avances en insulinoterapia dr paz 2014
TRANSCRIPT
JOSE LUIS PAZ IBARRA ENDOCRINOLOGO UNMSM – HNERM
24 Feb 2014
XII Congreso Internacional “TERAPÉUTICA MÉDICA Y QUIRÚRGICA” Cuerpo Médico del Hospital Nacional “Dos de Mayo” 140 Natalicio del Dr. Guillermo Gastañeta Espinoza
24, 25 y 26 Febrero 2014
¿Por Qué debemos Prevenir/Tratar la DM2 ?
Prevención de Complicaciones Micro Vasculares • Retinopatía - Nefropatía - Neuropatía
Prevención de Complicaciones Macro Vasculares • Cardiopatía (Enfermedad Coronaria, IC) • ACV y EVP
Cambiar la Historia Natural de la Diabetes y ECV • Reducir la Resistencia a la Insulina • Mejorar la función de los islotes/Preservar una adecuada masa de las celulas β • Tratar las Co-morbilidades
Mejorar la calidad de vida y prolongarla • Control de síntomas •Disminuir la carga económica de la Diabetes • Disminuir la polifarmacia • Reducir la Mortalidad ¿? Pre-diabetes: Clinical Relevance and Therapeutic Approach
Pratley R, et al / Br J Diabetes Vasc Dis 2007; 7 (3): 120
Impacto de la Terapia Intensiva para DM: Estudios Clínicos
Estudio Microvasculars CVD Mortalidad
UKPDS
DCCT / EDIC*
ACCORD
ADVANCE
VADT
Long Term Follow-up
Initial Trial
* in T1DM
Kendall DM, Bergenstal RM. © International Diabetes Center 2009 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545. Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum: Moritz T. N Engl J Med 2009;361:1024)
A medida que la enfermedad progresa resulta más desafiante lograr que los pacientes alcancen la meta
Lebovitz HE. Med Clin N Am. 2004;88:847–863; Turner RC y cols. JAMA. 1999;281:2005–2012; UKPDS 16. Diabetes. 1995;44:1249–1258; Warren RE. Diabetes Res Clin Pract. 2004;65:S3–S8; Resnick HE y cols. Diabetes Care. 2006;29:531–537; Koro CE y cols. Diabetes Care. 2004;27:17–20.
100
0
Funció
n d
e las c
élu
las β
(%)
-10 0
Diagnóstico de diabetes
Esquema basado en
Insulina
Requieren insulina
Fracaso de la monoterapia
Combinación
con Múltiples Fármacos
+/– Insulina
Tiempo aproximado (años)
Esquema
Dos Fármacos
Monoterapia
80
60
40
20 Prediabetes Diabetes
10–20
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
(Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)
ADA / EASD 2012
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Esquema Basal Bolo (Adicionar Insulina Prandial antes de las comidas)
Esquema Basal Plus (Adicionar Insulina Prandial en la Comida Principal)
Esquema Basal (Adicionar Insulina Basal y Titular)
Cambios de los Estilos de Vida + MTF (± otros agentes)
Optimizando la Insulinoterapia para Mantener el Control Glicémico cuando la Basal No es Suficiente
Basal + Inhibidores DPP4
o
Análogos de GLP1
Inhibidores SGLT2
Hitos en el desarrollo de la Insulina
Withdrawn.
Tattersall RB. In: Pickup JC, Williams G, eds. Textbook of Diabetes. 3rd ed. Blackwell Science: Malden, MA; 2003:1.1-1.22;
Drugs@ FDA; Bailey CJ, Barnett AH. BMJ. 2007;335:1156.
