pioglitazona, iddp4

1. TIAZOLIDINEDIONAS
Dr. Atilio Castillo Ruiz
Servicio de Endocrinologia y Metabolismo
HC-IPS

4. 4
Cambios microvascular
Cambios macrovascular
Caracteristicas
Clínicas
Kendall DM, et al. Am J Med 2009;122:S37-S50.
Kendall DM, et al. Am J Manag Care 2001;7(suppl):S327-S343.
IFG, impaired fasting glucose;
IGT, impaired glucose tolerance.
Years
RelativeAmount
-10 -5 0 5 10 15 20 25 30
Resistencia a la Insulina
Nivel de Insulina
0
50
100
150
200
250
-15
β-cell failure
Onset
diabetes
Glucose(mg/dL)
Diabetes
diagnosis
50
100
150
200
250
300
350
Glucemia en ayunas
Prediabetes
(Obesiidad, IFG, IGT)
Glucemia post prandial
-10 -5 0 5 10 15 20 25 30-15
Years
Progreso Natural de la Diabetes Tipo 2

5. 5
Contribución de la glucemia post prandil a A1C
%Contribution
A1C Range (%)
0
20
40
60
80
100
FPG (Fasting Plasma Glucose)
PPG (Postprandial Plasma Glucose)
>10.2
70%
30%
9.3-10.2
60%
40%
8.5-9.2
55%
45%
7.3-8.4
50%
50%
<7.3
30%
70%
Data from Monnier L, et al. Diabetes Care 2003; 26:881-885.

6. 6
A1C Metas no satisfechas en la mayoria de
pacientes con Diabetes
Upper limit of normal range (6%)
ACE recommended target (<6.5%)4
ADA recommended target (<7%)3
1. Data from Saydah SH, et al. JAMA 2004; 291:335-342.
2. Calculated from Koro CE, et al. Diabetes Care 2004; 27:17-20.
3. Data from ADA. Diabetes Care 2003; 26(suppl 1):S33-S50.
4. Data from ACE. Endocrine Practice 2002.
8.0
9.5
A1C (%)
6.0
8.5
10.0
6.5
5.5
9.0
7.0
7.5
37.2% have A1C >8%
20.2% have A1C >9%
12.4% have A1C >10%1
64.2% of patients with type
2 diabetes have A1C 7%2

7. Principal objetivo terapeutico en DM2
DeFronzo RA. Ann Intern Med. 1999;131:281-303. Buse JB, et al. In: Williams Textbook of Endocrinology. 10th ed.
WB Saunders; 2003:1427-1483.
Glucose
absorption
Hepatic glucose
overproduction
Insulin
resistance
Pancreas
Muscle and fat
Liver
Metformin
Thiazolidinediones
GLP-1 agonists
DPP-4 inhibitors
Sulfonylureas
Meglitinides
GLP-1 agonists
DPP-4 inhibitors
Thiazolidinediones
Metformin
Alpha-glucosidase inhibitors
GLP-1 agonists
Gut
Glucose
reabsorption
Kidney
Beta-cell
dysfunction
Glucose level
SGLT-2 inhibitors
Abbreviations: DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; T2DM, type 2 diabetes mellitus.

8. 8
ADOPT: A Diabetes Outcome Progression Trial
Rosiglitazone Sustained A1C Over Time

10. Glitazonas (Tiazolindionas)
• Agonistas de PPAR-y (receptores activadores de la
proliferación de peroxisomas)
• Insulinosensibilizantes
• Actuan en tejido adiposo, musculo y
principalmente en hígado
• Efecto máximo a las 12 semanas.
• Se metabolizan en hígado y se excretan los
metabolitos por heces y riñón

11. Efecto de las TZD

12. Glitazonas
• Aumenta la actividad y expresión de los
transportadores GLUT-1 y GLUT-4
• Disminuye la neoglucogenesis
• Mejora función y secreción de insulina
• Efecto antiinflamatorio y mejora la disfunción
endotelial.

