Davide Carvalho Insulinas

Davide Carvalho Insulinas
Serviço de Endocrinologia, Diabetes e Metabolismo Hospital de S. João / Faculdade de Medicina do Porto

Insulinoterapia na Diabetes tipo 2
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O Controlo Glicémico Permanece mau na Diabetes Tipo 2 com as
Actuais Terapêuticas Controlo por País A1c Belgica França Alemanha Itália Holanda Espanha Suécia UK Bom < 6,5% Limiar 6,5%-7,5% Mau > 7,5% 100 80 60 Patients (%) 40 20 The further need to optimise glycaemic control is evident from large surveys in various European countries. The European data shown in this slide come from the Costs of Diabetes in Europe–Type 2 (CODE-2) study, the first large-scale study to assess standard of care and to measure the costs associated with the management of type 2 diabetes in 8 European countries. The study measured FPG and HbA1c to assess glycaemic control and the risk for development or progression of complications of diabetes. The CODE-2 study used the 1999 European Diabetes Policy Group (EDPG) treatment guidelines as the benchmark of diabetes control. Regardless of healthcare system, the data consistently showed that a large percentage of patients are poorly controlled. Some 69% of subjects from many of the major European countries failed to meet EDPG guidelines. The overall mean HbA1c value for the entire CODE-2 population was 7.5%, ranging from a low of 7.0% in Sweden to a high of 7.8% in the United Kingdom. Forty-two percent of patients in the CODE-2 population had HbA1c levels above 7.5% and were therefore considered to be at high risk for microvascular and macrovascular complications. It is important to note that the EDPG treatment guidelines indicate that HbA1c levels of 6.5% to 7.5% confer arterial risk. Liebl A, et al Diabetologia 2002;45:S23-S28

A Taxa de Controlo Glicémico Está a Piorar nos EUA
Percentagem de Doentes Adultos com Diabetes tipo 2 com A1c <7% NHANES III (1988 - 1994) NHANES 1999 - 2000 Controlados Controlados 36% 55% 45% 64% Despite recommendations for early, aggressive therapy, fewer patients are achieving glycaemic control as evidenced by comparing data from the third National Health and Nutrition Examination Survey (NHANES III; ) with those of the NHANES survey. The study analysed subjects aged  29 years who responded positively to ‘Other than during pregnancy, has a doctor ever told you that you had diabetes or sugar diabetes?’ and who also had an HbA1c measurement. Subjects for whom information on diabetes medicine type, body mass index (BMI) or diabetes duration was missing were excluded. The 4 anti-hyperglycaemic regimens for this study were diet, insulin, OAs as monotherapy or in combination and OAs plus insulin. Glycaemic control was determined by calculating the proportion of subjects with type 2 diabetes with an HbA1c < 7%. This slide shows that glycaemic control in NHANES III was 45% compared with 36% in NHANES After adjusting for age, ethnicity, gender, BMI, medication use and diabetes duration, the odds of glycaemic control were 21% lower for NHANES than for NHANES III. A Pfizer analysis of the NHANES data suggests that rate of control has not substantially improved in diagnosed patients. NOTE: The proportion of subjects with type 2 diabetes who were taking insulin therapy alone decreased from 24% in NHANES III to 16.4% in NHANES Não controlados Não controlados NHANES = National Health and Nutrition Examination Survey. Koro CE, et al. Diabetes Care 2004; 27:17-20 12

O Uso da Insulina nos EUA não se Alterou Apesar do Mau Controlo
NHANES III (1988 - 1994) versus NHANES 1999 - 2000 NHANES III (1988 - 1994) 60 NHANES 1999 - 2000 Constante: 27% dos doentes tratados com insulina 50 40 Doentes (%) 30 20 10 In addition to demonstrating the decreased level of glycaemic control between 1988 and 1994 and 1999 and 2000 in the United States, the authors of this study analysed trends in the use of current treatment modalities. Among the most noteworthy findings is the decrease in insulin use alone from 24.2% to 16.4%. At the other end of the treatment algorithm, the percentage of subjects using only OAs increased from 45.4% to 52.5%. Combination therapy of OAs with insulin also increased, while the use of diet alone decreased. With the changes seen in the use of currently available treatment options, the use of insulin, whether in combination or as a single agent, has remained unchanged between 1988 and 1994 and 1999 and 2000, despite worsening glycaemic control as seen in the previous slide. Só Dieta AOs AOs + Apenas Insulina Insulina Entre o NHANES III ( ) e NHANES 1999 – 2000 a % de doentes tratados com AOs aumentou ~7% - Koro CE, et al. Diabetes Care 2004; 27:17-20

