Dúvidas
[email protected]
Arquivo
Medicamentos utilizados no tratamento do
diabetes mellitus
Site
www.gilbertodenucci.com
Diabetes Mellitus
Definição
Doença em que o organismo não produz ou utiliza
inadequadamente
a
insulina,
o
hormônio
hipoglicemiante, o que leva a estado de hiperglicemia
crônica
Glucose tolerance in normal person and in a person with diabetes
Guyton & Hall. Textbook of Medical Physiology. Tenth Edition.
Principais tipos de Diabetes Mellitus
Diabetes Mellitus tipo 1 (juvenil)
O DM tipo 1 resulta primariamente da destruição das
células pancreáticas tipo beta. Inclui casos decorrentes de
doença auto-imune e aqueles nos quais a causa da
destruição das células beta não é conhecida
Principais tipos de Diabetes Mellitus
Diabetes Mellitus tipo 1 (juvenil)
•
Corresponde a 5-10% do total de casos. A
forma rapidamente progressiva é geralmente
observada em crianças e adolescentes. A forma
lentamente progressiva ocorre geralmente em
adultos sendo referida como diabetes latente autoimune do adulto (LADA)
Principais tipos de Diabetes Mellitus
Diabetes Mellitus tipo 2 (adulto)
O DM tipo 2 resulta de graus variáveis de resistência
à insulina e deficiência relativa de secreção de
insulina. A maioria dos pacientes tem excesso de peso
Pathogenesis of type 2 diabetes. The two major metabolic abnormalities, i.e. insulin
resistance and insulin deficiency, contribute to hyperglycaemia and result from both
genetic and environmental factors.
Insulin Resistance
GENES
Hyperglycaemia
ENVIRONMENT
Insulin Deficiency
Pathophysiology of type 2 diabetes: Rationale for different oral antidiabetic treatment strategies - Diabetes Res Clin Pract. 2005 Jun;68 Suppl1:S22-9.
Principais tipos de Diabetes Mellitus
Diabetes Mellitus tipo 2 (adulto)
Corresponde a 90-95% do total de casos. O
diagnóstico é feito geralmente a partir dos 40 anos de
idade embora possa ocorrer mais cedo principalmente
em associação com a obesidade
Diabetes Mellitus tipo 1 x Diabetes Mellitus tipo 2
Tipo 1
Tipo 2
Início
< 30 anos
> 30 anos
História familiar de
Diabetes Mellitus
Raro
Comum
Peso corporal
Não obeso
Obeso
Cetoacidose
Comum
Raro
Tratamento com
insulina
Todos pacientes
Alguns pacientes
Auto-imunidade
Sim
Não
Prevalência na
população adulta
0.5%
5%
Associação com HLA
Sim
Não
Clinical Characteristics of Patients with Type I and Type II Diabetes
Mellitus
Guyton & Hall. Textbook of Medical Physiology. Tenth Edition.
Complicações comuns do diabetes tipo 2
Monografia de Glucovance – Site: http://www.merck.com.br/pdf/glucovance_monografia.pdf
Intensive glycemic control and risk for microvascular complications
Overview of insulin replacement therapy — The Journal of Family Practice - August 2009 (Vol. 58, No. 8)
Intensive glycemic control and risk for MI and microvascular
complications
Overview of insulin replacement therapy — The Journal of Family Practice - August 2009 (Vol. 58, No. 8)
Maiores reduções da HbA conferem maior proteção contra as complicações
do diabetes
Monografia de Glucovance – Site: http://www.merck.com.br/pdf/glucovance_monografia.pdf
Effect of removing the pancreas on the approximate concentrations of
blood glucose, plasma free fatty acids and acetoacetic acid
Guyton & Hall. Textbook of Medical Physiology. Tenth Edition.