1920 1930 1940 1960 1970 1980 2000 2010 1990 1950
Insulin discovered (1921)
First human treatment with bovine insulin (1922)
Protamine and protamine zinc insulins developed (1936)
NPH insulin developed (1946)
Lente (zinc) insulins developed (1952)
Recombinant human insulin developed (1979)
Insulin pump developed (≈ 1978)
Insulin pen developed (1981)
Insulin lispro approved in US (1996)
Insulin aspart and insulin glargine approved in US (2000)
Insulin glulisine approved in US (2004)
Insulin detemir approved in US (2005)
Inhaled insulin developed (2006)
Tipos de Insulina
•Insulinas Humanas:
•Neutral protamine Hagedorn (NPH)
•Regular
•Pre-mezclas
•Análogos de Insulina
•Análogos Basales (glargina, detemir)
•Análogos ultra-rapidos (lispro, aspart, glulisina)
•Pre-mezclas
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Formulaciones de Insulina Basales en Investigación
Farmacocinética de Insulina Glargina U-300a en Voluntarios Saludables
a U-300 insulin glargine is not FDA approved for clinical use. Becker R, et al. European Patent EP 2 387 989 A2. 2011.
U-100 0.4 U/kg (n = 24)
U-300 0.4 U/kg (n = 23)
35
30
25
20
15
10
5
0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Co
nce
ntr
atio
n (
uIV
/mL)
Time
Nueva Formulación de Insulina GLAR-300a vs. GLAR-100 en Pacientes en Insulina
Basal Plus Mealtime
Noninferior A1C change for GLAR-300 vs GLAR-100 (both groups, -0.83%)
No between-group differences in adverse events
Significantly fewer with nocturnal hypoglycemia (≥ 1 severe or confirmedb) with GLAR-300 (graph)
45.5
36.1
0
20
40
60
80
100
Seve
re o
r co
nfi
rme
d
no
ctu
rnal
hyp
ogl
yce
mia
, %
GLAR, glargine. a GLAR-300 is not FDA approved for clinical use. b Confirmed hypoglycemia, ≤ 70 mg/dL. Riddle M, et al. ADA 73rd Scientific Sessions. 2013;43-LB.
GLAR-100 (n = 403)
GLAR-300 (n = 404)
RR 0.79 (CI, 0.67-0.94) P = .0070
Insulina Lispro PEGylada
• Delayed insulin absorption • Reduced clearance
Análogos de Insulina Basales en Investigación
a Polyethylene glycol (PEG)
group may be attached at any of 3 points.
Jonassen I, et al. Pharm Res. 2012;29:2104-2114.
Beals JM, et al. US Patent 2011/0105392 A1. May 5, 2011.
N6
O
CO2H
H HN O
HO2C
PEGa
PEGa
PEGa
Insulina Degludec • Dihexamers form soluble multihexamers after injection
• Multihexamers disassemble slowly
• Monomers are released rapidly after hexamers disassemble
Insulin association state
Rapid absorption Slow absorption
Insulin
Molecular size
Absorption
Zn2+
Capillary membrane
Subcutaneous tissue
36 kDa 6 kDa
Zn2+
Zn2+
72 kDa >5000 kDa
Absorption rate
Brange et al. Diabetes Care 1990;13:923–54
High molecular weight forms
Insulin degludec
injected
Long multi-hexamers assemble
Phenol Zn2+
As phenol from the vehicle diffuses degludec hexamers link up via single
side-chain contacts
Insulin degludec
multi-hexamers
Zinc diffuses slowly causing individual hexamers to disassemble, releasing
monomers
Subcutaneous depot Zn2+
Monomers are absorbed from the depot into the circulation
Media Armónica
(hs)
CV
(%)
Vida ½ Terminal (estado estable)
Degludec 24.5 23
Glargina 12.2 56
Relative serum IDeg trough concentrations during initiation of once-daily (0.4 U/kg) dosing in patients with T1DM
0 1 2 3 4 5 6 7 8 9 10 0
10
20
30
40
50
60
70
80
90
100
110
120
Days since first dose
Seru
m I
Deg c
oncentr
ation
Pro
port
ion o
f D
ay 1
0 level (%
)
Values are estimated ratios and 95% CI relative to day 10
Heise T et al. IDF 2011 21st World Congress Abstract Book. IDF: Dubai, 2011; Poster 1453
Absorción desde el depósito SC Activación del Receptor &
Depuración de insulina
Perfiles Farmacodinámicos Glargina vs Degludec
Clamp studies of patients with T1DM.