Factores que Podem Atrasar o Início da Insulinoterapia
Receio dos doentes que as injecções sejam dolorosas e difíceis de administrar 25-50% dos doentes estão preocupados ou ansiosos com a injecção de insulina 76% expressam sentimentos negativos sobre as injecções Somente 2% indicaram que apreciariam a insulinoterapia 34% dos doentes já tinham recusado a insulinoterapia As hipoglicemias e o ganho de peso são preocupações de médicos e doentes Many studies have explored barriers to insulin use and means to prevent the delay in initiating insulin therapy. For example, the availability of non-invasive insulin delivery (eg, inhaled insulin) may help overcome these barriers, thus encouraging early insulin use and improving patient acceptance and satisfaction. The often underestimated fear that insulin injections will be painful and difficult to administer may hinder patient acceptance of needed therapy. Approximately 50% of patients in one study reported being fearful of injections, due in part to these reasons. In another study, 28% of insulin-treated patients exhibited high injection anxiety scores, and 42% expressed concern about more frequent injections. Insulin-naïve patients have also expressed needle concerns. In a survey of 99 insulin-naïve patients, 76% expressed negative feelings about injections, while only 2% indicated they would welcome insulin therapy. In a study of a low-income population, 34% of 44 subjects admitted to having refused insulin. Nearly a third of this group believed that insulin use indicated their disease had progressed to a serious stage, and some believed that not being prescribed insulin indicated relatively good health. Other concerns such as hypoglycaemia, weight gain and perceived sense of personal failure exist for both patients and physicians. . - . - Heinemann L. Eur J Endocrinol 2004;151(suppl 2):T23-27; Hunt L, et al. Diabetes Care 1997;20: ; Korytkowski M. Int J Obes 2002; 26 (Suppl 3): S18 -24; ZambaniniA et al Diabetes Res Clin Prta 1998; 46:

Insulina No Mercado Europeu (mega-unidades/por milhão de hab /Dez 2003)
50.00 100.00 150.00 200.00 250.00 300.00 350.00 Alemanha (R+H) Suécia Finlândia (R+H) Holanda Noruega Espanha (R+H) Reino Unido (R+H) Hungria (R+H) Polónia (R+H) Rep.Checa (R+H) Eslovénia Bélgica (R+H) Dinamarca Áustria (R+H) Grécia Eslováquia (R+H) Itália (R+H) França (R+H) Irlanda Portugal Letónia Lituânia Suiça (R+H) MAT Dec 2003 Insulina UI mega unidade/ milhão hab. MAT Dec Insulina UI mega undade/ mil hab.

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Como? ADO + insulina Insulinoterapia convencional
Terapêutica combinada ADO + insulina Insulinoterapia convencional Insulinoterapia intensiva Glicemia em jejum e pré-prandial mg/dL Terapêutica por objectivos Glicemia pós-prandial até 140 mg/dL Am Coll Endocrinology 2002 A1c - < 6,5%

Uso precoce da Terapêutica Insulínica na D
Uso precoce da Terapêutica Insulínica na D. Tipo 2 Vias para a Insulinoterapia Tradicional vs Precoce Tradicional >10 passos Traditional Early insulin Precoce >5 passos Estilo de vida (dieta e A. Física) Estilo de vida (dieta e A. Física) Adicione metformina ( titule a dose ) Adicione metformina ( titule a dose ) Adicione SU ( titule a dose ) Adicione Glitazona ( titule a dose ) Inicie insulina (continue metformina) ( e titule a dose )

Protocolo de Tratamento da Diabetes tipo 2
Glicemia de jejum >126 mg/dL (2 determinações) Modificação do estilo de vida + metformina Não A1c>7% Sim Adicione GT s/hipoglicemia Adicione SU mais barato Adicione Insulina mais eficaz Não Sim Não A1c>7% Sim Não A1c>7% Sim A1c>7% Adicione SU Adicione Insulina Adicione GT Intensifique Insulina Não A1c>7% Sim Não A1c>7% Sim Adicione Insulina Basal ou Intensifique Insulinoterapia intensiva+metformina +/- Gt Nathan D. A consensus statement from ADA/EASD. Diabetes Care 2006; 29:1963

