Dr. Veerle Verjans Nefroloog - Orpadt

Dr. Veerle Verjans 

Nefroloog – diabetoloog 

AZ Turnhout



AZ Turnhout



AZ Turnhout

AANDACHT-AANDACHT 

AANDACHT AANDACHT

1.Overzicht DM type 2 

2.Incretines: pathofysiologie 

3.Incretines: exenatide/ liraglutide/ DPP4inhibitoren 

4.ADA-richtlijnen

WHO: toename van prevalentie van type 2 DM en 

obesitas 

Diabetes1 Weight2 Individuals (Millions) 

WHO = World Health Organization 

1. WHO. Diabetes. Available at: http://www.who.int/mediacentre/factsheets/fs312/en/. Accessed March 2009. 

2. WHO. Obesity and overweight. Available at: http://www.who.int/mediacentre/factsheets/fs311/en/index.html. Accessed March 2009. 

Individuals (Billions)

Type 2 DM: gezondheidsprobleem 

* Meest frekwente oorzaak blindheid bij volw. 

* Frekwente oorzaak nierfalen (> 1/3 v.d. 

dialysepatiënten) 

* 2-4x hogere mortaliteit bij ischem hartfalen 

* 2-6x meer CVA 

* 4x meer perifeer vasculair lijden 

* 15x meer amputaties (> 65y x25) 

* 7-15% van volksgezondheidsbudget

UKPDS: HbA1c – 1 % 

DM type 2 

Microvascular 

complications 

Retinopathy, neuropathy, 

nephropathy 

-37% 

Myocardial 

infarction 

Fatal and nonfatal MI 

Deaths related 

to diabetes 

-14% -21% 

Daling van Hba1c vermindert aantal diabetescomplicaties 

UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.

Pathofysiologie DM type2 

Liver 

Excess 

glucagon 

Diminished 

insulin 

Insulin deficiency 

Pancreas 

Hyperglycemia 

Alpha cell 

produces 

excess 

glucagon 

Islet 

Muscle and fat 

Excess glucose output Insulin resistance 

Adapted from Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483; Buchanan TA Clin 

Ther 2003;25(suppl B):B32–B46; Powers AC. In: Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:2152–2180; 

Rhodes CJ Science 2005;307:380–384. 

Diminished 

insulin 

Beta cell 

produces 

less insulin

Perorale medicatie Type 2 DM 

Sulphonylurea 

Repaglinide 

Stimuleren pancreas 

Metformine 

Verminderen 

hepatische glucose 

output 

- 

+ 

Carbohydrate 

DIGESTIVE ENZYMES 

Glucose 

Insulin 

(I) 

Glucose (G) 

G 

I 

G 

I 

I 

G 

I 

G 

G 

I 

G 

I 

G 

I 

G 

I 

G 

G 

I 

G 

- 

- 

+ 

Thiazolidinediones 

Verminderen insuline resistentie

klasse generische naam producten 

biguaniden metformine Glucophage ® , Metformax ® , 

Merck-metformine 

Merck metformine ® 

gliniden repaglinide NovoNorm ® 

sulphonylurea gliclazide (Uni Uni)Diamicron )Diamicron ® , Merck- Merck 

Gliclazide ® 

glipizide Glibenese ® , Minidiab ® 

gliquidone Glurenorm ® 

glibenclamide Bevoren ® , Daonil ® , Euglucon ® 

gliclazide L.A. L.A Uni diamicron ® 

glimepiride Amarylle ® 

glitazones pioglitazone Actos ® 

glucosidase 

remmers 

Combinatie 

met meformine 

rosiglitazone Avandia ® 

acarbose Glucobay ® 

+ glibenclamide 

+ rosiglitazone 

Glucovance ® 

Avandamet ® 

Glucovance 

Avandamet

Glitazonen 

* Vochtretentie, CAVE hartfalen 

* Fracturen ( rosiglitazone ) 

