Atualidade no Tratamento do Diabetes Tipo 2

Atualidade no Tratamento do Diabetes Tipo 2

Ameaador, agourento, sinistro

Efeito das incretinas sobre a secreção de insulina em resposta a glicose oral ou e.v. em normais
Glicose e.v. Glicose oral 200 100 2.0 1.5 1.0 0.5 0.0 Glicose oral (50g) ou infusão isoglicêmica * Glicose (mg/dL) Peptídeo C (nmol/L) Food elicits dynamic changes in insulin secretion, beginning with the so-called cephalic phase, in which anticipation of a meal releases insulin. This is mediated by the CNS. An early prandial phase, mediated by gut-derived incretin hormones (eg, GLP-1 and GIP) occurs after food intake but before the ingested nutrients appear in the circulation. To identify the contributions of these endogenous substances, 6 young healthy subjects were first given increasing oral glucose loads of 25 g, 50 g, and 100 g. They then received an isoglycemic intravenous glucose infusion that was designed to mimic the plasma profile achieved by the oral load.1 The intravenous glucose bypassed the gastrointestinal tract and therefore enabled an investigation of the role of incretins. Shown here (left chart) is the response to 50 g oral glucose compared with the matched intravenous infusion, demonstrating essentially identical rises and falls in plasma glucose. Yet the insulin secretory response (β-cell responses), demonstrated here by the connecting peptide (C-peptide) concentrations, were dramatically different (right chart). The oral challenge was followed by a robust increase in C-peptide levels. In contrast, insulin secretion following the isoglycemic intravenous glucose infusion was significantly less. The difference is ascribed to incretins, which are secreted in response to the presence of food in the GI tract and not when glucose is administered parenterally. The incretin effect thus refers to the difference in the magnitude of insulin secretion seen after glucose is ingested compared with that seen after an isoglycemic intravenous infusion. These findings suggest that incretins, and not merely the direct actions of glucose, affect the insulin secretory response. 1. Nauck MA, Homberger E, Siegel EG, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63: 60 120 180 Tempo (min) 60 120 180 Tempo (min) Nauck MA, et al. J Clin Endocrinol Metab. 1986;63: 3

O efeito Incretínico em pacientes com Diabetes Tipo 2

Efeito da infusão de GLP-1

Pacientes com DM2 apresentam resposta de GLP-1 pos prandial diminuída

GLP-1 Actions Are Glucose Dependent in Patients With Type 2 Diabetes
* Minutes Insulin Glucagon Fasting glucose 250 150 5 200 100 50 40 30 20 mU/L 15 10 60 120 180 240 15.0 12.5 10.0 7.5 5.0 Infusion mmol/L mg/dL pmol/L Placebo GLP-1 *P <0.05 n = 10 Notes taken from Dr. Drucker’s Amsterdam presentation GLP-1 Actions Are Glucose Dependent in Patients With Type 2 Diabetes This slide shows results from a study that characterized changes in glucose, insulin, and glucagon levels in response to a pharmacologic dose of GLP-1. The patients were studied on two occasions (once with GLP-1 and once with placebo). Ten patients with type 2 diabetes mellitus received an intravenous infusion of GLP-1 over 240 minutes. During infusion, blood was drawn at 30-minute intervals to permit assay of glucose, insulin, and glucagon concentrations. A day later, the procedure was repeated with a placebo infusion. Infusion of GLP-1 over 240 minutes lowered plasma glucose to normal basal levels in all patients, with significant mean reductions observed at all time points from 60 minutes onward (p<0.05 vs. placebo). During GLP-1 infusion, plasma insulin increased and glucagon decreased. However, as plasma glucose values approached normal basal levels, insulin and glucagon returned to baseline or near-baseline values, thus indicating the glucose-dependent nature of the effects of GLP-1. Nauck NA et al. Diabetologia 1993;36:741–744. Reference: Nauck MA, Kleine N, Ørskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1993;36:741–744.