NORMAS PRÁTICAS Como iniciar a Insulina Basal
Continue o(s) agente(s) oral (is) na mesma dose (eventualmente reduza) Adicione uma única dose de insulina à noite (cerca 10 a 14 U) NPH (ao deitar) 70/30 (ao jantar) Glargina (ao deitar ou em qualquer outro momento) Ajuste a dose pela monitorização glicemia ambulatória Aumente a dose de insulina semanalmente como necessário Aumente 4 U se GJ >140 mg/dL Aumente 2 U se GJ = 110 até 140 mg/dL Trate para atingir o alvo (GJ <110 mg/dL)

Tipo de Insulina Início Picos Fim Insulinas Prandiais- Rápidas Insulina lispro 10 min 60 min 3-4 h Insulina aspártica Insulinas Prandiais – Curtas Insulina cristalina 30-60 min 2-4 h 6-8 h Insulinas Basais – Intermédias Insulina NPH 1,5 h 4-12 h 10-16 h Insulina lenta 2,5 h 7-15 h Insulinas Basais – Prolongadas Insulina ultralenta 4 h 8-16 h 18-20 h Insulina glargina 4-6 h Nenhum 24 h Insulinas Bifásicas - Pré-misturas fixas* 90/10; 80/20;70/30, 60/40; 50/50; 75/25 0,5-1,0 h Duplo (NPH/C) 12-20 h 75/25; 50/50 Duplo (NPL/L)(NPA/A)

Injecção de Insulina de Acção Prolongada na Diabetes tipo 2
NPH Glargina Efeito da Insulina Deitar

Terapêutica Combinada com Insulina Glargina – Perfil de Glicemia de Jejum Durante uma Semana

Taxa de hipoglicemias nocturnas confirmadas (por 100 d-ano)
A1c Previsível a Taxas Similares de Hipoglicemias Nocturnas Confirmadas 14 12 _ _ A1c previsível (Fimdo estudo) 10 _ _ _ NPH _ _ _ _ _ _ _ _ _ 8 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 0,87% _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 6 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Lantus 4 100 200 300 400 500 600 Taxa de hipoglicemias nocturnas confirmadas (por 100 d-ano)

Taxa de hipoglicemias nocturnas confirmadas (por 100 d-ano)
A1c Previsível a Taxas Similares de Hipoglicemias Nocturnas Confirmadas 14 12 A1c previsível (Fimdo estudo) _ _ 10 _ _ _ NPH _ _ _ _ _ _ _ _ _ 8 _ _ _ _ _ _ _ _ _ _ _ 7 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 6 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Lantus NPH 4 100 200 300 400 500 600 Taxa de hipoglicemias nocturnas confirmadas (por 100 d-ano)

Variação média no Peso Corporal do Início para o Fim (Kg)
Ganho de Peso - Menor Ganho de peso com a Glargina do que com a NPH Tipo 2 Insulina Glargina SC 1,6 Duração do Estudo 28 semanas; n=518 1,4 1,2 1,0 Variação média no Peso Corporal do Início para o Fim (Kg) 0,8 *p <0,0007 * 0,6 0, Weight gain is an essentially unavoidable side effect of insulin treatment, and may contribute to treatment non-adherence in some patients, particularly adolescents In this 16-week, open-label study, 619 patients with Type 1 diabetes who had previously received basal–bolus insulin therapy with NPH insulin and insulin lispro, were randomized to either subcutaneous insulin glargine (Lantus®) once daily or subcutaneous NPH insulin once or twice daily, both in combination with mealtime insulin lispro Comparison of weight gain in the two treatment groups demonstrated that average weight gain with insulin glargine (Lantus®) treatment was significantly lower than that with NPH insulin treatment (0.12 vs 0.54 kg; p=0.034) Thus, treatment with insulin glargine (Lantus®) may cause less weight gain compared with NPH insulin treatment, in patients with Type 1 diabetes References: Raskin P et al. Diabetes Care 2000;23:1666–1671 0,2 0,0 Insulina Basal SC (Insulina Glargina uma vez/dia ou NPH uma ou duas vezes/dia) + Insulina Regular pré-prandial Rosenstock J et al. Diabetes Care 2001;24:631