13. Efectos de las Glitazonas
• Mejora HDL y
trigliceridos.
• Reducción de eventos
cardiovasculares.
(Pioglitazona).
• Rara la hipoglicemia en
monoterapia.
• Demora hasta 2 meses.
• Alza de peso, anemia,
edemas y ICC.
• Riesgo de fracturas
• Potencial aumento de
riesgo cardiovascular
(Rosiglitazona)

14. N Engl J Med 2004;351

17. Indicaciones y Contraindicaciones
• Retarda fracaso secundario
• Prevención de diabetes
• En insuficiencia renal no hay que ajustar dosis
• Contraindicados en falla hepática e
insuficiencia cardiaca congestiva.

20. Diferencias de peso

21. Diferencias el cLDL

22. Diferencia en el cLDL

23. Diferencias en el cHDL

24. Diferencias en Triglicéridos

25. Hipoglucemias

26. ICC

28. P: 0,007

29. P: < 0,001
72% menos Diabetes
en el Grupo Pioglitazona

30. 30 mg de pioglitazona por 96 semanas

37. INCRETINAS
Inhibidores de la Dipeptidil
peptidasa 4
( IDPP4)

38. 50 gr de glucosa oral o infusión IV
Glucosaplasmática(mg/dL)
Insulinasérica(nmol/L)
200
100
0
0.4
0.2
0
01 02 60 120 180 minutos
01 02 60 120 180 minutos
Nauck MA. J Clin Endocrinol Metab 1986; 63: 492-98
Vía Oral
Vía IV
EL TRACTO GI ES CAPAZ DE PRODUCIR MOLÉCULAS
QUE ESTIMULAN LA SECRECION DE INSULINA.
INCRETINAS
INTESTINE SECRETION INSULIN
GIP GLP-1

39. Inh secreción
glucagón
Glucose-dependent
Insulinotropic Polypeptide
Glucagon-Like Peptide-1
GIP
GLP-1
K
L
Insulina Insulina
Vaciamiento
gástrico
¿Cuáles son las INCRETINAS?
Fetner R. Surg Obes Rel Dis. 2005; 1: 589-98
5/39

41. ACCIONES DEL GLP-1
Nauck MA, et al. Diabetologia 1993; 36: 741-744
Druker DJ. Mol Endocrinol 2003: 17:161-71
Secreción de Insulina
Secreción de Glucagón
Vaciamiento Gástrico
Apetito
GLUCEMIA
PESO

42. Efecto incretina disminuido
Efecto incretina normal
Glucosa oral (50 g/400 ml) Glucosa intravenosa
isoglucémica
0
–10
10
15
20
Glucosaplasmáticavenosa
(mmol/L)
5
60 120 180
Tiempo (minutos)
0
40
60
80
InsulinaIR(mU/L)
20
Controles sanos (n=8) Diabetes tipo 2 (n=14)
0
10
15
20
5
Tiempo (minutos)
0
40
60
80
IRinsulin(mU/L)
20
–5 –10 60 120 180–5
–10 60 120 180–5 –10 60 120 180–5
*
* * * * *
*
* *
*
Venousplasmaglucose
(mmol/L)
Adaptado de Nauck M et al Diabetologia 1986;29:46–52.
El efecto incretina en DM TIPO 2 esta disminuido

43. Postprandial GLP-1 Levels in IGT
and T2DM
Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86:3717-3723.
Abbreviations: AUC, area under the curve; IGT, impaired glucose tolerance; NGT, normal glucose tolerance.
1927
1587
907
0
500
1000
1500
2000
2500
NGT IGT T2DM
P <.001 for T2DM vs NGT
GLP-1AUCIncrementalfrom
Basal(pmol/L•240min)
2500
2000
1500
1000
0
500
1927
1587
907

46. Efectos del GLP-1 sobre las celulas b en sujetos sanos

47. GLP-1 en DM2

48. GLP-1 es dividido e inactivado por el DPP-4

49. Los Inhibidores del DPP-4 previenen la inactivación
del GLP-1

50. Linagliptin Pharmacodynamics
Effect on GLP-1 and Glucagon
Rauch T, et al. Diabetes Ther. 2012;3:10.
Statistically significant differences in postprandial intact GLP-1 (increased) and
glucagon (decreased) vs placebo after 4 weeks of treatment in T2DM patients
Change from baseline in intact GLP-1 AUEC0–2h:
Linagliptin: 18.5 pmol/h/L
Placebo: 0.4 pmol/h/L
P <.0001
Change from baseline in glucagon AUEC0–2h:
Linagliptin: -17.4 pg/h/L
Placebo: 1.3 pg/h/L
P = .0452

