Principles Principles in in treatment treatment of of type type 2 2 diabetes diabetes 1 i Dr hab. Jacek Dr hab. Jacek Daroszewski Daroszewski Department of Department of Endocrinology Endocrinology, , Diabetes Diabetes and and Isotope Isotope Therapy Therapy [email protected][email protected]
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Principles in treatment of type 2 diabetes · Dietary fat should provide 25-35% of total intake of calories but saturated fat intake should not exceed 10% of total energy. Cholesterol
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PrinciplesPrinciples inin treatmenttreatment of of typetype 2 2 diabetesdiabetes
1 i
Dr hab. Jacek Dr hab. Jacek DaroszewskiDaroszewski Department of Department of EndocrinologyEndocrinology, , DiabetesDiabetes
((Prof. Jean Claude Prof. Jean Claude MbanyaMbanya, , presidentpresident of IDF )of IDF )
3 J.Daroszewski
United Nations, World Population Prospect: 2008
Number of patients 3,082 mln prevalence 9,3% world 8,3% Europe 6,7% type 1 diabetes 10% type 2 diabetes 90% not treated 1,105 mln (29%)
DiabetesDiabetes inin PolandPoland
4 J.Daroszewski
IDF ATLAS 2010
CostsCosts of of treatmentreatment (per t (per patientpatient 2010 2010 –– EUR)EUR)
3751
979 779 145 238
J.Daroszewski
Costs overall 600 000 000 PLN
Education
Life style intervention
Diet
Physical activity
Smoking cessation
Glycaemic control
Achieve and maintain body weight goals
Management of blood pressure
Management of lipid disorders
Antiplatelet therapy
Rudiments of DM2 managementRudiments of DM2 management:: compcomprerehensivehensive treatment treatment
6 J.Daroszewski
STENO-2
Steno-2: •
160 patients with type 2 diabetes and the metabolic syndrome including microalbuminuria were randomized conventional therapy at their GP’s or intensive care at Steno Diabetes Center
Conventional group assigned to GPs
Intensive group assigned to Steno Diabetes Center
Endpoint examinations
Microvascular Macrovascular
4 years 8 years
80
80
n=160
STENO-2
LIFESTYLE Percentage of patients obtaining treatment goals for the
85 CVD events in 35 ’conventional’ patients 33 CVD events in 19 ’intensive’ patients
Stroke CVD death Myocardial infarction
Number of eventsNumber of events
Intensive Conventional
STENO-2
Percentage of patients achieving treatment goals set for the intensive therapy group at 7.8 yr
0
10
20
30
40
50
60
70
80
1
HbA1c<6.5% Cholesterol <4.5 mM
Triglycerides <1.7 mM
Systolic BP <130 mm Hg
Diastolic BP <80 mm Hg
Int Conv
%
p<0.0001 p=0.21
Int Conv Int Conv Int Conv Int Conv
p=0.06
p=0.19
p=0.001
Education
Life style intervention
Diet
Physical activity
Smoking cessation
Glycaemic control
Achieve and maintain body weight goals
Management of blood pressure
Management of lipid disorders
Antiplatelet therapy
Rudiments of DM2 managementRudiments of DM2 management:: compcomprerehensivehensive treatment treatment
11 J.Daroszewski
DiabeticDiabetic educationeducation
•• SelfSelf--monitoringmonitoring –– glucometer glucometer useuse •• DietDiet •• PhysicalPhysical activityactivity •• SymptomsSymptoms and management of and management of hypoglycaemiahypoglycaemia •• TechnicsTechnics of insulin of insulin injectioninjection •• FeetFeet inspectioninspection and and carecare ….….
•• InitialInitial educationeducation of of patientpatient treatedtreated withwith diet and diet and oraloral agentsagents –– min. 5 min. 5 hrshrs.. •• PatientPatient on insulin on insulin therapytherapy—— caca. 9 . 9 hrshrs..