* Myocardinfarct: rosiglitazone vs pioglitazone


AANDACHT AANDACHT 

1. Metformines stop zo klaring < 30 ml/min 

lactaatacidose 

1. Sulfonylurea’s: enkel gliquidon (glurenorm) 

zo klaring < 30 ml/min 

langdurige hypoglycemie

Type 2 DM: outcome 

43% van de patiënten behalen de targets niet 

(HbA 1c

R/ type 2 DM en gewichtstoename 

Change in weight (kg) 

UKPDS: up to 8 kg in 12 years 

8 

7 

6 

5 

4 

3 

2 

1 

0 

Insulin (n=409) 

Glibenclamide (n=277) 

Metformin (n=342) 

0 3 6 9 12 

Years from randomisation 

Conventional treatment (n=411); 

diet initially then sulphonylureas, insulin and/or 

metformin if FPG >15 mmol/L 

Weight (kg) 

100 

ADOPT: up to 4.8 kg in 5 years 

96 

92 

88 

0 

0 1 

Rosiglitazone 

Metformin 

Glibenclamide 

UKPDS 34. Lancet 1998:352:854–65. n=at baseline; Kahn et al. (ADOPT). NEJM 2006;355:2427–43 

2 3 4 

Years 

5

Hba1c < 7% blijft niet 

Median HbA 1c (%) 

UKPDS 

9 

8.5 

8 

7.5 

7 

6.5 

6 

0 

Conventional* 

Glibenclamide 

Metformin 

Insulin 

Recommended 

treatment 

target 15 mmol/L; †ADA clinical practice recommendations. UKPDS 

34, n=1704 

UKPDS 34. Lancet 1998:352:854–65; Kahn et al. (ADOPT). NEJM 2006;355:2427–43 

8 

7.5 

7 

6.5 

6 

ADOPT 

0 1 2 3 4 5 

Time (years) 

Rosiglitazone 

Metformin 

Glibenclamide

Diabetes type 2, een ziekte met een 

stille evolutie 

progressieve vermindering van 

insulinesecretie 

Functie van 

de ß-cellen (%) 

100 

75 

50 

25 

0 

jaren sinds de diagnose 

Lebovitz Diabetes Reviews 1999; 7: 139-153 

Glucose intolerantie 

Verhoogde postprandiale glycemie 

Verhoogde nuchtere glycemie 

-12 -10 -6 -2 0 2 6 10 14


2.Incretines: pathofysiologie

GLP = glucagon like peptide ( jejunum - colon ) 

GIP = glucose dependent insulinotropic peptide ( duodenum )

Fysiologie van Incretines 

Ingestion of 

food 

GI tract 

Release of 

incretin gut 

hormones 

Active 

GLP-1 and GIP 

Pancreas 

Beta cells 

Alpha cells 

Glucose dependent 

Insulin 

from beta cells 

(GLP-1 and GIP) 

Glucagon 

from alpha cells (GLP- 

1) 

Glucose dependent 

Insulin 

increases 

peripheral 

glucose 

uptake 

Increased insulin and 

decreased 

glucagon 

reduce 

hepatic 

glucose output 

Blood 

glucose control 

Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659; Zander M et al Lancet 2002;359:824–830; Ahrén B Curr Diab Rep 2003;3:365– 20 

372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.

Fysiologie van incretines 

Beta-cellen en alfacellen 

van de pancreas 

Hersenen: 

Stimuleert verzadiging en 

vermindert voedselinname 

Lever 

Maag : 

Vertraagt de maaglediging

Plasmaglycemie aders (mmol/l) 

Het “incretine incretine-effect effect” 

11 

5.5 

0 

Tijd (min) 

Peptide-c (nmol/L) 

0 1 60 120 180 0 1 60 120 180 

0 2 

Studie in cross over bij niet-diabetici (n=6) 

Gemiddelden ± SE; *p ≤.0,05; 0 1 -0 2 = Perfusietijd van glucose. 