Insulina
Proteína formada por 51 aminoácidos contidos no
interior de 2 cadeias peptídicas: uma cadeia A com 21
aminoácidos e uma cadeia B com 30 aminoácidos
As cadeias peptídicas são conectadas por duas pontes
dissulfeto e, além disso, há uma outra ponte dissulfeto
que liga as posições 6 e 11 da cadeia A
Insulina
Insulina
● = Carbono ● = Oxigênio ● = Nitrogênio, ● = Enxofre
Insulina
A insulina tende a formar dímeros em solução e
hexâmeros na presença do zinco
Dímero
Hexâmero
Hexâmero Insulina
Site: http://www.nature.com/nrd/journal/v4/n5/images/nrd1718-f2.jpg
Protein Crystal Recombinant Human Insulin
Site: http://mix.msfc.nasa.gov/IMAGES/HIGH/9802450.jpg
Insulina
A insulina endógena circulante tem meia-vida de 3-5
minutos
É catabolizada por insulinases no fígado, nos rins e na
placenta sendo que cerca de 50% da insulina são
removidos em uma única passagem pelo fígado
Insulina
A insulina é sintetizada nas células pancreáticas tipo beta
das ilhotas de Langerhans
Insulina
Célula
pancreática tipo
beta
Ilhotas de Langerhans
Insulina
Ilhotas de Langerhans
Insulina
Forma-se inicialmente um pré-pró-hormônio insulínico
Este pré-pró-hormônio é clivado para formar uma próinsulina que, em sua maior parte, é clivada
adicionalmente liberando o peptídeo C para formar a
insulina
Insulina
Pró-insulina
Peptidases da célula
pancreática tipo beta
Insulina
Peptídeo C livre
Insulina
Injeção de dextrose intra-peritoneal (5 g/kg)
½
1
2
3
½ hora: depleção dos grânulos de
insulina na célula tipo beta
4
5
6
Horas
6 horas: restauração dos grânulos de
insulina na célula tipo beta
Controle da liberação de insulina
Transportador de Glicose (1-5)
Glucose transporters
GLUT 1
Brain, erythrocytes,
placenta, fetal tissue
Low Km* (~ 1 mM). Allows relatively constant
uptake of glucose independent of the normal
extracellular concentration (4–6 mM).
GLUT 2
Liver, kidney, intestine,
pancreatic β-cell.
High Km (15–20 mM). Allows intracellular and
extracellular glucose to equilibrate across
membrane.
GLUT 3
Brain
Low Km (<1 mM) compared with GLUT2. Allows
preferential uptake in hypoglycemia.
GLUT 4
Muscle and adipose
tissue
Medium Km (2.5–5 mM). Insulin recruits
transporters from intracellular stores increasing
glucose uptake.
GLUT 5
Jejunum
Medium Km (~ 6 mM). Responsible for fructose
uptake.
Transportadores da glicose em humanos
GLUT-1
GLUT-2
GLUT-3
Todos os tecidos
Captação basal de glicose
Fígado e células pancreáticas tipo beta
Captação de glicose na hiperglicemia
Todos os tecidos
Captação basal de glicose
GLUT-4
Músculo esquelético e tecido adiposo
Captação de glicose dependente de insulina
GLUT-5
Intestino delgado e espermatozóides
Transportador de frutose
Aspectos anatômicos da ilhota de
Langerhans
Ação da Insulina
Captação de
glicose
Insulina
Fosforilação
Fusão
GLUT-4
Translocação
Effect of insulin in enhancing the concentration of glucose inside muscle
cells
Guyton & Hall. Textbook of Medical Physiology. Tenth Edition.
Schematic of the insulin receptor
Guyton & Hall. Textbook of Medical Physiology. Tenth Edition.