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Protocolo de Tratamento da Diabetes tipo 2
Inicie insulina de acção intermédia ao deitar ou acção prolongada de manhã ou ao deitar – 10 u ou 0,2u/Kg Determine a GJ por auto-vigilância diária e aumente a dose 2u de 2/2 ou 3/3 dias se glicemia > ou 4 u se >180 A1c > 7% aos 3 m Se hipoglicemia ou GJ <70 mg/dL reduza 4 u à dose da noite ou 10% se dose > 60 U Se GJ no alvo (70 a 130), verifique G antes Almoço, Jantar e Deitar; dependendo dos re- sultados adicione 2ª injecção, comece com ~ 4u e ajuste 2u cada 3 dias até atingir o alvo Não Continue o esquema e determine A1c de 3/3m Se G antes do Almoço fora do alvo adicione insulina rápida ao PA Se G antes do Jantar fora do alvo adicione insulina NPH ao PA ou rápida ao almoço Se G antes da ceia fora do alvo adicione insulina rápida ao jantar A1c > 7% aos 3 m Verifique antes da refeição e se fora do alvo adicione outra injecção; se A1c fora do alvo verifique G pós-prandial e ajuste a dose

Esquemas de 2 administrações de insulina
Dose Matinal (antes do Pequeno almoço): 2/3 da dose total do dia (2/3 da dose intermédia, 1/3 de acção curta ou rápida) Dose Vespertina : 1/3 da dose total diária (metade de acção intermédia, metade de acção curta ou rápida) Esquema Basal (acção intermédia) + Bólus Momento Tipo de insulina % da dose diária total Dose Matinal (NPH ou lenta) Acção intermédia 20% Antes das refeições Acção rápida ou curta 15%, 15%, 20% Dose Vespertina (NPH ou lenta) 30% Esquema Basal ( acção prolongada) + Bólus Ao deitar Glargina 50%

INSULINOTERAPIA Multiplas Injecções Diárias (MID) NPH + Cristalizada
NPH ao PA e Ceia + Regular ao PA e J NPH à Ceia + Cristalizada às refeições Cristalizada Cristalizada NPH NPH Efeito da Insulina Efeito da Insulina Slide 6-24 INSULIN TACTICS Multiple Daily Injections (MDI) NPH + Regular Another strategy, shown in this slide, consists of two injections of NPH (or lente) insulin daily plus two or three injections of regular insulin with meals. The second injection of NPH is given at bedtime, to confer less risk of nocturnal hypoglycemia while providing enough insulin to control overnight fasting glucose levels. This is often called a multiple daily injection (MDI) regimen. It is widely used for type 1 diabetes patients but is also appropriate for type 2 diabetes patients whose endogenous levels are declining. The match of insulin levels to endogenous needs is better with this approach than with twice-daily NPH and regular, but still not very good. PA A J Ceia PA PA A J Ceia PA 6-24

Como ajustar a dose de insulina rápida ou curta após estabilização do esquema insulínico
Se glicemia Insulina <50 mg/dL mg/dL mg/dL mg/dL mg/dL mg/dL mg/dL mg/dL mg/dL > 400 mg/dL Reduzir a dose de antes da refeição em 2-3 u; administrar a insulina no fim da refeição Reduzir 1-2 u Administrar a mesma dose Aumentar 1 u Aumentar 2 u Aumentar 3 u Aumentar 4 u; atrasar a refeição 10 a 20 minutos Aumentar 5 u; atrasar a refeição mn; pesquisar B-hidroxibutirato Aumentar 6 u; atrasar a refeição mn Aumentar 7u; atrasar a refeição 30 minutos

Efeito do DCCT e das Insulinas de Acção Rápida nas Hipoglicemias em Diabéticos Tipo 1
Insulina lispro *P <,001 vs ano anterior 9.60 0,60 * 9.40 9.20 0,50 9.00 0,40 8.80 A1c (%) 8.60 Episódios (sujeitos por ano) Hipoglicemias graves 0,30 8.40 8.20 DCCT 0,20 8.00 One of the major drawbacks of intensive insulin therapy is the increased risk of hypoglycemic episodes. Although publication of DCCT was associated with decreases in HbA1c levels, a significant increase in the number of severe hypoglycemic episodes occurred. In contrast,in this study the introduction of insulin lispro was associated witha further decrease in HbA1c levels without a concomitant increase in hypoglycemic episodes. HbA1c (%) 7.80 0,10 Hipoglicemias graves 7.60 7.40 0.00 1993 1994 1995 1996 1997 1998 Ano Chase, HP Garg SK et al. Diabetes Care. 2001;24:

Insulina humana Insulina Lispro
NPL (Suspensão de Insulina Protamina Lispro): O análogo de insulina Lispro é cristalizado com protamina para produzir uma insulina basal Insulina humana Insulina Lispro H L protamina protamina NPH NPL DeFelippis MR. J Pharm Sci 1998 Feb;87(2):170-6.