Curves shown are at steady state.
FDA Endocrinologic and Metabolic Drugs Advisory Committee Meeting.
FDA briefing document. UCM327015. November 8, 2012.
Glargine Degludec
• Peak effects earlier and slightly larger for glargine than degludec • Peak effects for glargine and degludec are dose-dependent
GIR
, mg/
kg/m
in
0
4
5
6
3
16 0 4 8 12 20 24
Time, h
2
1 GIR
, mg/
kg/m
in
0
4
5
6
3
16 4 8 12 20 24
Time, h
2
1
0
0.8 U/kg 0.4 U/kg 0.6 U/kg 0.8 U/kg 0.4 U/kg 0.6 U/kg
IDeg OD + metformin ± DPP-4 (n=773)
IGlar OD + metformin ± DPP-4 (n=257)
Insulin-naïve patients with type 2 diabetes
(n=1030)
0 52 weeks 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) Open label
DPP-4, dipeptidyl peptidase-4 inhibitor SU, sulphonylurea OD, once daily Data on file: NN1250-3579; Accepted for presentation at ADA 2012
Degludec QDa vs Glargina QD en Pacientes con DM2 Insulin-Naïve en 1 año
Similar A1C and weight changes -1.1% vs -1.2% (P = .40)
2.4 kg vs 2.1 kg (P = .28)
Similar overall hypoglycemia b 1.5 vs 1.9 events/y (NS)
Lower nocturnal hypoglycemiab with degludec QD (graph)
0.3
0.003
0.4
0.023
0.0
0.5
1.0
Nocturnal Severe
Hyp
ogl
yce
mia
, eve
nts
/y
DEG, insulin degludec; GLAR, insulin glargine; QD, once daily. a Insulin degludec is not FDA approved for clinical use. b Hypoglycemia, plasma glucose < 56 mg/dL or severe per ADA definition; nocturnal, occurring between 0100 h and 0559 h. Zinman B, et al. Diabetes Care. 2012;35:2464-2471.
DEG QD (n = 773; 0.59 U/kg)
GLAR QD (n = 257; 0.60 U/kg)
All P < .05
Degludec QD ó 3 veces/semana vs. Glargine QD en Adultos con DM2: Eficacia e Hipoglicemia en 16 ssa
Efficacy
-1.5 -1.3 -1.3
-1.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
ΔA
1C
(%
)
Hypoglycemia
2.3
0.2
0.1
0.6
0.1
0 0
.9
0.1
0
1.1
0
0
0
5
10
15
Confirmed Overall
Nocturnal Severe
Eve
nt
Rat
e (
EPY
)
a N = 245 (DEG 3TW, n = 62; DEG QD A, n = 60; DEG QD B, n = 61; GLAR
QD, n = 62); all patients treated with metformin (1500-2000 mg/d).
Hypoglycemia, plasma glucose < 56 mg/dL or severe per ADA definition. Zinman B, et al. Lancet. 2011;377:924-931.