The actions of insulin and glucagon in liver, muscle and adipose tissue on the
overall flow of fuels
http://www.ncbi.nlm.nih.gov/books/bv
Efeitos da insulina no metabolismo
Carboidratos
Aumenta o transporte de glicose
Aumenta a síntese de glicogênio
Inibe a glicogenólise
Inibe a gliconeogênese
Lipídeos
Aumenta a atividade da lipoproteína lipase
Aumenta o armazenamento de gordura nos adipócitos
Aumenta a síntese de lipoproteínas no fígado
Inibe a lipólise
Inibe a oxidação de ácidos graxos
Proteínas
Aumenta o transporte de aminoácidos
Aumenta a síntese de proteínas
Insulinas de Mamíferos
Rapid-acting analogue (clear)
•
•
•
•
•
Onset: 10–15 min
Peak: 60–90 min
Duration: 4– 5 h
Humalog® (insulin lispro)
NovoRapid® (insulin aspart)
Insulin LisPro
Insulina Lispro e Aspart
Fast-acting (clear)
•
•
•
•
•
Onset: 0.5–1 h
Peak: 2–4 h
Duration: 5–8 h
Humulin®-R
Novolin®ge Toronto
Intermediate-acting (cloudy)
•
•
•
•
•
•
Onset: 1–3 h
Peak: 5–8 h
Duration: up to 18 h
Humulin®-N
Humulin®-L
Novolin®ge NPH
Long-acting (cloudy)
•
•
•
•
Onset: 3–4 h
Peak: 8–15 h
Duration: 22–26 h
Humulin®-U
Extended long-acting analogue
• Onset: 90 min
• Duration:24 h
• Lantus®* (insulin glargine)
Insulina Glarginina (Lantus)
Premixed (cloudy)
• A single vial contains a fixed ratio of insulin
(% rapid- or fast-acting to % intermediateacting insulin)
• Humalog® Mix25TM
• Humulin® (20/80, 30/70)
• Novolin®ge (10/90, 20/80, 30/70, 40/60, 50/50)
Terapia com insulina
Insulina plasmática em não
diabéticos µU/mL
40
30
20
10
0
Glicemia em não
diabéticos mg/dL
120
100
80
8am 10 12 2pm 4 6
Desjejum
Almoço
8 10 12 2am 4
Jantar
Lanche
6 8am
Terapia com insulina
Regime misto
NPH
Regular
NPH + Regular
NPH + Regular
Insulina
Ultralente
Regular
Ultralente
8am 10 12 2pm 4 6
Ultralente
+ Regular
Regular
8 10 12 2am 4
Regular
6 8am
Pacientes em uso de CSII nos EUA
1400000
1200000
1200000
1000000
800000
600000
400000
200000
6600
8700
11400
15000
20000
1990
1991
1992
1993
1994
42000
60000
100000
35000
81000
26500
1995
1996
1997
1998
1999
2000
0
Ano
2012
Controle de glicemia em uso de CSII
n
Idade média
(anos ± DP)
HbA1c* préCSII (%)
HbA1c* pósCSII (%)
P
Folow-up
(meses)
143
34 ± 13
8.28
7.46
<0.001
42
Bode (adolescentes)
50
14.9 ± 2.6
9.64
8.24
<0.001
42
Rudolph and Hirsch
107
36 ± 10.4
7.6
7.1
<0.0001
36
Chanteleau
116
29 ± 1
7.7
6.7
<0.001
54
Roland
25
13.8 ± 2.1
8.4
7.5
0.02
12
Autores
Bode (adultos)
*
mg/dL
Controle de glicemia: adolescentes x adultos
10
9
HbA1c
(%)
9.64
*
8.24
8.28
*
7.46
8
7
6
Adolescentes
n = 50
Adultos
n=413
Pré-CSII
Pós-CSII
* P < 0.001
Hipoglicemia pré e pós CSII
n
Idade média
(anos ± DP)
Hipoglicemia
pré-CSII
(%)
Hipoglicemia
pós-CSII
(%)
P
55
39.2 ± 12.9
138
22
<0.0001
Rudolph and Hirsch
107
36 ± 10.4
73.2
19.2
<0.0001
Chanteleau
116
29 ± 1
ND
10
25
13.8 ± 2.1
134
76
Autores
Bode
Roland
ND – Não disponível
0.01
Hipoglicemia pré e pós CSII
150
138
100
39
50
0
22
Pré CSII
1 ano
36
26
2 anos
3 anos
-------------------CSII----------------
4 anos
Redução no número de episódios de
cetoacidose após uso de CSII
0,5
0,4
Eventos por
ano
0,3
0,3
0,2
0,1
0,1
0,1
0
* P < 0.001
*
0,01
Adolescentes
n = 43
Pré-CSII
Adultos
n = 229
Pós-CSII
Inhaled Insulin Device.
