Avances en Insulinoterapia Dr Paz 2014

JOSE LUIS PAZ IBARRA
ENDOCRINOLOGO
UNMSM – HNERM
24 Feb 2014
XII Congreso Internacional “TERAPÉUTICA MÉDICAY 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 enfermedadprogresa resultamás
desafiantelograr que los pacientesalcancenla 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
Funcióndelascélulasβ(%)
-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

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 yTitular)
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 201019901950
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

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
Concentration(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
Severeorconfirmed
nocturnalhypoglycemia,%
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
HHN
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 kDa6 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
SerumIDegconcentration
ProportionofDay10level(%)
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/min
0
4
5
6
3
160 4 8 12 20 24
Time, h
2
1
GIR,mg/kg/min
0
4
5
6
3
164 8 12 20 24
Time, h
2
1
0
0.8 U/kg 0.4 U/kg0.6 U/kg 0.8 U/kg 0.4 U/kg0.6 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 weeksInclusion 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
Hypoglycemia,events/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
ΔA1C(%)
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
EventRate(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
A1C 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)
Degludec OD Flexible ±OADs (n=229)
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
ΔA1C(%)
Hypoglycemia
3.6
0.6
2
3.6
0.6
2
0
5
10
15
Confirmed
Overall
Nocturnal Severe
(episodes)
EventRate(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%BLA1C:
FLEX QD (n = 229) FIXED QD (n = 228)

0
1
2
3
4
5
0 2 4 6 8 10 12 14 16 18 20 22 24
MeanGIR,mg/min/kg
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 withT2DM, 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)
PValue
∆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
MeanBlood
Glucose,mg/mLSEM
80
140
160
120
2400 60 120 180 420 480
Time from Injection, minutes
100
300 360
LIS
LIS + RHH
MeanBlood
Glucose,mg/mLSEM
80
140
180
120
2400 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
MealExcursion,
mg/dLSEM
20
40
40
0
-20
1 2 3
Time, h
MealExcursion,
mg/dLSEM
-40
20
40
40
0
-20
1 2 3
Time, h
MealExcursion,
mg/dLSEM
-40
20
40
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
BloodGlucose,
mg/dLSEM
150
266
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
ΔA1C(%)
2.9
0.4 0
7.3
1.1
0
0
5
10
15
EventRate(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
CumulativeNocturnal
Hypoglycemia(EPY)
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), inT2D 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 deTto.
 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
jlpi_09@yahoo.com

Avances en Insulinoterapia Dr Paz 2014

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