drug - treatment of type 2 diabetes mellitus oral antidiabetics as. mudr. pavlína piťhová
TRANSCRIPT
![Page 1: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/1.jpg)
Drug - treatment of Type 2 diabetes mellitusOral antidiabetics
as. MUDr. Pavlína Piťhová
![Page 2: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/2.jpg)
- 20 -10 0 10 20 30 yars
Manifestation DM
7mmol/l
Plasma glucose level
Β-cellfunction
Postprandial
fasting
Insulin resistance
Insulin secretion
Natural course of diabetes mellitus
![Page 3: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/3.jpg)
Glucose
IGT/diabetes
Normal
Early secretion late insulin secretion
Insulin release after glucose intake
![Page 4: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/4.jpg)
Insulin resistance
Insulin secretion
-Diet-Physical exercise-metformin-Glitazons α-glukosidaseinhibitors
↓ insulin requirements
↑ plasma insulin level-sekretagogues of insulin-Exogenous insulin
Typ 2 diabetes treatment
GLP-1R agonistsDPPIV inhibitors
![Page 5: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/5.jpg)
Metformin Used over 50 years activates enzyme adenosinmonofosfate(AMP)-
proteinkinase Key regulator of glucose and lipid metabolism Responsible for cell sensitivity for insulin action Enhances activity of glucose transporters GLUT 4 and
GLUT-1 Normalizes activity of enzymatic pathway in insulin
signalling Result of this action: decreasing of hepatic glucose
production and increasing of glucose disposal in muscles
![Page 6: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/6.jpg)
metformin
Bowel :↑ anaerobic
glucosemetabolism
Adipose tissue:↑ glucose absorption
and oxidation
Liver:↓ glukoneogenesis↓ glykogenolysis
↓ fatty acids oxidation
Muscle:↑glucose absorptin and oxidation
↑ glykogen syntesis↓ fatty acids oxidation
↑ laktate ↓ free fatty acids
↓ glucose hepatic production ↑ glucose utilisation
↓ plasma glucose level
![Page 7: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/7.jpg)
Next metformin actions Protective influence on β – cells (oxidative stress
reduction, increases survival rate of β – cells) Decreases levels of PAI-1 43 – 100% →↓ risk of
trombotic complication in insulinresistant patients Direct protective effect against damage of endotelial
cells caused by chronic high glucose level→reduction in cardiovascular complication rate
↓free oxygen radicals formation ↓vWf, ↓E-selektin, ↓tPA = improvement in endotelial
function
![Page 8: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/8.jpg)
↓TG (30%), total cholesterol and LDLchol ( ↓ C – reactive protein level Doesn´t cause weigh gain ↓ IR = ↓ plasma insulin level Absence of low glucose levels = reduction of „extra snacks“
(very often of sweet taste) = reduction of energy intake EBM – reduction of cardiovascular complication in diabetic
patients (UKPDS 36% lower mortality and morbidity)
Next metformin action
![Page 9: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/9.jpg)
Lowering HbA1c by 1% decreases risk of....
0
p<0.0001 p<0.0001
p<0.0001 p<0.0001p=0.035
p<0.0001
p<0.0001
p<0.0001
-50
-45
-40
-35
-30
-25
-20
-15
-10
-5
Red
ukc
e ri
zika
(%)
Any diabetes-related death
Myocardial infarction
Stroke Peripheralvascular disease*
Microvascular disease
Cataract extraction
Diabetes-related death
All-cause mortality
21 21
14 1412
43
37
19
Stratton IM et al (UKPDS 35). BMJ 2000; 321: 405-412
![Page 10: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/10.jpg)
Next metformin action: PCOS: anovulation, infertility, hyperandrogenism,
IR + ↑IRI → metformin ↓ IR, ↓IRI, ↓ testosteron, ↓PAI-1, ↑pregnancy possibility
NASH: ↓fat deposits in liver databases DARTS a MEMO – diabetics treated by
metformin have lower risk of malignancy development
Risk of lactate acidosis
![Page 11: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/11.jpg)
Metformin contra-indication
Risk of lactate acidosis Limited liver function Limited kidney function Respiratory and heart failure Alcohol abusus
![Page 12: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/12.jpg)
Metformin – drugs and dosage 500 – 850– 1000mg 3x daily GLUCOPHAGE (tbl, XR tbl, eff ) SIOFOR METFIREX STADAMET Metformin GAL, AL, TEVA…
![Page 13: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/13.jpg)
rosiglitazon
pioglitazon
O
OO
S
NHNN
CH3
OO
S
NH
CH3CH2
N
O
Thiazolidindions - glitazones
1. ciglitazon 1982 – derivát klofibrátu2. troglitazon (Rezulin® )– antidiabetikum 1996 uveden na trh v USA a 1997 ve VB3. rosiglitazon a pioglitazon – 20004. netoglitazon
![Page 14: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/14.jpg)
Pleiotropic effects of PPAR receptors family
HDLchol.