52. Therapeutic Effect of GLP-1 in T2DM
GLP-1 significantly increased
• Insulin (17.4 nmol x 1-1 x
min)*
• C-peptide (228 nmol x 1-1 x
min)*
GLP-1 significantly reduced
• Fasting plasma glucose (normal
levels reached in all patients)
• Pancreatic glucagon secretion
(-1418 pmol x 1-1 x min)
• Plasma nonesterified fatty acids
(-26.3 mmol x 1-1 x min)
Nauck MA, et al. Diabetologia. 1993;36:741-744.
10 patients with unsatisfactory control of T2DM received
infusions of GLP-1 or placebo
*Decreased again after plasma glucose normalized.

54. Current DPP-4 Inhibitors
Sitagliptin
Vildagliptin
(approved outside
United States)
Saxagliptin
Alogliptin
Linagliptin

60. Placebo-corrected change from baseline in HbA1c - Monotherapy
Comparative Efficacies of DPP-4s
-0.1
-0.3
-0.2
-0.4
-0.8
-0.5
-0.6
-0.7
-0.9
-1.0
-1.1
-1.2
ΔHbA1c(%)
Alogliptin1
12.5 mg 25 mg
7.9% 7.9%
Linagliptin2
5 mg 5 mg
8.1% 8.0%
Saxagliptin3
5 mg 5 mg
7%-10% 8.0%
Sitagliptin4
100 mg 100 mg
8.0% 8.0%
Vildagliptin5
50 mg BID 50 mg
8.6% 8.4%
The current DPP-4s have comparative efficacy
1. DeFronzo R, et al. Diabetes Care 2008;31:2315-2317. 2. Linagliptin Prescribing Information. 3. Saxagliptin Prescribing
Information. 4. Sitagliptin Prescribing Information. 5. Vildagliptin Summary of Product Characteristics.
-0.56
-0.59 -0.6
-0.7
-0.4
-0.6 -0.6
-0.8
-0.5
-0.7

70. Neutral Effect of DPP-4 Inhibitors on
Body Weight
• Sitagliptin produced statistically significant (P <.05) decreases of 0.5–0.8 kg
in body weight from baseline at week 12 at all doses1
– Not significantly different from weight loss seen with placebo (-0.5 kg)
• Saxagliptin reduced body weight by -0.1 to -1.2 kg at week 24 compared
with baseline2
– Weight loss was -1.4 kg with placebo
• In a comparative trial, mean weight loss after 26 weeks was -0.96 kg
with sitagliptin vs -3.38 kg with liraglutide 1.8 mg and -2.86 kg with
liraglutide 1.2 mg3
• Linagliptin produced no significant difference in body weight from baseline4
– No significant difference in body weight from baseline with placebo
1. Hanefeld M, et al. Curr Res Med Opin. 2007;23:1329-1339. 2. Rosenstock J, et al. Curr Med Res Opin.
2009;25:2401-2411. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Del Prato S, et al. Diabetes Obes Metab.
2011;13:258-267.

71. Effect of Linagliptin on Lipids in Patients
at High Risk for Renal and CVD
• Post-hoc pooled analysis of T2DM patients with hypertension and
microalbuminuria from 6 phase III linagliptin trials (N = 512)*
• No significant difference in lipid changes from baseline for linagliptin
vs placebo
*Study durations: 18–24 weeks. †Adjusted for baseline HbA1c, parameter measured, prior oral antidiabetic medications, study
and treatment.
Abbreviations: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol.
von Eynatten M, et al. Cardiovasc Diabetol. 2013;12:60

72. Saxagliptin’s Effects on Lipids
• Specific data were not provided in the published
phase III trial
• “Modest numerical improvements from baseline
to week 24 in total cholesterol were
demonstrated in the saxagliptin treatment
groups.”
• “There were no clear effects of saxagliptin on
fasting lipid concentrations.”
Rosenstock J, et al. Curr Med Res Opin. 2009;25:2401-2411.