12 J.Daroszewski
Don’t scold a patient
Self-monitoring of glycaemia – how often
OnlyOnly dietdiet 1x 1x inin monthmonth shortshort prolifeprolife ((fastingfasting and 2 and 2 hrshrs. . afterafter mainmain mealsmeals)) OralOral agentsagents oror GLPGLP--11 1x 1x inin weekweek shortshort prolifeprolife FixFix insulin insulin dosesdoses 11--2 measurements daily 2 measurements daily 1x in week short prolife1x in week short prolife 1x in month full prolife1x in month full prolife (fasting , (fasting , preprandialpreprandial, 2 hrs. after , 2 hrs. after maimainn
Rudiments of DM2 managementRudiments of DM2 management:: compcomprerehensivehensive treatment treatment
15 J.Daroszewski
J.Daroszewski 16
Diet is a basic part of management in every case. Treatment cannot be effective unless adequate attention is given to ensuring appropriate nutrition.
Dietary treatment should aim at: ◦ ensuring weight control ◦ providing nutritional requirements ◦ allowing good glycaemic control with blood glucose
levels as close to normal as possible ◦ correcting any associated blood lipid abnormalities
Diet
Dietary fat should provide 25-35% of total intake of calories but saturated fat intake should not exceed 10% of total energy. Cholesterol consumption should be restricted and limited to 300 mg or less daily.
Protein intake can range between 10-15% total energy (0.8-1 g/kg of desirable body weight). Protein should be derived from both animal and vegetable
sources (50%-50%).
Carbohydrates provide 50-60% of total caloric content of the diet. Carbohydrates should be complex and high in fibre. GI> 50
Excessive salt intake is to be avoided. It should be particularly restricted in people with hypertension and those with nephropathy.
Diet (cont.)
Education
Life style intervention
Diet
Physical activity
Smoking cessation
Achieve and maintain body weight goals
Management of blood pressure
Management of lipid disorders
Antiplatelet therapy
Glycaemic control
Rudiments of DM2 managementRudiments of DM2 management:: compcomprerehensivehensive treatment treatment
19 J.Daroszewski
20 J.Daroszewski
LifestyleLifestyle interventionintervention preventsprevents the the progressprogress of of prediabeticprediabetic statesstates to to overtovert diabetesdiabetes
Education
Life style intervention
Diet
Physical activity
Smoking cessation
Achieve and maintain body weight goals
Management of blood pressure
Management of lipid disorders
Antiplatelet therapy
Glycaemic control
Rudiments of DM2 managementRudiments of DM2 management:: compcomprerehensivehensive treatment treatment
21 J.Daroszewski
The cover of "The Economist", Dec. 13-19, 2003.
100 -150 years
22 J.Daroszewski
Body mass Body mass isis connectedconnected withwith mortalitymortality inin DM DM typetype 22
Mulnier. Diabet Med 2006;23:516–21
(n=28 725)
Re
lati
ve
risk
23 J.Daroszewski
HowHow much much doesdoes 1 kg 1 kg weightweight inin DM?DM?
Reduction of body mass by 1 kg resuts in:
Decrease CHD risk 6% women 3% men
Reduction RR (systolic and diastolic) by 1 mm Hg
tot Ch 1% LDL 0,7% HDL 0,2% TG 2%
Decrease glycaemia 3% (ca. 5,6mg%)
24 J.Daroszewski
FemalesFemales
> 80 cm increased risk of complications > 88 cm need of treatment
MalesMales
> 94 cm increased risk of complications > 102 cm need of treatment
Lean MEJ, et al. Lancet;1998:351:853–6
cm
The role od The role od adiposeadipose tissuetissue distributiondistribution. . IncreasedIncreased waistwaist circumferencecircumference ((abdominal abdominal fatfat) )
is is associated with an increased associated with an increased riskrisk of CV of CV complicationscomplications
25 J.Daroszewski
CostsCosts of of treatmenttreatment inin relationrelation to BMI to BMI (per (per yearyear))
Data from Wolf and Colditz. Am J Clin Nutr 1996; 63(Suppl): 466S–9S
(bil US$)