A NPL foi desenvolvida devido à troca entre insulina Lispro e insulina humana na NPH com armazenamento prolongado L H 1 2 4 NPH + 3 NPL When Humalog is mixed with NPH in long-term storage, Humalog binds to protamine in place of regular insulin. The resulting solution contains Humalog, Regular insulin, NPL, and NPH and has new PK and PD characteristics closer to human pre-mixed insulins with a similar ratio of fast-acting component. To avoid this exchange between Humalog and NPH, NPL was developed. When mixed over time, the PK and PD activity of rapid-acting Humalog and the basal component NPL remain unchanged.

Tempo desde a refeição (hrs)
Humalog® Mix25™ vs Humulin® 30/70 na diabetes tipo 2: excursão glicémica pós-prandial Ambas as insulinas foram injectadas 5 min antes da refeição (pequeno-almoço) 1 2 3 90 54 36 18 72 Tempo desde a refeição (hrs) Humulin 30/70 Mix25 Mix25 associada a uma menor excursão glicémica pós-prandial após 2 horas (p<0,001) N=82 doentes Mix25 N=82 doentes 30/70 Excursão glicémica (mg/dl) Malone J et al. Diabetes Metab 2000;26:

Humalog® Mix25™ (BID) mais Metformina (Met) vs Lantus® uma vez por dia em doentes naïve à insulina: Diminuição da A1c Mix25 + Met ficou associado a menores valores médios da HbA1c*(p=0,002) e a uma maior variação da HbA1c média † (p=0,003) do que Lantus + Met Início (N=71 doentes DM tipo 2) Endpoint (N=71) Variação em relação ao início (N=67) p<0,001 p<0,001 10 * 8 8,7 8,7 7,8 7,4 A1c média (%) 6 4 2 -0,93 -1,32 † -2 Lantus + Met Mix25 + Met Dose diária de insulina (Média ±DP)(U/kg) 0,57 ±0,37 ** 0,62 ±0,37 ** p<0,001 Malone JK et al. Clin Ther 2004;26:

Humalog® Mix25™ (BID) mais Metformina (Met) vs Lantus® uma vez por dia em doentes naïve à insulina : Perfil glicémico de 8 pontos Mix25 + Met ficou associado com valores menores da glicémia após o pequeno-almoço, o jantar e ao deitar mas com valores mais elevados da glicémia em jejum do que Lantus + Met Mix25 + Met Lantus + Met 220 *p<0,05 * 200 * * 180 Glicemia média (ng/dL) 160 * * 140 It is important to note that although fasting BG was better when the basal insulin Lantus was used, the overall glycemic control was still better in the LowMix BID group. In other words, reaching the fasting BG target alone may not produce optimal overall glycemic control. 120 100 Jejum PP 2-hr Antes almoço PP 2-hr Antes jantar PP 2-hr Deitar 3:00 Malone JK et al. Clin Ther 2004;26:

Humalog® Mix25™ (BID) mais Metformina (Met) vs Lantus® uma vez por dia em doentes naïve à insulina: Percentagem de doentes que atingiu os objectivos Houve uma percentagem maior de doentes tratados com Mix25 + Met a atingir os objectivos terapêuticos excepto a glicemia em jejum Lantus + Met Mix25 + Met p=0,036 90 p<0,001 80 p=0,019 70 60 p<0,001 Percentagem de doentes 50 40 30 20 10 Valores HbA1c ≤ 7,0% Glicemia em jejum ≤ 126 mg/l Glicemia pós-prandial de manhã ≤ 180 mg/l Glicemia pós-prandial à tarde ≤ 180 mg/l Malone JK et al. Clin Ther 2004;26:

Humalog® Mix25™ (BID) mais Metformina (Met) vs Lantus® uma vez por dia em doentes naïve à insulina : Hipoglicemia total e nocturna Hipoglicemia (total) Hipoglicemia (nocturna) p=NS p=0,041 0.8 0.25 Episódios/doente/30 dias Média 0.7 0.20 0.6 0.5 0.15 0.4 0.10 0.3 0.2 0.05 It is important to observe that a potential further dose increase of Lantus to counterract daily hyperglycemia could increase the risk of nocturnal hypoglycemia. 0.1 Lantus + Met Mix25 + Met Lantus + Met Mix25 + Met N=101 N=100 N=101 N=100 Dados extraídos de Malone JK et al. Clin Ther 2004;26:

