the pivotal role of basal insulin replacement in the ... · initiation of basal insulin is usually...
TRANSCRIPT
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.
Hb
A1
cc
ha
ng
es
(%
)
TTT1 LANMET2 APOLLO3 LAPTOP4 Triple Therapy5 INITIATE6
Baseline Study endpoint (after insulin glargine treatment)
10
45
0
10
20
30
40
50
0 2 4 6 8 12 18 24 weeks
Units : Starting dose 10 units
To
tal D
aily
Do
se
(u
nits)
Both Treatment Groups
0
2.7
5.5
8.3
11.1
8.6
6.9
6.5
7.0
7.5
8.0
8.5
9.0
HbA1c
%
FBG
mmol/l
6.5
11
Rosenstock J, et al. Diabetes. 2001;50(suppl 2):A520.
Proof of Concept: Initial Report on the Treat To Target Study
Combination Oral Agents + Glargine vs NPH
0.4-0.5 units/Kg
titration of basal insulin in practice
• prefer semplicity, safety, empowerment
of patients
measure fasting BG every morning,
after 3 days take the mean/median:
if BG is >110 mg/dl, add 2 U
if BG = 110 mg/dl, continue same dose
if BG is <110 mg/dl, decrease 2 U
Educate a nurse
Answer telephone, use telemedicine
No need for patient to come to the clinic
1. Riddle M et al. Diabetes Care 2003;26:3080–862. Janka H et al. Diabetes Care 2005;28:254–259
3. Rosenstock J et al. Diabetes Care 2006 4. Gerstein HC et al. Diab. Med. 2006
5. Rosenstock J et al. Diabetologia, 2008
Basal + OHA studies in Type 2 DM
TTT2003
Triple Therapy2006
Rosenstock2008
Glargine
Comparator
Insight2005
0
10
20
30
40
50
60
70
Laptop2005
% o
f p
atie
nts
wh
o d
o
no
t re
ach
tar
get
A1
c
after intensive treatment and near-normal fasting PG,
it is post-prandial hyperglycaemia the cause
of A1C >7.0%
Woerle JH et al, Diab Res Clin Pract, 2007
A1C 7.60.1
A1C 6.20.4
relative contribution of post-prandial
hyperglycemia to A1C
Woerle JH et al, Diab Res Clin Pract, 2007
Diabetes Care, Diabetologia. 19 April 2012
Beyond basal Insulin in T2 DM
Insu
lin
Eff
ect
meal mealmeal bedtime
basal
• lispro• aspart• glulisine
• or GLP-1 RA
{
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 Subjects
Meals
30-60 pmol/l
5-10 mU/L
Ideal Basal Insulin
• Flat PK/PD, long (24 h and a little beyond) –
mimicking CSII*
• Low within-subject, within-day and day-to-day
variability
• Flexible dosing
• Available to all patients at a sustainable price
*CSII: continuous subcutaneous insulin infusion
basal insulin preparations
➢NPH
➢Gla-100 (and biosimilars, copies outside EU/USA)
➢Detemir
➢Degludec
➢Gla-300
21
NPH Insulin needs resuspension
prior to injection
NPH Insulin needs resuspension prior to injection
95
150
205
95
150
205
Pla
sm
a G
luc
os
e
mg
/dl
NPH
0 2 4 6 8 10 12 14 16 18 20 22 24
1
2
3
4
0
Time (hours)
Glu
co
se
Infu
sio
nR
ate
mg
/Kg
/min INSULIN ACTION
Subjects with Type 1 DMMean±SE
NPH
basal insulin
s.c. injection
Rossetti P. et al., Arch. Physiol. Biochem., 114:3-10, 2008
Limitations of NPH
NPH limitations
• peak at 4-6 hours post-injection (riskhypoglycaemia)
• Day-to-day high variability in PK/PD ifnot properley re-suspended
Variability of NPH Insulin
in Type 1 Diabetes
O R+
▼R- down
▲R- up
■R- horizontal
Lucidi P. et al., Diabetes Care 2015
Within subjects C.V.
62%
Variability of NPH Insulin
in Type 1 Diabetes
O R+
▼R- down
▲R- up
■R- horizontal
Lucidi P. et al., Diabetes Care 2015
Within subjects C.V.