The Exubera inhaled insulin device is
closed for portability and opened before
use. It is activated after insertion of an
insulin blister. The release unit must be
changed every 2 weeks.
Exubera
Action of insulin on the adipocyte
The effects of insulin on adipose tissue.
http://www.ncbi.nlm.nih.gov/books/bv
Sulfoniluréias
Sulfoniluréias
(clorpropamida,
glipizida, gliclazida e glimepirida)
glibenclamida,
Estimulam a secreção de insulina ligando-se a um
receptor específico na célula beta o qual determina
o fechamento dos canais de potássio dependentes
de ATP resultando em despolarização da célula
Controle da liberação de insulina
Chlorpropamide (t ½ = 36 h)
(1st generation)
Site: http://en.wikipedia.org/wiki/File:Chlorpropamide.svg
Gliclazide (t ½ = 10 h)
(1st generation)
Site: http://en.wikipedia.org/wiki/File:Gliclazide.svg
Tolbutamide (t ½ = 4.5-6.5 h)
(1st generation)
Site: http://en.wikipedia.org/wiki/File:Tolbutamide.svg
Glibenclamide (t ½ = 10h)
(2st generation)
Site: http://en.wikipedia.org/wiki/File:Glibenclamide.svg
Glipizide ( t ½ = 2-4 hs)
(2st generation)
Site: http://en.wikipedia.org/wiki/File:Glipizide.svg
Glimepiride (t ½ = 5 h)
(3st generation)
Site: http://en.wikipedia.org/wiki/File:Glimepiride.svg
Meglitinidas
Derivados do ácido benzóico (repaglinida)
Derivados da d-fenilalanina (nateglinida)
Estimulam a secreção de insulina ligando-se a
receptores na célula beta em sítios distintos dos canais
de potássio dependentes de ATP.
Controle da liberação de insulina
Repaglinide
Nateglinide
Metformin
Biguanides
Suggested mode action:
Reduces hepatic glucose production and glycogen metabolism
Improves insulin resistance via enhancing insulin-mediated
glucose uptake by skeletal muscle
Lowers triglycerides and total cholesterol levels
Raises high-density lipoprotein (HDL) levels and causes weight
loss
Metformin
Helpful in stabilizing blood sugar in brittle diabetics on insulin
therapy
Indicated alone in obese, mild diabetics because, unlike insulin, it
does not enhance lipogenesis
Glucose
Glucose-PO4
Lipogenesis
Krebs
cycle
Blood Glucose,
mg/100ml
Inhibition
of oxidative
metabolism
Lactic
acid
Blood glucose (diabetic)
100
Blood glucose (nondiabetic)
15
Blood insulin
Hours
0
1
2
3
Insulin
Microunits/ml
Pyruvic
acid
Administration
200
Mechanisms of action of metformin.
Metformin
Phosphorylation / Activation of AMP Kinase
↓ SREBP-1 Expression/Activuty
↓ ACC Activity
↓ Hepatic Gene Expression (e.g., FAS)
↑ Muscle Glucose Transport
↓ Hepatic FA and VLDL Synthesis
(↑ Hepatic FA Oxidation)
↓ Hepatic Steatosis
↑ Hepatic Insulin Sensitivity
↓ Hepatic Glucose Production
↓ Plasma Glucose and Triglycerides
The major target of metformin is the enzyme AMP-activated protein kinase (AMP kinase). Activation of AMP kinase by metformin results in decreased SREBP-1 expression
in the liver, with consequent reduced expression of enzymes regulating FA synthesis, including fatty acid synthase (FAS), and inhibition of acetyl-CoA carboxylase (ACC)
activity, also leading to decreased FA synthesis. Furthermore, AMP kinase activation results in decreased hepatic glucose production and increased glucose transport in
skeletal muscle. The overall effect is to decrease glucose and triglyceride levels, particularly in the post-absorptive state. FA, fatty acid; SREBP, sterol regulatory elementbinding protein 1.
Pathophysiology of type 2 diabetes: Rationale for different oral antidiabetic treatment strategies - Diabetes Res Clin Pract. 2005 Jun;68 Suppl1:S22-9.