A potencia insulinotropica do GLP-1 esta diminuída no DM2

Efeito insulinotrópico do GIP se encontra abolido

GLP-1 preserva a morfologia da Célula-β

Farilla; Endocrinology 2003
DAPI staining of islet cells nuclei. Human islets were cultured for 1 (A and B), 3 (C and D), and 5 (E and F) d in M199 medium, with 6 mM glucose, 10% FCS, and 0.1 mM diprotin-A and in the presence (B, D, and F) or absence (A, C, and E) of GLP-1 (10 nM, added every 12 h). Pictures (x100) are representative of cell apoptosis, as observed by culturing human islets from three independent donors. The arrows show the condensed nuclei of apoptotic cells. Farilla; Endocrinology 2003

Glucagon-like peptide-1 prevents beta cell glucolipotoxicity
Diabetologia 47 (5):806-15; 2004

Percentual de Alimento
Glucagon-like Peptide 1 Promotes Satiety and Suppresses Energy Intake Humans Saciedade Fome Percentual de Alimento Ingerido Plenitude J. Clin. Invest 101(3), 515–520; February 1998

Effect of GLP-1 on gastric volume, emptying, maximum volume ingested, and postprandial symptoms in humans 23% 7% Am J Physiol Gastrointest Liver Physiol 282: G424-G431, 2002;

Inibidores de DPP-IV Incretinomimeticos
Sitagliptina Vildagliptina Saxagliptina Linagliptina Exenatida Liraglutida

Incretin-Based Therapies
Madsbad S. Lancet. 2009;373:

SITA GLIPTINA VILDA SAXA LINA
ELIMINAÇÃO Rins (inalterado) Fígado (85%) e Rim (15%) Metabolito ativo Fígado e Rim Excretada inalterada pelo figado NECESSIDADE DE AJUSTE POSOLÓGICO EM IR Sim Não, em casos de IR leve Não POTENCIAL DE INTERAÇÃO MEDICAMEN- TOSA Baixa Potencial com drogas que atuam via CYP 3A4/5

Em estudos randomizados tanto a exenatide quanto liraglutide demonstraram efeitos sobre a redução da glicemia, com diminuição da Hb A1c de até 1,3%. Tanto a exenatide quanto a liraglutide promovem podem promover perda de peso em torno de 5 kg, nas doses preconizadas no tratamento do diabetes tipo 2. Tambem foi observada diminuição da pressão arterial de 2 – 7 mmHg. A posologia de 1 X ao dia da liraglutide e a vantagem de poder ser administrada em qualquer horario, faz com que sua aceitação seja melhor.

Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6) Buse JB, Rosenstock J, Sesti G, et al. Lancet. 2009; 374(9683):39–47

Variação no peso corporal de acordo com o quartil de perda de peso
Variação do peso (kg) Q1 Q4 Q3 Q2 Q3-Q4 Post-hoc analysis of change in body weight by weight loss quartile Wt by quartile tab_bw_exploratory_ _all Liraglutida 1.8 mg + metformina Q1: variação média de peso para os 25% dos pacientes que tiveram a maior perda de peso Q2: variação média de peso para o quartil de perda de peso Q3: variação média de peso para o quartil de perda de peso Q4: variação média de peso para o quartil de perda de peso, isto é, os 25% que tiveram a menor perda de peso Presentation title Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2; variação de peso corporal de acordo com o quartil de perda de peso). 24

Efeitos Extraglicemicos dos Agonistas
Tecido Alvo Efeitos Potenciais Benefícios CELULA β  βproliferação  βapoptose Durabilidade do efeito Potencial para prevenir DM2 SISTEMA CARDIOVASCULAR  Contratibilidade Miocardica  PA sistólica e diastólica Melhora do perfil lipidico Morbi-mortalidade DCV FIGADO Gliconeogenese e Glicogenolise Gordura hepática Melhora da sensibilidade hepática Melhora do controle glicemico  Progressão ou Regressão da esteatose PESO  Melhora da glicemia, PA e lipideos