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O Pulmão como Portal para Administração Sistémica de Fármacos
Sistema pulmonar – uma árvore ramificada que termina em alvéolos revestidos de uma fina membrana Brônquio Primário Fluxo Sanguíneo Vénula Pulmonar Brônquio Secundário Brônquio terciário Arteríola Pulmonar Rede Capilar na superfície do alvéolo The lung may be likened to a large, branching tree, the leaves of which represent the finest and thinnest part of the lung—the alveoli—where the exchange of gases between air and blood takes place. There are approximately 17 layers of branching between the trachea and the respiratory bronchioles. The tiny air sacs at the end of the bronchioles, the alveoli, are where the exchange of oxygen and carbon dioxide takes place, between the blood and inhaled air. On average, at each level the number of branches doubles. Therefore, we end up with 217, or approximately 130,000 respiratory bronchioles. For perspective, the surface area of the lung is equal to the size of a tennis court. The lungs’ vast and richly perfused surface areas, created by the combination of bronchial and pulmonary circulatory pathways, may be used not just for gas exchange, but for resorption of inhaled peptide drugs. Bronquíolo primário Bronquíolo terminal Alvéolo Tortora GJ, Grabowski SR. Principles of Anatomy and Physiology. 10th ed. New York, NY: Wiley & Sons; Van De Graaff KM, et al. Synopsis of Human Anatomy and Physiology : William Dubuque, Iowa C. Brown, Publishers; 1997 .

EXUBERA Insulina em Pó ¿
As partículas de EXUBERA são desenhadas para terem 1 a 3 µm, o tamanho óptimo da janela para absorção pulmonar - EXUBERA consiste em insulina humana recombinante mistu- rada com uma pequena quantidade de excipientes O pó de insulina esta embalado em pequenos blisteres A inalação oral proporciona ~10% da insulina biodisponível relativamente à insulina sc Deposition of drug to the deep lung depends on particle size—the smaller the particle the greater the deposition. The optimal particle size is 1 m to 3 m. The EXUBERA insulin particle was developed to maximise absorption in the deep (alveolar) lung and minimise loss on exhalation. EXUBERA particles consist of recombinant human insulin and stabilisers, have an aerodynamic diameter < 5 m and are packaged in unit doses of 1- and 3-mg blisters. EXUBERA bioavailability is approximately 10%. This does not mean that 10 times more insulin is deposited in the lungs per dose. Approximately 60% of the insulin powder is ‘lost’ in the blister, device, mouth or throat. Of the 30% to 40% that reaches the lungs, a portion is deposited in the large airways, where absorption is not possible. The remainder may undergo enzymatic degradation in the peripheral lung, resulting in the limited bioavailability. The amount of insulin deposited in the lungs is 3 times that of the insulin at the site of an injection of SC insulin. However, inhaled insulin is distributed over a far greater surface area (approximately the size of a tennis court) than SC insulin. The EXUBERA dry powder insulin formulation is stable at room temperature (unopened blisters are stable for up to 2 years), has a low susceptibility to microbial growth, delivers a greater dose per inhalation than inhaled liquid formulations and has the ability to be delivered in high or low doses. Because of its reliance on the lung for administration, EXUBERA is contraindicated in patients who smoke or have smoked in the previous 6 months; in patients with poorly controlled, unstable or severe asthma; and in patients with severe chronic obstructive pulmonary disease (COPD). Os blisteres fechados de pó de insulina é estável à tempe- ratura ambiente durante 2 anos Patton JS, et al. Clin Pharmacokinet. 2004;43:781 - 801.

EXUBERA Libertação Pulmonar
Inalador Nuvem de Insulina Since insulin was discovered more than 80 years ago, a non-injectable method of insulin delivery has remained an elusive goal. Now, EXUBERA is the first and only inhaled human insulin, which may assist in overcoming some barriers. EXUBERA is delivered through the lungs by a simple yet technologically advanced inhaler that is used to deliver a cloud of fine human insulin powder. Patients breathe normally and hold their breath for 5 seconds.

Vasos san- guíneos pulmonares Sacos alveolares Since insulin was discovered more than 80 years ago, a non-injectable method of insulin delivery has remained an elusive goal. Now, EXUBERA is the first and only inhaled human insulin, which may assist in overcoming some barriers. EXUBERA is delivered through the lungs by a simple yet technologically advanced inhaler that is used to deliver a cloud of fine human insulin powder. Patients breathe normally and hold their breath for 5 seconds.

Partícula de EXUBERA Câmara alveolar Since insulin was discovered more than 80 years ago, a non-injectable method of insulin delivery has remained an elusive goal. Now, EXUBERA is the first and only inhaled human insulin, which may assist in overcoming some barriers. EXUBERA is delivered through the lungs by a simple yet technologically advanced inhaler that is used to deliver a cloud of fine human insulin powder. Patients breathe normally and hold their breath for 5 seconds.