Tiazolidinedionas
•
•
•
•
Reduz glicose plasmática
Aumenta uptake periférico de glicose
Reduz níveis de triglicerídeos
Aumenta a sensibilidade à insulina em tecidos
periféricos
Tiazolidinedionas
• Troglitazona (retirada do mercado)
• Rosiglitazona (retirada do mercado)
• Pioglitazona
Thiazolidinedione
Site: http://en.wikipedia.org/wiki/File:Thiazolidinedione.png
Pioglitazone
Site: http://www.dalton.com/images/pioglitazone.gif
Peroxisome proliferator-activated receptor (PPAR)
α (alpha) - liver, kidney, heart, muscle, adipose tissue and others
β/δ (beta/delta) - expressed in many tissues but markedly in brain,
adipose tissue and skin
γ (gamma) - although transcribed by the same gene, this PPAR
through alternative splicing is expressed in three forms:
• γ1 - expressed in virtually all tissues, including heart, muscle,
colon, kidney, pancreas, and spleen
• γ2 - expressed mainly in adipose tissue (30 amino acids longer)
• γ3 - expressed in macrophages, large intestine, white adipos tissue.
Alternative splicing resulting in protein isoforms
Site: http://en.wikipedia.org/wiki/File:Splicing_overview.jpg
Peroxisome proliferator - activated receptor pathway diagram
Site: http://en.wikipedia.org/wiki/File:PPAR-diagram.png
Thiazolidinediones
Bioactive GLP-1(7-36)amide and GIP (1-42) are released from the small intestine after meal
ingestion and enhance glucose stimulated insulin secretion (incretin action). DPP-4 rapidly
converts GLP-1 and GIP to their inactive metabolites GLP-1 (9-36) and GIP (3-42) in vivo.
Inhibition of DPP-4 activity prevents GLP-1 and GIP degradation, thereby enhancing incretin
action.
Biology of Incretins: GLP-1 and GIP - GASTROENTEROLOGY 2007;132:2131–2157
GIP actions in peripheral tissues.
Biology of Incretins: GLP-1 and GIP - GASTROENTEROLOGY 2007;132:2131–2157
Exenatide (Byetta)
•
•
•
•
•
•
53% idêntico ao GLP-1
Resistente a DPP-IV
Aumenta a secreção de insulina
Reduz a secreção de glucagon
Aumenta o tempo de esvaziamento gástrico
Sensação de saciedade – provoca queda de peso
GLP-1 actions in peripheral tissues. The majority of the effects of GLP-1 are mediated by direct
interaction with GLP-1Rs on specific tissues. However, the actions of GLP-1 in liver, fat, and
muscle most likely occur through indirect mechanisms.
Biology of Incretins: GLP-1 and GIP - GASTROENTEROLOGY 2007;132:2131–2157
The inactivation process of GLP-1 by DPP-IV.
GLP-1 based therapy for type 2 diabetes - european journal of pharmaceutical sciences 2 8 ( 2 0 0 6 ) 96–1081
Saxagliptin
Site: http://en.wikipedia.org/wiki/File:Saxagliptin.svg
Sitagliptin
Site: http://en.wikipedia.org/wiki/File:Sitagliptin.svg
Vildagliptin
Site: http://en.wikipedia.org/wiki/File:Vildagliptin_Structural_Formulae.png
Mechanism of action of vildagliptin.
In response to a meal, active glucagonlike peptide-1 (GLP-1) is secreted by the L cells of the intestines. Without the
presence of vildagliptin, GLP-1 is rapidly inactivated and degraded by the enzyme dipeptidyl peptidase IV (DPP4); when
vildagliptin is present, vildagliptin binds to DPP4, allowing GLP-1 to remain active. Active GLP-1 causes the pancreas to
increase insulin release and decrease glucagon release.