8.6
%
8.7
%
8.7
%
8.8
%
BL
A
1C
DEG 3TW (3.4 U/kg) DEG QD A (3.1 U/kg)
DEG QD B (4.5 U/kg) GLAR QD (3.3 U/kg)
Patients with type 2 diabetes
(n=687)
0 26 weeks
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
Open label
Glargine OD ±OADs (n=230)
(metformin/SU/pioglitazone)
Degludec OD Fixed ±OADs (n=228)
(metformin/SU/pioglitazone)
Degludec OD Flexible ±OADs (n=229)
(metformin/SU/pioglitazone)
Birkeland et al. IDF 2011:P-1443; Bain et al. IDF 2011:O-0508; Birkeland et al. Diabetologia 2011;54(suppl. 1):S423; Atkin et al. Diabetologia 2011;54(suppl. 1):S53; Meneghini et al. Diabetes 2011;60(suppl. 1A):LB10 (NN1250-3668)
morning
Mon Tue Wed Thu Fri Sat Sun
morning morning
evening evening evening evening
40h 40h 40h
8h 8h
24h
8-12 AND 36-40 hours between insulin administration
Degludec QD Dosis Flexible vs Fija en Adultos con DM2:Eficacia e Hipoglicemia en 26 ssa
Efficacy
-1.3 -1.1
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
ΔA
1C
(%
)
Hypoglycemia
3.6
0.6
2
3.6
0.6
2
0
5
10
15
Confirmed Overall
Nocturnal Severe (episodes)
Eve
nt
Rat
e (
EPY
)
a N = 457; DEG OADs (not specified). FIXED, administered with evening meal daily; FLEX, administered 8-40 hours apart; hypoglycemia, plasma glucose < 56 mg/dL or severe per ADA definition. Birkeland KI, et al. EASD 2011. Abstract 1041.
8.4% 8.5% BL A1C:
FLEX QD (n = 229) FIXED QD (n = 228)
= 20-40 kDa PEG
PEG
PEG
0
1
2
3
4
5
0 2 4 6 8 10 12 14 16 18 20 22 24
Me
an
GIR
, m
g/m
in/k
g
0.33 U/kg 0.50 U/kg
0.67 U/kg 1.00 U/kg
a PEGylated insulin lispro is not FDA-approved for clinical use. Heise T, et al. Diabetes. 2012;61(suppl 1):A256 [abstract 1000-P].
Time, h
PEGLisproa vs. Glargine en Adultos con DM2 en 12 ss Patients with T2DM, 12 weeks
After adjusting for baseline rates, nocturnal hypoglycemia was 48% lower in the pegylated lispro group (P = .021)
EPY, events/patient-year; GLAR, insulin glargine; PEGL, pegylated
insulin lispro; QD, once daily.
2-period, phase 2 randomized trial. a PEGylated insulin lispro is not FDA approved for clinical use.
Hypoglycemia, plasma glucose ≤ 70 mg/dL or severe per ADA
definition. Bergenstal RM, et al. Diabetes Care. 2012;35:2140-2147.
Outcome PEGL QD
(n = 195; 0.59 U/kg) GLAR QD
(n = 93; 0.60 U/kg) P Value
∆A1C, % ‒0.7 ‒0.7 NS
∆Weight, kg ‒0.6 0.3 .001
Overall hypoglycemia, EPY 1.3 1.5 .804
Nocturnal hypoglycemia, EPY 0.3 0.4 .178
Severe hypoglycemia, no. of episodes
0 0
Contribución de la Glicemia de Ayuno vs. PP a la A1C: Antes & después de Insulina basal
Fasting hyperglycemia
Post-prandial hyperglycemia
Antes
Insulina Basal
Riddle, et al. Diabetes Care 2011; 34 (12): 2508-2514
Insulinas Prandiales en Investigación
Adición de Hialuronidasa a Insulina Acelera su absorción SC
Hyaluronidase is a naturally occurring enzyme
Temporarily degrades hyaluronan, a naturally
occurring space-filling gel-like substance that is a major
component of soft connective tissue such as skin
Facilitates penetration of drugs at the injection site
Natural and synthetic hyaluronidase formulations
are available
FDA-approved as adjuvants to increase the dispersion and
absorption of injected drugs
Transient locally acting permeation enhancers
Girish KS, Kemparaju K. Life Sci. 2007;80:1921-1943;
Drugs@FDA. Hyaluronidase.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021859s006lbl.pdf.
