principles in treatment of type 2 diabetes · diabetes affects 6% of the global adult population....

PrinciplesPrinciples inin treatmenttreatment of of typetype 2 2 diabetesdiabetes

1 i

Dr hab. Jacek Dr hab. Jacek DaroszewskiDaroszewski Department of Department of EndocrinologyEndocrinology, , DiabetesDiabetes

and and IsotopeIsotope TherapyTherapy

[email protected]@umed.wroc.pl

0

50

100

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200

250

300

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1985 2000 2010 2030

mln

DiabetesDiabetes inin thethe worldworld

2 J.Daroszewski

160 000 000

550 000 000

370 000 000

„…„… DiabetesDiabetes affectsaffects 66%% ofof thethe globalglobal adultadult populationpopulation.. ItIt isis aa leadingleading causecause ofof blindness,blindness, heartheart disease,disease, stroke,stroke, kidneykidney failurefailure andand amputationamputation.. EveryEvery year,year, overover 33..88 millionmillion deathsdeaths areare duedue toto diabetes,diabetes, makingmaking diabetesdiabetes aa moremore significantsignificant globalglobal killerkiller thanthan HIV/AIDSHIV/AIDS andand malariamalaria combinedcombined.. EveryEvery 1010 secondsseconds aa personperson diesdies fromfrom diabetesdiabetes--relatedrelated causescauses.. InIn thatthat samesame 1010 seconds,seconds, twotwo peoplepeople developdevelop thethe diseasedisease.

((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

intensive therapy group after 7.8 yrs

Fat intakeFat intake <30% E<30% E

Saturated fatSaturated fat <10% E<10% E

NonNon--smokerssmokers

ExerciseExercise >150 min/week>150 min/week

Intensive Convent Intensive Convent Intensive Convent Intensive Convent 0

10

20

30

40

50

60

70

80

1

p=0.09

p=0.02 p=0.13

p=0.58

STENO-2

0

5

10

15

20

1 2 3 4 5 6

PCI or CABG

Vascular surgery Amputation

Macrovascular complications

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


Diet

Physical activity

Smoking cessation

Glycaemic control






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

meals, at bed time)meals, at bed time)

J.Daroszewski 13

Reality Reality inin thethe diabeticdiabetic educationeducation inin PolandPoland

81,8 91,0 68,5

8,2 17,8 30,5

14 J.Daroszewski

Education


Diet

Physical activity

Smoking cessation





Glycaemic control


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


Diet

Physical activity

Smoking cessation





Glycaemic control


19 J.Daroszewski

20 J.Daroszewski

LifestyleLifestyle interventionintervention preventsprevents the the progressprogress of of prediabeticprediabetic statesstates to to overtovert diabetesdiabetes

Education


Diet

Physical activity

Smoking cessation





Glycaemic control


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


Diet

Physical activity

Smoking cessation

Glycaemic control






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


Diet

Physical activity

Smoking cessation





Glycaemic control


32 J.Daroszewski

Ramlo-Halsted i wsp. Prim Care. 1999;26:771–789.

DM DM isis a a chronicchronic and progressive and progressive diseasedisease

Disease progression

prediabetes

insulinemiainsulinemia

Insulin Insulin resistaneresistane

HepaticHepatic gluconeogenesisgluconeogenesis

Diagnosis DM

PostprandialPostprandial glycemiaglycemia

FastingFasting glycemiaglycemia

ΒΒ--cellcell functionfunction

overt diabetes

4–7 years

0

50

100

Re

lati

ve

Bew

ta c

ells

fu

nct

ion

%

33 J.Daroszewski

UKPDS: UKPDS: loweringlowering ofof HbAHbA1c1c decreasesdecreases DM DM connectedconnected complicationscomplications

REDUCTION

HbA1c by 1% REDUCED RiSK (P<0,0001)

1%

Death connected with DM

Myocardial infarction

Microvascular complications

Peripheral atheromatosis

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%



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

Both high and low HbA1c

values are connected with increased mortality

Currie et al. Lancet. 2010;375:481–9.

2,0

1,4

1,0

0,8

MO

RT

ALIT

Y H

R (

95%

CI)

1,2

1,6

HbA1c (%)

1,8

6,0 6,5 7,0 7,5 8,0 8,5 9,0 9,5 10,0 10,5 11,0 11,5

HbA1c = 7,5%

Patients with DM 2

Age 50 yrs <

n=47970

Conclusion from large RCT: increase hipoglycaemic events in line with intensification

of therapy

Turnball et al. Diabetologia 2009;52:2288–98.

6

3

1

0

Ilo

raz

szan

s (h

ipo

glik

em

ia)

2

4

ACCORD

5

ADVANCE UKPDS VADT all

3,07

1,8

3,01

2,3 2,48

Comparison to standard therapy

MetaanalysisMetaanalysis ACCORD, ADVANCE, ACCORD, ADVANCE, UKPDS, VADT i UKPDS, VADT i PROactivePROactive

Ray K i wsp. Lancet 2009; 373: 1765–72

In type 2 diabetics intensive reduction of glycaemia decreases macrovascular events but doesn’t influence death risk.