Cholelithiasis Hypertension CHD Type 2 diabetes
12
10
8
6
4
2
0
BMI (kg/m2)
23–24.9
25–28.9
29
26 J.Daroszewski
Intensification of the treatment Intensification of the treatment isis usually connected usually connected with increase of body masswith increase of body mass
UKPDS 33. Lancet 1998;352:837–53
Years of follow up
Bad
y m
ass
gain
(kg
)
intensive therapy conventional therapy
27 J.Daroszewski
ChangesChanges inin body mass body mass duringduring differentdifferent medicationmedication inin DMDM
Na podstawie:Mitri and Hamdy. Expert Opin Drug Saf 2009;8:573–84
Ch
ange
in b
od
y m
ass
(kg)
28 J.Daroszewski
Education
Life style intervention
Diet
Physical activity
Smoking cessation
Glycaemic control
Achieve and maintain body weight goals
Management of blood pressure
Management of lipid disorders
Antiplatelet therapy
Rudiments of DM2 managementRudiments of DM2 management:: compcomprerehensivehensive treatment treatment
29 J.Daroszewski
0
10
20
30
40
50
60
24
PP=0.0046=0.0046
All end points
connected
with DM
32
PP=0.019=0.019
CV deaths
44
PP=0.013=0.013
strokes
37
PP=0.0092=0.0092
Microvascular
end points
34
PP=0.0038=0.0038
Progression of
retinopathy
47
PP=0.0036=0.0036
Sight
deterioration
56
PP=0.0043=0.0043
Heart feilere
UKPDS Group. BMJ. 1998, 317, 703-713
Tight blood pressure control leads to the reduction
of risk of vascular complications
Goals for arterial hypertension
• < 140/90 mmHg - if higher – need for therapy
Goals for lipids
• cholesterol total < 175 mg/dl (< 4,5 mmol/l)
• LDL-cholesterol < 100 mg/dl (< 2,6 mmol/l)
• LDL-cholesterol (CHD) < 70 mg/dl (< 1,9 mmol/l)
• HDL-cholesterol > 40 mg/dl (> 1,0 mmol/l)
• non-HDL-cholesterol < 130 mg/dl (< 3,4 mmol/l)
• Triglycerides < 150 mg/dl (< 1,7 mmol/l)
Zalecenia PTD 2011
31 J.Daroszewski
Education
Life style intervention
Diet
Physical activity
Smoking cessation
Achieve and maintain body weight goals
Management of blood pressure
Management of lipid disorders
Antiplatelet therapy
Glycaemic control
Rudiments of DM2 managementRudiments of DM2 management:: compcomprerehensivehensive treatment treatment
32 J.Daroszewski
Ramlo-Halsted i wsp. Prim Care. 1999;26:771–789.
DM DM isis a a chronicchronic and progressive and progressive diseasedisease
UKPDS = Badanie Prospektywne Cukrzycy (ang. United Kingdom Prospective Diabetes Study) Opracowano na podstawie: Stratton IM i wsp. UKPDS 35. BMJ. 2000;321:405–412.
*P<0,0001 34 J.Daroszewski
Lowering of glycaemia:
•• As early as possibleAs early as possible
•• As low as possibleAs low as possible (?)(?)
•• As long as possibleAs long as possible
•• As safely as possibleAs safely as possible
•• As reasonably as possibleAs reasonably as possible
David N Kendall, ADA, New Orlean 2007
35 J.Daroszewski
„…whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2
diabetes who had either established cardiovascular disease or additional cardiovascular risk factors.”
ACCORD study
36 J.Daroszewski
ACCORD study - Median Glycated Hemoglobin Levels at Each Study Visit.
mediana HbA1c = 8.1%
mediana HbA1c = 7.5%
mediana HbA1c = 6.4%
ACCORD Study group, The NEJM 2008, vol. 358: 2545-2559
ACCORD: intensive therapy may be harmful?
Gerstein et al. N Engl J Med 2008;358:2545–59.
• Randomised study in type 2 DM (n=10251)
• Comparison intensive vs standard therapy
• Study has been stopped since increased mortality in intensive treated
group 25
10
0
Pai
en
ts r
em
ain
ing
in t
he
stu
dy
(%
)
5
20
YEARS
15
0 1 2 3 4 5 6 7
All cause mortality
Iloraz szans (CI) 1,22 (1,01; 1,46); p=0,04
standard
intensive
What was the reason of increased mortality in intensive arm?
% o
f p
atie
nts
wit
h a
t le
ast
1 in
cid
en
t o
f h
ypo
glyc
aem
ia
Duration of follow-up (years)
Yearly mortality in treated intensively:
• 2.8% - when hypoglycaemia occured
• 1.2% - without hypos
Hypoglycaemia?