PPARα PPARγ PPARσ/βreceptor
ligand
effect
leukotriensfibrates
prostaglandinsthiazolidindions
fatty acids
reversalCholesteroltransport
vasculareffects
Lipidoxidation
diferentiationredistributionof adipous tissue
Glucosemetabolism
![Page 15: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/15.jpg)
Glitazon effect on glucose disposal in tissues
Cell membrane
insulininsulin
glitazon
Insulin resistance Glitazon treatment
Cell nucleus
Glucose intake
glucose in
take
PPAR activation
buněčná membrána
![Page 16: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/16.jpg)
Next effects TZD: Preservation of β-cell function (↓IR and
stimulation of pancreatic PPAR) Effects on inflammation, atherosclerosis,
apoptosis (regulators of genes transkription) ↓ blood pressure immunomodulator (PPARγ inhibit release of
pro-inflammatory cytokines from macrophages)
![Page 17: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/17.jpg)
60
40
20
0
20 40 60
Months after randomisation
Inci
denc
e ne
w D
M/y
ear
(%)
Study time after finishing the study
12,1% /year
21,2% /year
5,4% /year3,1% /year
placebo
troglitazon
Studie TRIPOD – troglitazon and diabetes prevetion
![Page 18: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/18.jpg)
Weight Mean weight gain 2 – 3 kg/year Support formation of subcutaneous adipose tissue and fat
redistribution from visceral to subcutaneous tissue Fluid retention Improved metabolic control could cause the weight gain
![Page 19: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/19.jpg)
Benefits x risk of glitazons treatmentBenefits: Better metabolic control ↓insulin rezistance ↓visceral adipose tissue
(redistribution) ↓blood pressure improving β-cell function Improving endotelial function ↓fat deposits in liver (NASH)
Risk: Hepatotoxicity Weight gain/ ↑ body
adipose tissue/ ↑subcutaneous adipose tissue
Fluid retention/edema Pulmonary edema Risk of heart failure Risk of ischemic vascular
attacks????
![Page 20: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/20.jpg)
Pioglitazonu (ACTOS), 15 – 45mg 1x denně. Contra-indications: Hypersensitivity Heart failure present or in history (NYHA III – IV) Restricted liver function Pregnancy and breast feeding Glitazony are not to use in combination therapy with
insulin Be careful in vascular patients
![Page 21: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/21.jpg)
Acarbose pseudotetrasacharide, doesn´t absorb inhibits alfa-glukosidase → glucose absorption is limited and delayed; ↓ PPG 1,5-3
mmol/l ↓ FGP ↓ TG (↓ syntesis VLDL in hepatocytes) and ↓chol ↓risk of cardiovascular complication
GLUCOBAY – 100mg tbl – 1 - 2 tbl 3x daily
![Page 22: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/22.jpg)
Sulfonylurea - insulin secretagogues stimulate insulin secretion B-cell function must be efficient
![Page 23: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/23.jpg)
Sulfonylurea – insulin secretagogues Glibenclamid – MANINIL, GLUCOBENE (3,5 – 5mg
3x daily), risk of hypoglycemia!!! Gliclazid – DIAPREL MR 1 – 4tbl 1 – 2x daily Glipizid - MINIDIAB Glimepirid – 1 – 4mg 1x(2x) daily – AMARYL,
GLYMEXAN Gliquidon – GLURENORM 1tbl 3x daily – possible
to use in patients with restricted kidney function
![Page 24: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/24.jpg)
Incretin mimetics and incretin „enhancers“
mimic the normal effect of incretin hormons
Glucagon like peptid 1
![Page 25: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/25.jpg)
GLP 1 mimics the physiological state
Source: Kieffer & Habener (1999): Endocrine Reviews 20: 876-913
![Page 26: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/26.jpg)
GLP - 1 metabolits
DPP-4
Inhibition of DPP-4
GLP-1 Receptor agonists
![Page 27: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/27.jpg)
![Page 28: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/28.jpg)
Incretins GLP-1 receptor agonists exenatid (Byetta – 2x daily 5 – 10ug) liraglutid (Victoza – 1x daily 0,6 – 1,2 – 1,8mg) Inhibitors of dipeptidyl-peptidase IV Sitagliptin (JANUVIA – 100mg 1x daily), combination
with metformin JANUMET 50/850, 50/1000mg 2x daily
Vildagliptin (GALVUS), with metformin EUCREAS Saxagliptin (ONGLYZA)
![Page 29: Drug - treatment of Type 2 diabetes mellitus Oral antidiabetics as. MUDr. Pavlína Piťhová](https://reader035.vdocuments.pub/reader035/viewer/2022062318/551c02bb550346a34f8b4cea/html5/thumbnails/29.jpg)
Thank you for your attention