Vildagliptin: A novel oral therapy for type 2 diabetes mellitus - Am J Health-Syst Pharm—Vol 64 Jun 15, 2007
Target 2 physiologic glucose-lowering actions with a single
oral agent
Glucose-dependent mechanism target 2 key defects: insulin release and hepatic glucose
production
Site: www.januvia.com
In a single-dose pharmacokinetic study of patients with
type 2 diabetes
Rapidly increased active incretins (GLP-1 and GIP) through a full 24 hours
Site: www.januvia.com
A single oral dose sustains powerful DPP-4 inhibition for a
full 24 hours
Site: www.januvia.com
Significantly improved key meassures of beta-cell and
alpha-cell responsiveness to glucose
Site: www.januvia.com
Amylin
37 amino acid compound
Co-secreted with insulin from beta cells
Deficient in type 1 and type 2 DM
Renal clearance
Amylin - Physiological effects
1. Suppression of endogenous glucagon production
(especially in the postprandial state)
2. Reduction in postprandial hepatic glucose production
3. Reduction in gastric emptying time
4. Centrally mediated induction of satiety
5. Reduction in postprandial glucose levels
Pramlintide
Synthetic analogue of Amylin (3 amino acid substitutions with
proline for native amino acids)
Subcutaneous administration
Pramlintide
The most commonly reported adverse
effects associated with pramlintide use in type 1
DM were nausea, anorexia, and hypoglycemia in
these studies.
Acarbose
É um inibidor competitivo de α-glicosidases
intestinais tais como maltase, isomaltase, sacarase e
glicoamilase, retardando a absorção de carboidratos
Forest plot of comparison: colesevelam vs. placebo, outcome: mean
change in fasting blood glucose from baseline to endpoint (mmol/l).
Systematic Review or Meta-analysis Colesevelam for Type 2 diabetes mellitus: an abridged Cochrane review - DIABETICMedicine DOI: 10.1111/dme.12295 – Fig 04
Forest plot of comparison: 1 colesevelam vs. placebo, outcome: 1.4 mean change in
HbA1c from baseline to endpoint (%).
Systematic Review or Meta-analysis Colesevelam for Type 2 diabetes mellitus: an abridged Cochrane review - DIABETICMedicine DOI: 10.1111/dme.12295 – Fig 05
Forest plot of
comparison:
colesevelam vs.
placebo, outcome:
adverse events. M-H,
Mantel-Haenszel.
Systematic Review or Meta-analysis Colesevelam for Type 2 diabetes mellitus: an abridged Cochrane review - DIABETICMedicine DOI: 10.1111/dme.12295 – Fig 06
Forest plot of comparison: 1 colesevelam vs. placebo, outcome: 1.5 mean change in LDL
cholesterol from baseline to endpoints (mmol/l).
Systematic Review or Meta-analysis Colesevelam for Type 2 diabetes mellitus: an abridged Cochrane review - DIABETICMedicine DOI: 10.1111/dme.12295 – Fig 07
Chemical Structure of Canagliflozin
Canagliflozin For The Treatment of Type 2 Diabetes Drugs Today 2013, 49(6):363-376. fig 01
Renal glucose transport
Both SGLT1 and SGLT2 reabsorb the filtered glucose, although the majority of glucose is reabsorbed by SGLT2
Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes - Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2012:5 313–327 – Fig 01
At plasma glucose concentration around 8.3 mmol/liter, glucose appears in the
urine.
After the saturation threshold of 13.3 mmol/liter, glucosuria increases linearly along with plasma glucose. SGLT2 inhibition promotes glucosuria at an earlier
saturation threshold, permitting less reabsorption of glucose.
Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes - Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2012:5 313–327 – Fig 02
Change from baseline in A1c, percentage fasting plasma glucose concentration, and
total body weight in dapagliflozin 2.5, 5 and 10 mg and placebo groups up to week
24.
Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes - Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2012:5 313–327 – Fig 03
Change from baseline in A1c, percentage fasting plasma glucose concentration, and
total body weight in dapagliflozin 2.5, 5 and 10 mg and placebo groups up to week
24.
Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes - Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2012:5 313–327 – Fig 03
Change from baseline in A1c, percentage fasting plasma glucose concentration, and
total body weight in dapagliflozin 2.5, 5 and 10 mg and placebo groups up to week
24.
Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes - Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2012:5 313–327 – Fig 03
A and B) Change in body mass component as measured by dual-energy X-ray
absorptiometer fat mass and lean mass and Visceral Adipose Tissue (VAT) and
Subcutaneous Adipose Tissue (SAT) volume as measured by magnetic resonance
substudy, in type 2 diabetes patients inadequately controlled on metformin,
randomized to dapagliflozin versus placebo.
Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes - Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2012:5 313–327 – Fig 04
(A and B) Change in A1c and body weight over a 52 week trial of type 2 diabetes
patients uncontrolled on metformin randomized to glipizide versus dapagliflozin
Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes - Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2012:5 313–327 – Fig 05
(A–C) Mean A1c, Fasting Plasma Glucose (FPG) and change in body weight from
baseline over 12 weeks in patients with type 2 diabetes receiving insulin plus
insulin sensitizers, randomized to dapagliflozin versus placebo.
Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes - Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2012:5 313–327 – Fig 06
Efficacy of dapagliflozin in various studies
Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes - Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2012:5 313–327 – Tablr 01
Mechanisms underlying the putative cardiovascular effects of incretinbased therapies
The cardiovascular safety of incretin-based therapies: a review of the evidence - Petrie Cardiovascular Diabetology 2013, 12:130 – Fig 01
Mean weight loss in clinical trials with anti-obesity drugs
Do we need anti-obesity drugs? - Diabetes Metab Res Rev 2012; 28(Suppl 2): 8–20. – Table 01
Antidiabetogenic effects of GLP-1
GLP-1 based therapy for type 2 diabetes - european journal of pharmaceutical sciences 2 8 ( 2 0 0 6 ) 96–1081
Potency and selectivity of some DPP-IV inhibitors
GLP-1 based therapy for type 2 diabetes - european journal of pharmaceutical sciences 2 8 ( 2 0 0 6 ) 96–1081
Physiological processes modulated by DPP-IV activity
GLP-1 based therapy for type 2 diabetes - european journal of pharmaceutical sciences 2 8 ( 2 0 0 6 ) 96–1081
The family of glucose transporters (GLUTs 1–5)
http://www.ncbi.nlm.nih.gov/books/bv
Therapies for DM - 1 Human insulin replacement
http://www.ncbi.nlm.nih.gov/books/bv
Therapies for DM - 1 Human insulin replacement
http://www.ncbi.nlm.nih.gov/books/bv
Bariatric Surgery and Prevention of Type
2 Diabetes in Swedish Obese Subjects
ABSTRACT
BACKGROUND
Weight loss protects against type 2 diabetes but is hard to maintain with behavioral
modification alone. In an analysis of data from a nonrandomized, prospective,
controlled study, we examined the effects of bariatric surgery on the prevention of type 2
diabetes.
n engl j med 367;8 nejm.org august 23, 2012
Bariatric Surgery and Prevention of Type
2 Diabetes in Swedish Obese Subjects
ABSTRACT
METHODS
In this analysis, we included 1658 patients who underwent bariatric surgery and 1771 obese matched controls
(with matching performed on a group, rather than individual, level). None of the participants had diabetes at
baseline. Patients in the bariatric-surgery cohort underwent banding (19%), vertical banded gastroplasty (69%),
or gastric bypass (12%); nonrandomized, matched, prospective controls received usual care. Participants were
37 to 60 years of age, and the body-mass index (BMI; the weight in kilograms divided by the square of the height
in meters) was 34 or more in men and 38 or more in women. This analysis focused on the rate of incident type 2
diabetes, which was a prespecified secondary end point in the main study. At the time of this analysis (January 1,
2012), participants had been followed for up to 15 years. Despite matching, some baseline characteristics differed
significantly between the groups; the baseline body weight was higher and risk factors were more pronounced in
the bariatric-surgery group than in the control group. At 15 years, 36.2% of the original participants had dropped
out of the study, and 30.9% had not yet reached the time for their 15-year follow-up examination.