Efectos de la adición de Hialuronidasa Recombinante Humana en la farmacodinámica de Lispro
T1DM, 60 g CHO, n = 221,a T2DM, 80 g CHO, n = 212,b
Profiles obtained in liquid meal tests. a Identical insulin doses; b LIS, 0.275 units/kg; LIS + RHH, 0.254
units/kg + 5 mcg/mL; RHI + RHH, 0.288 units/kg + 5 mcg/mL.
1. Hompesch M, et al. Diabetes Care. 2011;34:666-668.
2. Hompesch M, et al. Diabetes Technol Ther. 2012;14:218-224.
RHH: bigger early peak effect, similar tail
Me
an B
loo
d
Glu
cose
, mg/
mL
SEM
80
140
160
120
240 0 60 120 180 420 480
Time from Injection, minutes
100
300 360
LIS
LIS + RHH
Me
an B
loo
d
Glu
cose
, mg/
mL
SEM
80
140
180
120
240 0 60 120 180 420 480
Time from Injection, minutes
100
300 360
160
RHH: slightly earlier peak, less tail
LIS
LIS + RHH
RHI + RHH
Hialuronidasa Recombinante Humanaa en Combinación con un análogo reduce GPP en DM1
a RHH is not approved for chronic administration with insulin.
Two-period, 12-week, double-blind, randomized crossover trial.
N = 117, all using BBT; solid lines, means; dashed lines, SEM. Hirsch IB, et al. Diabetes. 2012;61(suppl 1):A92 [abstract 353-OR].
Breakfast Lunch Dinner
40
0
-20
1 2 3
Time, h
Mea
l Exc
urs
ion
, m
g/d
L S
EM 20
4 0
40
0
-20
1 2 3
Time, h
Mea
l Exc
urs
ion
, m
g/d
L S
EM
-40
20
4 0
40
0
-20
1 2 3
Time, h
Mea
l Exc
urs
ion
, m
g/d
L S
EM
-40
20
4 0
LIS or ASP + RHH LIS Alone
LIS or ASP + RHH LIS Alone
LIS or ASP + RHH LIS Alone
Hialuronidasa Recombinante Humanaa en Combinación con un análogo reduce GPP en DM2
a RHH is not approved for chronic administration with insulin.
Two-period, 12-week, double-blind, randomized crossover trial.
N = 121, all using BBT; solid lines, means; dashed lines, SEM.
Bergenstal RM, et al. Diabetes. 2012;61(suppl 1):
A224 [abstract 882-P].
140
130
12 18 24
Time of Day
Blo
od
Glu
cose
, m
g/d
L S
EM
150
26 6
120
160
170
LIS or ASP + RHH
LIS Alone
Degludec-Asparta BID vs. Aspart Bifásico BID en DM2
a Degludec and degludec-aspart are not approved in the US. b Significantly different between groups. Niskanen L, et al. Eur J Endocrinol. 2012;167:287-294.
-1.8 -1.8
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
ΔA
1C
(%
)
2.9
0.4 0
7.3
1.1 0
0
5
10
15
Eve
nt
Rat
e (
EPY
)
BL A1C: 8.5% 8.6%
DEG 70/ASP 30 (0.57 U/kg) (n = 61) BIASP 70/30 (0.66 U/kg) (n = 62)
Hypoglycemia
b
Efficacy
DEG 70/ASP 30 vs BIASP 70/30 • A1C < 7% without hypoglycemia: 67% vs 40%b • Weight gain: 1.1 kg vs 1.4 kg
Degludec + Aspart BBT vs. Glargine + Aspart BBT en Adultos con DM2: Eficacia e Hipoglicemia Nocturna en 1 añoa
Efficacy
5.0
5.5
6.0
6.5
7.0
7.5
8.0
8.5
9.0
0 20 40 60
A1C
(%)
Time (Weeks)
DEG + ASP BBT (n = 744)
GLAR + ASP BBT (n = 248)
Nocturnal Hypoglycemia
0.0
0.5
1.0
1.5
2.0
0 20 40 60
Cu
mu
lati
ve N
oct
urn
al
Hy
po
gly
cem
ia (
EP
Y)
Time (Weeks)
DEG + ASP BBT (n = 753)
GLAR + ASP BBT (n = 251)
Nocturnal hypoglycemia, BG < 56 mg/dL from 12:00 AM to 5:59 AM.
