U-300
compared with glargine U-100 (courtesy of Matt Riddle)
Ratner RE et al. Diab Obes Metab 2013;15: 175-184 Ritzel R et al. Diab Obes Metab 2015;17: 859-867
Meta-analyses of phase 3 clinical studies of type 2 diabetes
Degludec (Ratner et al) Glargine U-300 (Ritzel et al)