n engl j med 367;8 nejm.org august 23, 2012
Bariatric Surgery and Prevention of Type
2 Diabetes in Swedish Obese Subjects
ABSTRACT
RESULTS
During the follow-up period, type 2 diabetes developed in 392 participants in the control group and in 110 in
the bariatric-surgery group, corresponding to incidence rates of 28.4 cases per 1000 person-years and 6.8
cases per 1000 person-years, respectively (adjusted hazard ratio with bariatric surgery, 0.17; 95% confidence
interval, 0.13 to 0.21; P<0.001). The effect of bariatric surgery was influenced by the presence or absence of
impaired fasting glucose (P = 0.002 for the interaction) but not by BMI (P = 0.54). Sensitivity analyses,
including end-point imputations, did not change the overall conclusions. The postoperative mortality was
0.2%, and 2.8% of patients who underwent bariatric surgery required reoperation within 90 days owing to
complications.
n engl j med 367;8 nejm.org august 23, 2012
Bariatric Surgery and Prevention of Type
2 Diabetes in Swedish Obese Subjects
ABSTRACT
CONCLUSIONS
Bariatric surgery appears to be markedly more efficient than usual care in the prevention of type 2
diabetes in obese persons. (Funded by the Swedish Research Council and others; ClinicalTrials.gov
number, NCT01479452.)
n engl j med 367;8 nejm.org august 23, 2012
Natural history of type 2 diabetes
(A) Elevations above normal in postmeal and fasting glucose concentrations over time and (B) progression from compensatory bcell function to b-cell decline and failure, leading to a decline in insulin concentrations and insulin resistance. Zero indicates time of
diagnosis; dotted lines indicate (A) normal glucose concentrations and (B) 100% b cell function.
Choice of early treatment regimen and impact on b-cell preservation in type 2 diabetes - Int J Clin Pract, September 2013, 67, 9, 876–887 – Fig. 01
Bariatric Surgery versus Intensive Medical Therapy
in Obese Patients with Diabetes
ABSTR ACT
Background
Observational studies have shown improvement in patients with type 2 diabetes mellitus after bariatric surgery.
Methods
In this randomized, nonblinded, single-center trial, we evaluated the efficacy of intensive medical therapy alone
versus medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy in 150 obese patients with uncontrolled
type 2 diabetes. The mean (±SD) age of the patients was 49±8 years, and 66% were women. The average glycated
hemoglobin level was 9.2±1.5%. The primary end point was the proportion of patients with a glycated hemoglobin
level of 6.0% or less 12 months after treatment.
Bariatric Surgery versus Intensive Medical Therapy
in Obese Patients with Diabetes
ABSTR ACT
Results
Of the 150 patients, 93% completed 12 months of follow-up. The proportion of patients with the primary end point was 12% (5 of 41
patients) in the medicaltherapy group versus 42% (21 of 50 patients) in the gastric-bypass group (P = 0.002) and 37% (18 of 49
patients) in the sleeve-gastrectomy group (P = 0.008). Glycemic control improved in all three groups, with a mean glycated
hemoglobin level of 7.5±1.8% in the medical-therapy group, 6.4±0.9% in the gastric-bypass group (P<0.001), and 6.6±1.0% in the
sleeve-gastrectomy group (P = 0.003). Weight loss was greater in the gastric-bypass group and sleeve-gastrectomy group (−29.4±9.0
kg and −25.1±8.5 kg, respectively) than in the medical-therapy group (−5.4±8.0 kg) (P<0.001 for both comparisons). The use of
drugs to lower glucose, lipid, and blood-pressure levels decreased significantly after both surgical procedures but increased in patients
receiving medical therapy only. The index for homeostasis model assessment of insulin resistance (HOMA-IR) improved significantly
after bariatric surgery. Four patients underwent reoperation. There were no deaths or life-threatening complications.
Bariatric Surgery versus Intensive Medical Therapy
in Obese Patients with Diabetes
ABSTR ACT
Conclusions
In obese patients with uncontrolled type 2 diabetes, 12 months of medical therapy plus bariatric surgery
achieved glycemic control in significantly more patients than medical therapy alone. Further study will
be necessary to assess the durability of these results. (Funded by Ethicon Endo-Surgery and others;
ClinicalTrials.gov number, NCT00432809.)