62%
NPH limitations
• peak at 4-6 hours post-injection (riskhypoglycaemia)
• Day-to-day high variability in PK/PD ifnot properley re-suspended
the insoluble NPHshould not be used,
neither the pre-mixed
Never in type 1 DM
Neither in type 2 DM
prefer alternatives(soluble insulins)
NPH in vials and cartridgesLucidi P. et al.,
Diabetes Metab, 2017
Re-suspended
Not re-suspended
Not re-suspended
95
150
205
95
150
205
Pla
sm
a G
luco
se
mg
/dl
glargine
detemir
NPH
0 2 4 6 8 10 12 14 16 18 20 22 24
1
2
3
4
0
Time (hours)
Glu
co
se
Infu
sio
nR
ate
mg
/Kg
/min INSULIN ACTION
Subjects with Type 1 DMMean±SE
NPH
glarginedetemir
basal insulin
s.c. injection
Rossetti P. et al., Arch. Physiol. Biochem. 2008
physiology
0
0.2
0.4
0.6
0.8
1
1.2
1.4
20 21 22 23 24 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Time of day
Glargine
NPHInsulin
injection
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)
N of studies 5 3
N of participants 3372 2496
Definition of confirmed <3.1 mmol/L ≤3.9 mmol/L
hypoglycemia or severe or severe
Rate Ratio (95% CI)
Anytime events 0.83 (0.74-0.94 0.86 (0.77-0.97)
Nocturnal events 0.68 (0.57-0.82) 0.69 (0.57-0.84)
With both new insulins, ~15% fewer overall and ~30% fewer nocturnal events
QUESTION in year 2017
difference between IDeg and Gla-U300
degludec vs glargine U-300acylated, forms multihexamers s.c. iso-electic pH, precipitates s.c.
longer? Half-life 18 h
Titration time: similar
Flexibility: similar
A1C lowering: similar
Risk Reduction Hypoglycemia: similar
? Variability ?
COST: different
Head-to-head studies needed
PK and PD of clinical doses ofGla-300 vs Gla-100 in type 1 DM (N=18)
Porcellati F et al.,
Diabetes 2017 (abs)
Head-to-head trial in T2DM:Gla-300 vs. IDeg
Outcomes: HbA1cHypoglycemia
24-week, multicenter, randomized, open-label, parallel-group study
ClinicalTrials.gov. NCT02738151. Available at: https://clinicaltrials.gov/ct2/show/02738151. Last accessed September 2017.
Heise T et al., Diabetes Obes Metab 2017
0.4 U/kg fixed dose 1/day for 12 days (evening)
Gla-300 vs IDegl in type 1 diabetes mellitusGIR (insulin activity)
Heise T et al., Diabetes Obes Metab 2017
Lower variability of IDegl explained by failure of the
clamp which is not euglycemic with Gla-300
Heise T et al., Diabetes Obes Metab 2017
Lower within-day variability of GIR profiles with Gla-300 vs
IDeg-100 at 0.4 U/kg/day
For GIR data a smoothing factor (LOESS factor 0.15) was applied.
CI, confidence interval; GIR, glucose infusion rate; GIR-smFL0–24, fluctuation of the smoothed GIR curve over 24 hours
Results
• Within-day variability of the smoothed GIR (GIR-smFL0–24) was significantly lower (20%)
with Gla-300 vs Deg-100 at the 0.4 U/kg/day dose
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
0 2 4 6 8 10 12 18 20 22 24 26 28 30 16 14
Me
an
GIR
(m
g/m
in/k
g)
Gla-300 (0.4 U/kg)
Deg-100 (0.4 U/kg)
Time after dosing on day 8 (h)
GIR-smFL0–24 treatment ratio
0.80 (90% CI: 0.66 to 0.96)
p=0.047
Bailey T et al., in preparation 2017
0.4 U/kg fixed dose 1/day for 8 days (morning)
CONCLUSIONS
• The new insulins IDeg and Gla-U300 have the potential of more
physiological PK/PD vs Gla-100 and detemir
• They are indicated especially in Type 1 DM (total B-cell failure)
however…
• We need more experience in its use, to get the benefits and
avoid the risks for patients (hypoglycemia from prolonged
fasting, exercise)
• We also need more studies head-to-head in Type 1 DM to
understand differences and similarities
• A new approach to compare Gla-300 to IDeg at clinical doses in
individual patients (cross-over study) is underway
IN T2 DMUSE BASAL INSULIN…
…according to the rule of the
5 M
• MORE (in more patients)
• MORE EARLY (at diagnosis, or shortly after)
• MORE PHYSIOLOGICALLY (prefer basal insulin first, add prandial later as needed – do not mix…)
• MORE AGGRESSIVELY (treat to target) and
• MORE SAFELY (minimize hypoglycaemia)
IN T2 DM, USE BASALINSULIN…
INSULIN…
…a natural hormone created by Nature, not by drug companies !!!
…exactly what it is missing in people with diabetes!!!
THANK YOUfrom Torgiano!