TheThe optimaloptimal modemode ofiofi HbAHbA1c1c reductionreduction maymay be be differentdifferent inin somesome patientspatients populationspopulations

42 J.Daroszewski

infarct

CHD

stroke

All cause mortality

IndividualisationIndividualisation of of goalsgoals inin antihyperglycemicantihyperglycemic treatmenttreatment

DM 2 DM 2 •• inin youngyoung, , •• newlynewly diagnoseddiagnosed, , •• withoutwithout vascularvascular complicationscomplications

DM 2 DM 2 •• inin elderlyelderly •• long long durationduration •• withwith vascularvascular episodesepisodes

43 J.Daroszewski

SO WHAT A1C TARGETS?

Glycemic goals in DM treatment (PTD 2014)

General General goalgoal HbAHbA1c 1c <<7.07.0%%

HbAHbA1c 1c << 6.56.5%% NewlyNewly diagnoseddiagnosed and of and of shortshort durationduration

HbAHbA1c 1c << 8.08.0%% PatientsPatients > 70 > 70 yrsyrs Long Long durationduration (> 20 (> 20 yrsyrs) ) MacroangiopathyMacroangiopathy ( MI / ( MI / strokestroke))

HbAHbA1c 1c < < 7.07.0%% PatientsPatients > 65 > 65 yrsyrs ExpectedExpected survivalsurvival > 10 > 10 yrsyrs

45 J.Daroszewski

Strategia Strategia ABCDABCD ((AAgege-- BBody ody weightweight-- CComplicationsomplications-- DDurationuration))

young middle Advanced

- + - + - +

<6,5 6,5 -7 <6 <6,5 < 7 7 - 8

A

C or D > 10 yrs

HbA1C%

HbA1C > 9%

HbA1C < 9%

Insulin

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



alfa-glucosidase Inhibitors

Glitazons (TZD)


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

•• Inhibits gluconeogenesisInhibits gluconeogenesis

•• Decreases glucose absorption in gutDecreases glucose absorption in gut

•• Doesn’t induce hypoglycaemiaDoesn’t induce hypoglycaemia

•• Beneficial Beneficial oror neutralneutral for body massfor body mass

•• The most commonly used agent in treatment of DMThe most commonly used agent in treatment of DM

•• Be aware of contraindicationsBe aware of contraindications

54 J.Daroszewski

Contraindications for MTF use

•• AllergyAllergy to to biguanidesbiguanides

•• AcuteAcute diabeticdiabetic complicationscomplications

•• TypeType 1 1 DiabetesDiabetes (?) (?) –– inin monotherapymonotherapy

•• PregnancyPregnancy

•• DiabetesDiabetes withwith cachexycachexy

•• UncontrolledUncontrolled alcoholalcohol consumptionconsumption

•• ImpairedImpaired liverliver functionfunction

•• ImpairedImpaired renalrenal functionfunction

don’tdon’t start MTF start MTF ifif eGFReGFR < 60ml/min/1,73m< 60ml/min/1,73m2 2

stop MTF stop MTF eGFReGFR < 30ml/min/1,73m< 30ml/min/1,73m2 2

•• ShockShock, , inadequateinadequate bloodblood perfusionperfusion, , cardiaccardiac insufficiencyinsufficiency, , acuteacute coronarycoronary episodeepisode, ,

55 J.Daroszewski

Gastrointestinal symptoms during MTF treatment

(usually at the beginning)

•• DrynessDryness of of mouthmouth

•• MetallicMetallic tastetaste

•• AnorexiaAnorexia

•• NauseaNausea

•• FFlatulencelatulence

•• EpigastricEpigastric painpain

•• DDiarrheaiarrhea

56 J.Daroszewski

Treatment with metformin „start low go slow”

•• 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

Nathan i wsp. Diabetologia 2006 57 J.Daroszewski




Glitazons (TZD)


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

58 J.Daroszewski

Sulfonylureas (gliclazide, glipizide, glimepiride)

•• Stimulate insulin secretionStimulate insulin secretion

•• Efficient in lowering glycaemiaEfficient in lowering glycaemia

•• ExtraExtra--pancreatipancreaticc action action -- liver, adipose tissue, muscles liver, adipose tissue, muscles (accelerated translocation GLUT(accelerated translocation GLUT--4, increase glucose 4, increase glucose use, use, adiponectinadiponectin ststiimulationmulation in adipose tisin adipose tisssueue))

•• PleiotropicPleiotropic action (antaction (antiitthhromboticrombotic, , fibrfibryynolyticnolytic, , antiantiooxxiidative)dative)

•• Commonly use in clinical practice Commonly use in clinical practice

•• Low costLow cost

59 J.Daroszewski

•• hepatotoxicityhepatotoxicity

•• leukopenialeukopenia

•• anemia anemia

•• thrombocytopeniathrombocytopenia

•• skin skin reactionsreactions

•• hypoglycaemiahypoglycaemia

•• interactionsinteractions: : salicylatessalicylates, , NSAD, NSAD, fibratesfibrates, , betabeta--blockersblockers, , alcoholalcohol