Garber A, et al. Diabetes. 2011;60(suppl 1):A20 [abstr 74-OR].
Hollander PA, et al. EASD 2011. Abstract 1035.
P = .04
Adicionar Exenatide a Insulin Glargine mejora control en DM2
Buse, et al. Ann Intern Med. 2011;154:103-112. Rosenstock, et al. Diabetes Care 2012; 35(5):955-8. Epub 2012 Mar 19.
A1C 8.3-8.5%
Insulin 0.5 u/kg
BMI 33-34
-1.0% +20u +1.0kg
-1.7% +13u -1.8kg
Minor hypoglycemia 25% (EXE) vs 29% (PLB)
Longer diabetes duration and lower BMI had greater A1C reductions. Longer diabetes
duration also lost the most weight.
The use of IDegLira, a fixed-ratio combination of Liraglutide (Victoza) and insulin Degludec (Tresiba) in a single-injection delivery device (1 unit of insulin degludec is combined with 0.036 mg of liraglutide. The maximum doses available for the combination would include 50 units of degludec with 1.8 mg of liraglutide), in T2D patients inadequately controlled on basal insulin led to improved overall glycemic control, with significant weight loss, in the phase 3 DUAL II trial reported at the World Diabetes Congress 2013.
Importantly, there was no increased risk for hypoglycemia among those patients who received IDegLira compared with those who were randomized to insulin degludec alone, despite the former group having a significantly lower HbA1c level.
And the rate of nausea observed in those receiving IDegLira was low, at around 7%, vs. 4% among the insulin-only patients.
Conclusiones
Los Algoritmos ADA/EASD y AACE recomiendan el uso de Insulina si el objetivo glicémico no es alcanzado dentro del 1° año de Tto.
Los pacientes pueden auto-titular satisfactoriamente la insulina basal
La insulina basal es titulada hasta alcanzar una GPA objetivo
Los análogos de insulina basal proveen un perfil más fisiológico (tiempo-acción) que insulina NPH.
Insulina puede ser usada en combinación con otros agentes.
Considerar detener titulación de insulina basal si dosis es > 0.5 IU /kg/day o hay incremento de riesgo de hipoglicemia
Análogos emergentes tienen el potencial de mejorar la insulinoterapia por proveer perfiles (tiempo-acción) relativamente con menos picos y menores tasas de hipoglicemia
Conclusiones…
Análogos basales con duración de acción > 24 hs están en desarrollo.
Insulinas Degludec y PEGLispro demuestran perfiles farmacocinéticos relativamente sin picos
Datos disponibles para Degludec en pacientes con DM2 demuestran: Ninguna diferencia estadísticamente significativa en eficacia o
hipoglicemia con intervalos de dosis de 8-40 hs Menos variabilidad que Glargina Menor riesgo de hipoglicemia que Glargina cuando es usada como
componente del regimen BBT con aspart.
Datos disponibles para Degludec plus en pacientes con DM2 demuestra eficacia equivalente a, y menos hipoglicemia que aspart bifásica con dosis BID.
Uso combinado de análogos basales con análogos de GLP1 prometen un mejor control glicémico sin ganancia ponderal con esquemas simples.
Insulinas prandiales deben considerarse cuando los objetivos glicémicos no son alcanzados con la insulina basal.
Algunos pacientes pueden requerir insulina prandial solamente con su comida principal
Los regímenes Basal-bolo, basal plus 1, y pre-mezclas son efectivos
Los esquemas con pre-mezclas y basal bolo tienen mayores tasas de hipoglicemia.
El uso de hialuronidasa podrían permitir un control más efectivo de la GPP con menor tasa de hipoglicemia,
Conclusiones…
Gracias por su Atención