Após contacto com o fluído de revestimento alveolar, a partícula de EXUBERA dissolve-se rapidamente e é absorvida através da fina membrana alveolar Partícula de EXUBERA Fluído alveolar Epitélio pulmonar Endotélio capilar Capilar Since insulin was discovered more than 80 years ago, a non-injectable method of insulin delivery has remained an elusive goal. Now, EXUBERA is the first and only inhaled human insulin, which may assist in overcoming some barriers. EXUBERA is delivered through the lungs by a simple yet technologically advanced inhaler that is used to deliver a cloud of fine human insulin powder. Patients breathe normally and hold their breath for 5 seconds.

Glargina ao Deitar + AO ou Insulina Inalada
I- Secretagogo Insulina Inalada I-Sensibilizador Glargina Glargina Efeito da Insulina Efeito da Insulina PA A J Ceia PA PA A J Ceia Pa 6-56

EXUBERA Diabetes Tipo 2 após Falência de Monoterapia Oral (SU ou Met)
Benefício estatisticamente significativo para doentes com A1c > 9,5% Falência SU1 Falência Met2 ∆ A1c: -0,38% (P = 0,002) ∆ A1c: -0,37% (P = 0,004) 9,5 8,5 A1c Pos-tratamento (%) 7,5 In both studies, a subset of patients, those with HbA1c  9.5%, showed similar benefit whether treated with EXUBERA and 1 OA or treated with a combination of 2 OAs. However, in the subset of patients with HbA1c > 9.5%, subjects in both studies receiving adjunctive EXUBERA demonstrated significantly greater reductions in HbA1c than those receiving a second OA. There was a -0.38% difference in HbA1c in favour of EXUBERA compared with Met at the end of the study, which reached significance (P = 0.002). In the study of EXUBERA versus glibenclamide, the difference in HbA1c at study end was -0.37%, again favouring EXUBERA, and was statistically significant at P = Baseline levels for the HbA1c > 9.5% subset for both studies are as follows: SU Failure: SU + EXUBERA, 10.5 SU + Met, 10.6 Met Failure: Met + EXUBERA, 10.4 Met + Glibenclamide, 10.5 6,5 5,5 SU + SU + Met Met + Met + Glibenclamida EXUBERA EXUBERA 1. Barnett AH, et al. Diabetes Care. 2006; 29: , 2. Barnett AH, et al. Diabetes Care. 2006; 29:

EXUBERA Diabetes Tipo 2 após Dupla Falência A O
Variação na A1c EXUBERA 2 AOs EXUBERA + 2 AOs -2 -1 ? - 0,2 Variação Média na A1c % Mean baseline HbA1c levels were comparable among the 3 groups (2 OAs, 9.6%; EXUBERA monotherapy, 9.6%; EXUBERA + 2 OAs, 9.5%). At Week 12, mean HbA1c significantly decreased in both EXUBERA groups. The HbA1c reduction in the EXUBERA + 2 OAs group was -1.9%. With EXUBERA monotherapy, the reduction was -1.4% and in the 2 OAs group, the reduction was -0.2% (adjusted treatment group differences listed in slide footnote). Both EXUBERA groups demonstrated greater reductions in FPG and PPG than the 2 OAs group. FAQ EXUBERA doses for the monotherapy group generally were twice the average dose in other studies (attributed to discontinuation of OA therapy). 86%, 55.9% and 19% of EXUBERA + 2 OAs, EXUBERA monotherapy and 2 OAs patients, respectively, achieved HbA1c < 8.0%. Adjusted OR versus 2 OAs for EXUBERA + 2 OAs was 40.5 (95% CI, ); for EXUBERA monotherapy, 7.5 (95% CI, ). Thirty-two percent, 16.7% and 1.0% of EXUBERA + 2 OAs, EXUBERA monotherapy and 2 OAs patients, respectively, achieved HbA1c < 7.0%. Adjusted OR versus 2 OAs for EXUBERA + 2 OAs was 44.7 (95% CI, ); for EXUBERA monotherapy, 19.0 (95% CI, ). EXUBERA + 2 OAs vs 2 OAs EXUBERA vs 2 OAs Adjusted treatment group difference FPG mmol/L -2.9 (95% CI, -3.7 to -2.3) -1.3 (95% CI, -2.0 to -0.6) Adjusted treatment group difference PPG mmol/L -4.2 (95% CI, -5.2 to -3.2) -3.4 (95% CI, -4.4 to -2.5) * ? - 1,4 * LOCF – last observation carried forward ? - 1,9 Diferença ajustada à 12ª semana (LOCF): EXUBERA – 1,18%; IC 95% -1,41 a -0,95; EXUBERA+AO –AO: -1,67; IC 95%, -1,90 a -1,44 Rosenstock J, et al. Ann Intern Med . 2005;143:549 - 558. Pfizer Inc All rights reserved. Version 1 67