ACCORD Study group, The NEJM 2008, vol. 358: 2545-2559
Metformin Pozilli P et al. Diabetes Metab Res Rev 2010;26:239-244 46 J.Daroszewski
Correlation between % of HbA1c and mean glycaemia
47 J.Daroszewski
Glycemic control in diabetes in Poland meanmean HbA1C 8.07%
J.Daroszewski PolDiab
Getting Patients to Goal Becomes More Challenging as Disease Progresses
NHANES= badanie NHANES (ang.National Health and Nutritional Examination Survey). Opracowano na podstawie: Lebovitz HE. Med Clin N Am. 2004;88:847–863; Turner RC i wsp. JAMA. 1999;281:2005–2012; UKPDS 16. Diabetes. 1995;44:1249–1258; Warren RE. Diabetes Res Clin Pract. 2004;65:S3–S8; Resnick HE i wsp. Diabetes Care. 2006;29:531–537; Koro CE i wsp. Diabetes Care. 2004;27:17–20.
Parameter (NHANES)
% of patients with HbA1c<7% 49,8% (2001–2002)
Mean HbA1c 7,9% (1999–2000)
100
0
Β -
cell
fu
nct
ion
( %
)
-10 0
DM diagnosis
Insulin therapy
Demand of insulin Failure of monotherapy
Combination of more agents
+/– insulin
Estimated time (years)
Combination of 2 agents
Monotherapy
80
60
40
20 Preclinical stage Prediabetic states Diabetes
10–20
49 J.Daroszewski
Life style modification
The choice of treatment mode in DM2 patient
•• Pathogenesis Pathogenesis of of DM 2DM 2
•• Presence of insulinPresence of insulin resistanceresistance
•• Duration of diseaseDuration of disease
•• Chronic complicationsChronic complications
•• CoCo--morbiditymorbidity
•• Economic ability of the patientEconomic ability of the patient
•• Cognitive ability of the patientCognitive ability of the patient
50 J.Daroszewski
Treatment algorithm (PTD 2013)
PSM – pochodna sulfonylomocznika
* na każdym etapie leczenia zalecana jest modyfikacja stylu życia ** rzadko, ewentualnie u osób szczupłych # agonista receptora GLP-1 (inkretynomimetyk) lub inhibitor DPP-4 (gliptyna)
metformin
(SU)
metformin
+
SU
metformin
+ 2 agents with
different
mechanisms
(SU or incretin
agent or
acarbose)
metformin
+ basal
insulina
or
metformin +
insulin
in 2 doses
(basal or
premixted)
metformin
+
Intensive
insulin
therapy
metformin
+
incretin
agent
Stage 1
Oral monotherapy
Stage 2a
Oral combined therapy *
Stage 2b
Elementary
Insulin thyerapy*
Stage 3
Combined Insulin therapy
premixted
insulin
51 J.Daroszewski
Life style Life style modificationsmodifications atat allall stagesstages
Features of oral antidiabetic agents
Metformin SU and glinids
alfa-glucosydase Inhibitors
Glitazons (TZD)
GLP-1 receptor agonists
DPP-IV Inhibitors
HbA1C 1-2% 1-2% 0,5-1,0% 0,5-1,0%
0,5-1,0%
0,5- 0,8%
Fasting Glycaemia
60-70 60-70
20-30 60-70 50 50
Insulin in plasma
Chol LDL
Chol HDL
TG
Body Mas
52 J.Daroszewski
Features of oral antidiabetic agents
Metformin SU and glinids
alfa-glucosidase Inhibitors
Glitazons (TZD)
GLP-1 receptor agonists
DPP-IV Inhibitors
HbA1C 1-2% 1-2% 0,5-1,0% 0,5-1,0%
0,5-1,0%
0,5- 0,8%
Fasting Glycaemia
60-70 60-70
20-30 60-70 50 50
Insulin in plasma
Chol LDL
Chol HDL
TG
Body Mas
53 J.Daroszewski
Metformin - mechanism of action
•• Increases periIncreases perippheralheral action of insulinaction of insulin
•• Start form a low dose (500 mg) 1x or 2x daily during meals Start form a low dose (500 mg) 1x or 2x daily during meals
(breakfast /supper)(breakfast /supper)