Reduced incretin effect in type 2 diabetes:
cause or consequence of the diabetic state? Knop; Diabetes 56(8):1951;2007 We aimed to investigate whether the reduced incretin effect observed in patients with type 2 diabetes is a primary event in the pathogenesis of type 2 diabetes or a consequence of the diabetic state. Eight patients with chronic pancreatitis and secondary diabetes (A1C mean [range] of 6.9% [ ]), eight patients with chronic pancreatitis and normal glucose tolerance (NGT; 5.3 [ ]), eight patients with type 2 diabetes (6.9 [ ]); and eight healthy subjects (5.5 [ ]) were studied. Blood was sampled over 4 h on 2 separate days after a 50-g oral glucose load and an isoglycemic intravenous glucose infusion, respectively. The incretin effect (100% x [beta-cell secretory response to oral glucose tolerance test - intravenous beta-cell secretory response]/beta-cell secretory response to oral glucose tolerance test) was significantly (P < 0.05) reduced (means +/- SE) in patients with chronic pancreatitis and secondary diabetes (31 +/- 4%) compared with patients with chronic pancreatitis and NGT (68 +/- 3) and healthy subjects (60 +/- 4), respectively. In the type 2 diabetes group, the incretin effect amounted to 36 +/- 6%, significantly (P < 0.05) lower than in chronic pancreatitis patients with NGT and in healthy subjects, respectively. These results suggest that the reduced incretin effect is not a primary event in the development of type 2 diabetes, but rather a consequence of the diabetic state PG, plasma insulin, plasma C-peptide, and ISR in patients with chronic pancreatitis and NGT (triangles), patients with chronic pancreatitis and secondary diabetes (squares), healthy subjects (circles), and patients with type 2 diabetes (diamonds) after 50-g OGTT (ﬁlled symbols) and isoglycemic intravenous glucose infusion (open symbols), respectively. *Signiﬁcant differences (P < 0.05) between the individual OGTT and isoglycemic intravenous glucose infusion curves (repeated-measures ANOVA). CP, chronic pancreatitis; CTRL, control; T2DM, type 2 diabetes.

二○一七年十一月十二日 POORLY CONTROLED TYPE 2 DIABETIC PATIENTS, BEFORE AND AFTER 4 WEEKS INTENSIVE INSULIN TREATMENT The Integrated Insulin Secretory Response to the Incretin GIP in 8 poorly controled Type 2 Diabetes Was Diminished but Not Absent Speaker notes A hyperglycemic clamp was used to compare the insulinotropic actions of synthetic human GIP and GLP-1 in matched groups of patients with type 2 diabetes (n=9) and in subjects with NGT (n=9). In each group, GIP was infused at rates that resulted in plasma levels approximating physiologic concentrations (low rate; 0.8 pmol kg–1 min–1) and, subsequently, at pharmacologic (supraphysiologic) concentrations (high rate; 2.4 pmol kg–1 min–1). This slide shows results for infusion of GIP at 2 rates. Whereas the low rate of infusion resulted in similar insulin levels in both groups (P=0.14), the insulinotropic action of GIP infused at supraphysiologic doses (high rate) was significantly less in patients with type 2 diabetes than in subjects with NGT (P=0.047). In this study, infusion of GIP did not stimulate insulin release in patients with type 2 diabetes to the same extent as it did in subjects with NGT. However, a dose-dependent increase in insulin secretion was still observed among patients infused with GIP at a higher supraphysiologic rate compared with a lower rate (7.7 nmol/L/min vs 3 nmol/L/min; P<0.05). This study demonstrates that the insulinotropic effect of GIP in patients with type 2 diabetes, though diminished, is not absent. Purpose: To demonstrate the abnormality of the incretin axis in patients with type 2 diabetes. Takeaway: GIP increases insulin secretion in healthy subjects. In patients with type 2 diabetes, this insulinotropic effect is reduced but not absent. Hojberg et al. Diabetologia. 2009;52:199 Reference Nauck MA, Heimesaat MM, Ørskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993;91:301–307. 31