•• increseincrese inin body massbody mass

Sulfonylureas – side effects

60 J.Daroszewski

•• hepatohepatotoxicitytoxicity

•• leukopenia leukopenia

•• anemia anemia

•• thrombocytopeniathrombocytopenia

•• skin skin reactionsreactions

•• hypoglycaemiahypoglycaemia

•• interactionsinteractions: : salicylatessalicylates, , NSAD, NSAD, fibratesfibrates, , betabeta--blockersblockers, , alcoholalcohol

•• iincreasencrease in body massin body mass

Sulfonylureas – side effects

61 J.Daroszewski

Glinids (nateglinid, repaglinid)

•• SSimilarimilar to SU to SU -- anotheranother receptor on Breceptor on B--cellscells

•• ShortShort and and rapidrapid action action –– useuse beforebefore mealmeal

•• SStimulatetimulate insulin insulin secretionsecretion

•• ControlControl postprandialpostprandial hyperglycemiahyperglycemia

•• UseUse inin patientspatients withwith irregularirregular feedingfeeding

•• LowLow riskrisk of of hypoglycaemiahypoglycaemia

62 J.Daroszewski




Glitazons (TZD)


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

63 J.Daroszewski

Alpha-glucosidase Inhibitors (acarbose)

•• InhInhiibit digestion of carbohydrates in gut and bit digestion of carbohydrates in gut and moderate their absorptionmoderate their absorption

•• Decrease postprandial glycemiaDecrease postprandial glycemia

•• 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




Glitazons (TZD)


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



alfa-glucosydase Inhibitors

Glitazons (TZD)


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.

Incretins are new treatment option in typ 2 DM

GLP-1 deficincy i DM

Quick breakdown of native GLP-1 with

dipeptidylopeptidase IV (DPP- IV)

t½ = 1- 2 min

Dipeptydylopeptidase-IV Inhibitors (DPP- IV) inhibit GLP-1 breakdown

GLP-1 receptors agonists stimulate GLP-1 production, increasing insulin secretion

Secretion GLP-1 In gut

GLP-1 inactivatiion

MEAL

Native GLP-1

Inhibitor

DPP-IV

DPP-IV

Rothenberg P i wsp. Diabetes. 2000;49(supl 1):A39.

Incretins are new treatment option in typ 2 DM

IncretinIncretin agentsagents (i(in n combinedcombined therapytherapy))

GLP-1 receptor agonists (Egzenatide, liraglutide)

DPP-IV Inhibitors (saxagliptin, sita-, vida- alo-)

Gastro-intestinal (nausea,

vomiting)

Gastrio-intestinal neuropathy

Significant not accure

Renal insufficincy

Liver insufficincy

74 J.Daroszewski

SideSide effectseffects::

Lancet Vol 378 July 9, 2011

Drugs targeting β-cell dysfunction New incretin - based treatments Non-incretin - β-cell stimulants

Drugs targeting β-cell dysfunction Drugs targeting β-cell and α-cell dysfunction Insulin-action enhancers Drugs targeting non-insulin-dependent pathways

SGLT2 inhibitors Hepatic targets

Drugs targeting the metabolic syndrome GIP antagonists 11 β-hydroxysteroid dehydrogenase-1-inhibitors

PPAR modulators Drug with unknown mechanisms

Dopamine D2-receptor agonists Bile acid sequestrants

Matabolic surgery

„…„… DiabetesDiabetes affectsaffects 66%% ofof thethe globalglobal adultadult populationpopulation.. ItIt isis aa leadingleading causecause ofof blindness,blindness, heartheart disease,disease, stroke,stroke, kidneykidney failurefailure andand amputationamputation.. EveryEvery year,year, overover 33..88 millionmillion deathsdeaths areare duedue toto diabetes,diabetes, makingmaking diabetesdiabetes aa moremore significantsignificant globalglobal killerkiller thanthan HIV/AIDSHIV/AIDS andand malariamalaria combinedcombined.. EveryEvery 1010 secondsseconds aa personperson diesdies fromfrom diabetesdiabetes--relatedrelated causescauses.. InIn thatthat samesame 1010 seconds,seconds, twotwo peoplepeople developdevelop thethe diseasedisease.

((Prof. Jean Claude Prof. Jean Claude MbanyaMbanya, prezes IDF ), prezes IDF )

76 J.Daroszewski

PrinciplesPrinciples inin treatmenttreatment of of typetype 2 2 diabetesdiabetes

77 i

Dr hab. Jacek Dr hab. Jacek DaroszewskiDaroszewski Department of Department of EndocrinologyEndocrinology, , DiabetesDiabetes

and and IsotopeIsotope TherapyTherapy

[email protected]@umed.wroc.pl

principles in treatment of type 2 diabetes · diabetes affects 6% of the global adult population....

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