•• In 5In 5--7 days (if not GI side effects) titrate dose to 850 mg or 7 days (if not GI side effects) titrate dose to 850 mg or 1000 mg before breakfast and supper1000 mg before breakfast and supper
•• When GI side effects When GI side effects -- reduce a dose and try to increase in reduce a dose and try to increase in few daysfew days
•• MaMaxximalimal effect can be expected by the dose 2 x 850 effect can be expected by the dose 2 x 850 mg/day, with mg/day, with modermoderaatete increased effect by maximal dose increased effect by maximal dose 3000 mg/day3000 mg/day
•• UseUsedd in combined therapyin combined therapy
•• Frequent flatulence and diarrhoea Frequent flatulence and diarrhoea
•• AcarbosAcarbosee 22--3 x times daily (max. 3003 x times daily (max. 300 mg)mg)
•• Start form low dose and titrate weeklyStart form low dose and titrate weekly
64 J.Daroszewski
Features of oral antidiabetic agents
Metformin SU and glinids
alfa-glucosidase Inhibitors
Glitazons (TZD)
GLP-1 receptor agonists
DPP-IV Inhibitors
HbA1C 1-2% 1-2% 0,5-1,0% 0,5-1,0%
0,5-1,0%
0,5- 0,8%
Fasting Glycaemia
60-70 60-70
20-30 60-70 50 50
Insulin in plasma
Chol LDL
Chol HDL
TG
Body Mas
65 J.Daroszewski
Glitazons (pioglitazone, rosiglitazone -Avandia)
• PPAR-γ ligands
• Increase insulin action in adipose tissue and in muscles
• Reduce insulin resistance
• Beneficial effect on lipids
• Combine with MTF and SU
• Don’t use with insulin
66 J.Daroszewski
Controversy concerning glitazons - metaanalyses
• Increased risk of MI (rosiglitazone)
• Increased risk of bone fractures
• Increased risk o cardia insufficincy (rosiglitazone, pioglitazone)
• Acceleration of Graves’ orbitopathy?
67 J.Daroszewski
Features of oral antidiabetic agents
Metformin SU and glinids
alfa-glucosydase Inhibitors
Glitazons (TZD)
GLP-1 receptor agonists
DPP-IV Inhibitors
HbA1C 1-2% 1-2% 0,5-1,0% 0,5-1,0%
0,5-1,0%
0,5- 0,8%
Fasting Glycaemia
60-70 60-70
20-30 60-70 50 50
Insulin in plasma
Chol LDL
Chol HDL
TG
Body Mas
68 J.Daroszewski
Incretin effect
Wartości średnie SE; N = 6; *P .05; 01-02 = czas podawania glukozy we wlewie. Nauck MA, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab.
1986;63:492-498. Copyright 1986, The Endocrine Society.
Gly
caem
ia (
mm
ol/
l)
time (min)
Pep
tyd
C (
nm
ol/
l)
11
5,5
0
01 60 120 180 01 60 120 180
0,0
0,5
1,0
1,5
2,0
time (min) 02
02
incretin effect
Glucose p.o.
Glucose i.v. *
*
*
*
* *
*
Glucose load orally vs. intraveously
69 J.Daroszewski
Incretin effect in MD2 is blunted
IR=Immunologicznie reaktywna Opracowano na podstawie: Nauck M i wsp. Diabetologia. 1986;29:46–52.
Czas min
Insu
lina
IR, m
U/L
nm
ol/L
0.6
0.5
0.4
0.3
0.2
0.1
0
80
60
40
20
0
180 60 120 0
Control group (n=8)
DM2 patients (n=14)
Czas min
Insu
lina
IR, m
U/L
nm
ol/L
0.6
0.5
0.4
0.3
0.2
0.1
0
80
60
40
20
0
180 60 120 0
Oral glucose load (i.v.) glucose infusion
Incretin effect - physiology Incretin effect in DM2
70 J.Daroszewski
Glucagon-like peptide 1 (GLP-1)
action in peripheral tissues
71 J.Daroszewski
Insulin secretion
Glucagon secretion
Stomach
emptying
Neuroprotection
Appetite
Insulin synthesis
Β cell proliferation
Β cell apoptosis Insulin sensitivity
Cardioprotection
Cardiac output
Gluconeugenesis
Secretion GLP-1 in gut
GLP-1 inactivatiion
MEAL
Native GLP-1
DPP-IV
Rothenberg P i wsp. Diabetes. 2000;49(supl 1):A39.