Beneficial Endocrine but Adverse Exocrine Effects of Sitagliptin in the Human Islet Amyloid Polypeptide Transgenic Rat Model of Type 2 Diabetes Estudo realizado com o objetivo de avaliar, a extensão e os mecanismos de ação, da sitagliptina e da metformina, isoladas ou em associação, no DM2, em modelo de ratos transgenicos (HIP human islet amyloid polypeptide). Os ratos foram tratados com sitagliptina, metformina e sitagliptina + metformina, ou placebo por 12 semanas. Foram avaliadas a glicose, a sensibilidade insulinica, a massa, “turnover “ e função de celula β. Diabetes 58 (7): , July 2009

Beneficial Endocrine but Adverse Exocrine Effects of Sitagliptin in the Human Islet Amyloid Polypeptide Transgenic Rat Model of Type 2 Diabetes O estudo mostrou que a sitagliptina + metformina possuem efeito sinergico de preservação da celula β. A metformina inibiu mais a apoptose do que a sitagliptina. A função da celula β foi parcialmente preservada por sitagliptina + metformina. Sitagliptina foi associado com aumento do turnover da celula ductal pancreatica , metaplasia ductal e uma rato apresentou pancreatite. Diabetes 58 (7): , July 2009

Novas indicações

Efeitos Cardiovasculares do GLP-1
Presença de receptores no coração Camundongos com knockout de receptores tem diminuição da contratilidade de VE e resposta diminuida à epinefrina exogena (Gros et al, Endocrinology 2003) GLP-1 melhora a disfunção endotelial em DM 2 com CHD (Nystrom et al, Am J Physiol 2004)

GLP-1 melhora a função do VE em seres humanos após IAM e angioplastia
pre-PCI post-PCI 10 20 30 40 50 GLP-1 CONTROLS * p< 0.01 LVEF (%) Nikolaidis et al, Circulation 2004

Eur Heart Eur Heart J 2009; 30(Suppl. 1): 917

GLP-1 preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and parkinsonism Li et al, Proc Natl Acad Sci 2009)

Papel do Rim na Homeostase de Glicose
Gliconeogenese Capacidade do rim de produzir e liberar glicose durante periodos de jejum, durante acidose e em situações patologicas. Filtração e Reabsorção de Glicose that renal glucose production accounts for approximately 25% of systemic glucose production Drugs 2010; 70 (4)

Filtração e Reabsorção de Glicose
O Sodium-Glucose Co-Transport 2 (SGLT2) é responsavel por 90% da reabsorção da glicose filtrada no tubulo proximal do nefron. Desta forma a inibição deste transportador diminui de forma significativa a reabsorção de glicose levando à glicosuria. Drugs 2010; 70 (4)

Effect of dapagliflozin inpatients with type 2 diabetes who have inadequate glycaemic control withmetformin: a randomised, double-blind, placebo-controlled trial. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. A correção da hiperglicemia e prevenção da glicotoxicidade são importantes objetivos no tratamento do diabetes tipo 2. Estudo realizado para avaliar a eficácia e segurança de dapagliflozin em pacientes diabeticos, com controle inadequado com metformina. Lancet Jun 26;375(9733):

Objetivo Primario: Hemoglobina Glicada ao termino de 24 semanas.
Effect of dapagliflozin inpatients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Estudo multicentrico, duplo cego, de 546 adultos em uso de metformina (>/=1500 mg por dia) Randomizados para dapagliflozin 2,5 mg (n:137); 5mg (n: 137); 10 mg (n:135) ou placebo (n: 137)uma vez ao dia Objetivo Primario: Hemoglobina Glicada ao termino de 24 semanas. Lancet Jun 26;375(9733):

Dapagliflozin 2,5 mg -0.67 % (-0.81 to -0.53, p=0.0002)
Effect of dapagliflozin inpatients with type 2 diabetes who have inadequate glycaemic control withmetformin: a randomised, double-blind, placebo-controlled trial. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Placebo -0.30% (95% CI to -0.16) Dapagliflozin 2,5 mg % (-0.81 to -0.53, p=0.0002) Dapagliflozin 5 mg % (-0.85 to -0.56, p<0.0001) Dapagliflozin 10 mg % (-0.98 to -0.70, p<0.0001) Lancet Jun 26;375(9733):