Eficácia Comparável à Insulina SC na Diabetes tipo 2
EXUBERA Eficácia Comparável à Insulina SC na Diabetes tipo 2 EXUBERA + UL deitar (n = 134) 10 Insulina SC +NPH 2-3x (n = 140) DP 9 (%) 8 7 A1c Média 6 At the end of the 24 weeks, the mean HbA1c decreased similarly for both groups. The EXUBERA group had a reduction of mean HbA1c from 8.1% to 7.4% (-0.7%), and the SC insulin mean HbA1c went from 8.2% at baseline to 7.6% (-0.6%). The authors also reported greater reductions in FPG in favour of EXUBERA as we will see in a later slide. NOTE: Adjusted treatment group difference at Week 24 (last observation carried forward): -0.07%; 95% CI, to 0.17. The EXUBERA and SC insulin arms in conventional insulin regimen studies consisted of different SC insulin therapies, and, as such, only the 2 overall regimens may be compared. FAQ HbA1c < 8.0% was achieved in more patients receiving EXUBERA (76.3%) than SC (68.9%) insulin. HbA1c < 7.0% was achieved in more patients receiving EXUBERA (46.9%) than SC (31.7%) insulin (OR, 2.27; 95% CI, ). 5 Rastreio Base 6 12 18 24 Duração do Tratamento (sem) Hollander PA, et al. Diabetes Care 2004; 27: .

Controlo Glicémico Mantido com EXUBERA até 4 anos
Ensaio aberto, a longo prazo 11,0 Type 2 diabetes 10,0 (%) 9,0 A1c Média 8,0 7,0 As seen in Phase 2 extension studies of up to 4 years’ duration, EXUBERA achieved and maintained glycaemic control in subjects with type 1 or type 2 diabetes. At the end of 4 years, the combined mean HbA1c for subjects with type 1 or type 2 diabetes was 8.2% in the EXUBERA group compared with 8.71% at the start of treatment. During this time, the dose of EXUBERA increased slightly from 0.15 mg/kg to mg/kg. Clinical trial results demonstrate that EXUBERA is as effective as monotherapy or combination therapy with OAs. 6,0 3 6 12 18 24 30 36 42 48 Duração de Tratamento (meses) Skyler J, et al. Diabetes 2004;53(suppl 2):A115.

Terapêutica com Bomba Infusora (CSII) Reduz a A1c na diabetes tipo 2
Base Fim do estudo (24 semanas) 8,4 8,2 8,0 n=127 7,8 A1C (%) 7,6 7,4 7,2 7,0 CSII MID Raskin et al. Diabetes. 2001;50(suppl 2):A128.

Satisfação do Uso de Bombas em Doente na Diabetes Tipo2
CSII MID Menos dor Menos limitações sociais Preferência Aconselharia a outros Menos embaraçoso < interferência no dia a dia Satisfação Geral Flexibilidade Figure 2. Change-from-baseline improvements in patient satisfaction subscores at end of study. Improvements were compared between treatment groups, controlling for patient age. Responses to baseline questionnaires are based on prestudy insulin treatment. Change-from-baseline scores are available for 52 (79%) subjects in the CSII group and 52 (85%) subjects in the MDI group. Scoring of satisfaction categories ranged from 0 to 100, for least satisfaction to most satisfaction, respectively. P-values: * p<0.025, ** p<0.01, and *** p<0.001. Conveniência Menos sobrecarga -5 5 10 15 20 25 30 35 Variação na pontuação (unitdades em bruto)da base até final Testa et al. Diabetes. 2001;50(suppl 2):1781

Na Diabetes tipo A terapêutica deve ser orientada por objectivos As glicemias de jejum e pré-prandiais de 80 a 110 mg/dL, pós- prandiais 140 mg/dL e A1c <6,5% são os objectivos actuais Dado o carácter progressivo da doença é frequente a necessidade do recurso a insulinoterapia para atingir aqueles objectivos A terapêutica combinada é uma boa opção para eliminar a relutância em aderir à insulinoterapia que alguns doentes apresentam, embora caso não se atinjam os objectivos, possa ser abandonada em favor de uma terapêutica mais intensiva

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