73. Effect of Linagliptin on Blood Pressure in
Patients at High Risk for Renal and CVD
• Post-hoc pooled analysis of T2DM patients with hypertension and
microalbuminuria from 6 phase III linagliptin trials (N = 512)*
• No significant difference in blood pressure changes from baseline
for linagliptin vs placebo
*Study durations: 18–24 weeks. †Adjusted for baseline HbA1c, parameter measured, prior oral antidiabetic medications,
study and treatment.
Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.
von Eynatten M, et al. Cardiovasc Diabetol. 2013;12:60

76. Add another class of agent best suited to the individual (agents listed in alphabetical order):
Class Relative
A1C
Lowering
Hypo-
glycemia
Weight Effect in
Cardiovascular
Outcome Trial
Other therapeutic considerations Cost
-glucosidase
inhibitor (acarbose)
 Rare neutral to  Improved postprandial control, GI side-
effects
$$
Incretin agents:
DPP-4 Inhibitors
GLP-1R agonists

 to

Rare
Rare
Neutral to 

Neutral (alo, saxa, sita)
Neutral (lixi)
Caution with saxagliptin in heart failure
GI side-effects
$$$
$$$$
Insulin  Yes  Neutral (glar) No dose ceiling, flexible regimens $-
$$$$
Insulin secretagogue:
Meglitinide
Sulfonylurea


Yes
Yes


Less hypoglycemia in context of missed
meals but usually requires TID to QID
dosing
Gliclazide and glimepiride associated
with less hypoglycemia than glyburide
$$
$
SGLT2 inhibitors  to

Rare  Superiority
(empa in T2DM
patients with clinical
CVD)
Genital infections, UTI, hypotension,
dose-related changes in LDL-C, caution
with renal dysfunction and loop
diuretics, dapagliflozin not to be used if
bladder cancer, rare diabetic
ketoacidosis (may occur with no
hyperglycemia)
$$$
Thiazolidinediones  Rare  Neutral CHF, edema, fractures, rare bladder
cancer (pioglitazone), cardiovascular
controversy (rosiglitazone), 6-12 weeks
required for maximal effect
$$
Weight loss agent
(orlistat)
 None  GI side effects $$$
alo=alogliptin; glar=glargine; saxa=saxagliptin; sita=sitagliptin; lixi=lixisenatide; empa=empagliflozin
2016

77. eGFR (mL/min/1.73 m2): <15 15–29 30–59 60–89 ≥ 90
CKD Stage: 5 4 3 2 1
Acarbose Not recommended 25
Dapagliflozin 60
Empagliflozin 45
Thiazolidinediones 30
Contraindicated SafeCaution and/or reduce dose
Canagliflozin 25 60*100 mg45
60*
Adapted from: Product Monographs as of March 2016 Harper W et
al. Can J Diabetes 2015;39:440.
* = do not initiate if eGFR <60 ml/min
Not recommended
Metformin 30 60
15Linagliptin
Sitagliptin 5030 50 mg25 mg
Saxagliptin 5015 2.5 mg
Alogliptin Not recommended 506.25 mg 12.5 mg30
Exenatide (BID/QW) 30 50
Liraglutide 50
Albiglutide 50
30
Repaglinide
Gliclazide/Glimepiride 15 30
Glyburide 30 50
Insulin
Secreta-
gogues
SGLT2
inhibitors
GLP-1R
agonists
Alpha-glucosidase
Inhibitor
Biguanide
DPP-4
inhibitors
Dulaglutide 50
Anti Hiperglucemiantes segun la función renal
2016

79. En quien iniciaría Pioglitazona?
En un paciente con Hígado Graso.
En un paciente con Dislipidemia.
En un paciente que ya tuvo en evento
Cardiocerebrovascular.
En un paciente que presento hipoglucemias con
otros fármacos
En Prevención de Diabetes Tipo 2

80. En quien iniciaría IDPP4
Cuando no tolere la Metformina, podría ser
el primer fármaco de elección
Cuando presente hipoglucemias con otros
fármacos.
En un paciente con ERC moderada, que no
acepte Insulina de entrada.