EFICACIA Placebo -0.30% (95% CI -0.44 to -0.16)
Effect of dapagliflozin inpatients with type 2 diabetes who have inadequate glycaemic control withmetformin: a randomised, double-blind, placebo-controlled trial. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Placebo -0.30% (95% CI to -0.16) Dapagliflozin 2,5 mg % (-0.81 to -0.53, p=0.0002) Dapagliflozin 5 mg % (-0.85 to -0.56, p<0.0001) Dapagliflozin 10 mg % (-0.98 to -0.70, p<0.0001) EFICACIA Lancet Jun 26;375(9733):

Effect of dapagliflozin inpatients with type 2 diabetes who have inadequate glycaemic control withmetformin: a randomised, double-blind, placebo-controlled trial. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Sintomas de hipoglicemia ocorreram em proporções semelhantes no grupo placebo (3%) e nos grupos dedapagliflozin (2-4%) Sinais e sintomas sugestivos de infecção genital foram mais comuns nos grupos de dapaflozin (2.5 mg, 11 pacientes [8%]; 5 mg, 18 [13%]; 10 mg, 12 [9%]) do que no grupo placebo (sete pacientes [5%]). 17 pacientes tiveram efeito adverso grave (4 em cada grupo de dapagliflozin e 5 no gripo placebo) Lancet Jun 26;375(9733):

Effect of dapagliflozin inpatients with type 2 diabetes who have inadequate glycaemic control withmetformin: a randomised, double-blind, placebo-controlled trial. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Sintomas de hipoglicemia ocorreram em proporções semelhantes no grupo placebo (3%) e nos grupos dedapagliflozin (2-4%) Sinais e sintomas sugestivos de infecção genital foram mais comuns nos grupos de dapaflozin (2.5 mg, 11 pacientes [8%]; 5 mg, 18 [13%]; 10 mg, 12 [9%]) do que no grupo placebo (sete pacientes [5%]). 17 pacientes tiveram efeito adverso grave (4 em cada grupo de dapagliflozin e 5 no gripo placebo) SEGURANÇA Lancet Jun 26;375(9733):

In addition to treatment-naive patients and those receiving metformin monotherapy, efficacy data for dapagliflozin as add-on therapy in T2DM patients poorly controlled on insulin plus oral antidiabetic drugs (OADs) was also recently reported from a randomized, double-blind,placebo-controlled study Weight loss was also achieved The placebo-subtracted changes in body- weight (95% CI) from baseline were -2.6 kg (-4.0, -1.2) and -2.4 kg (-3.8, -1.0) in the dapagliflozin 10 mg and 20 mg groups, respectively

A eficacia foi demosntrada em estudos com pacientes virgens de tratamento, em adição a antidiabeticos orais e insulina. A perda de peso tambem foi alcançada. A diferença de peso foi de kg (-4.0, -1.2) nos pacientes que utilizaram 10 mg de dapagliflozin e -2.4 kg (-3.8, -1.0) nos que utililizaram 20 mg.

Fingerstick Blood Glucoses
400 Glucose measurement 300 Insulin bolus Glucose (mg/dL) 200 Target Range 100 12:00 AM :00 AM : :00 PM :00 AM

Continuous Glucose Monitoring Provides More Comprehensive Picture of Glycemic Patterns
400 Glucose measurement 300 Insulin bolus Glucose (mg/dL) 200 Target Range 100 12:00 AM :00 AM : :00 PM :00 AM

GuardControl Study 162 subjects (half children/half adults) T1 DM randomized to: Guardian RT continuously Guardian RT 3 days every 2 weeks Continued SBGM Initial A1c >8.1% Control Intermittent use Continuous use Deiss D, Bolinder J, Riveline JP, et al. Improved glycemic control in poorly controlled patients with type 1 diabetes using real-time continuous glucose monitoring. Diabetes Care. 2006;12: P-value: Change from baseline between Continuous & Control groups Deiss D, et al. Diabetes Care. 2006;12:

Glucose Sensors

Combined glucose sensing and insulin delivery

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