(1) Nauck MA, et al.. J Clin Endocrinol Metab. 1986;63:492-498. 

Orale glucose 

IV glucose 

2.0 

1.5 

1.0 

0.5 

0.0 

0 2 

* 

* 

* 

Tijd (min) 

* 

* 

Incretine- 

* 

effect 

*

Incretine-effect Incretine effect is 

verminderd bij DM type 2 

Glucose 

(mg/100 ml) 

Insulin 

(µU/ml) 

Glucagon 

(µµg/ml) 

360 

330 

300 

270 

240 

110 

80 

150 

120 

90 

60 

30 

0 

140 

130 

120 

110 

100 

90 

Type 2 diabetes mellitus (n=12)* 

Nondiabetic controls (n=11) 

–60 

Meal 

*Insulin measured in five patients 

23 

Adapted from Müller WA et al N Engl J Med 1970;283:109–115. 

Nonsuppressed glucagon 

0 60 120 180 240 

Time (minutes) 

Depressed/delayed insulin response

Incretin-effect Incretin effect is 


GLP-1 (pmol/L) 

20 

15 

10 

5 

0 

*p

Incretine-effect Incretine effect is 


Insulin (nmol liter –1 min) 

60 

50 

40 

30 

20 

10 

0 

7.4 

*Low rate=0.4 pmol kg –1 min –1 

**High rate=1.2 pmol kg –1 min –1 

***vs. corresponding NGT group 

NGT (n=9) 

Type 2 diabetes (n=9) 

Study included four examinations per patient: 1) an oral glucose challenge; and hyperglycemic clamp experiments with 

administration of 2) glucagon; 3) GIP; and 4) GLP-1. Only results for GLP-1 are shown. 

Adapted from Nauck MA et al J Clin Invest 1993;91:301–307. 

51.4 

GLP-1 infusion (low rate)* 

GLP-1 infusion (high rate)** 

P=NS*** 

7.5 

P=NS*** 

38.2 

Normale GLP-1 werking

GLP-1 GLP 1 infusie bij DM type 2 

Glucose 

(mmol/L) 

Insulin 

(pmol/L) 

Glucagon 

(pmol/L) 

15.0 

12.5 

10.0 

7.5 

5.0 

250 

200 

150 

100 

50 

20 

15 

10 

5 

N=10 patients with type 2 diabetes. Patients were studied on two occasions. A regular meal and drug schedule was allowed for 

one day between the experiments with GLP-1 and placebo. 

*p

GLP-1 GLP 1 infusie bij DM type 2 

Snelle inactivatie (DPP-4), 

Korte halveringstijd (~1-2 min) 

GLP-1 moet onophoudelijk worden toegediend 

(perfusie) 

Niet geschikt voor de behandeling 

van een chronische ziekte zoals diabetes type 2 

Nabootsen van effecten van GLP-1 : Incretine mimetica 

Verlengen van het half-leven van GLP-1 na de maaltijden: DPP-4 inhibitoren

Medicaties voor Type 2 DM 

Sulphonylurea 

Repaglinide 

Stimuleren pancreas 

Metformine 

Verminderen 

hepatische glucose 

output 

- 

+ 

Carbohydrate 


Glucose 

Insulin 

(I) 

Insulines 

Glucose (G) 

G 

I 

Incretines (DPP-4, GLP-1 

Effect op beta- (insuline) 

en alfacel (glucagon) 

G 

I 

I 

G 

I 

G 

G 

I 

G 

I 

G 

I 

G 

I 

G 

G 

I 

G 

- 

- 

+ 

Thiazolidinediones 

Verminderen insuline resistentie

Incretines 

DPP-4 inhibitoren: (oraal, incretine enhancers) 

– Januvia (Sitagliptine) 

– Galvus (Vildagliptine) 

– Saxaglipitine 

Incretinemimetica: (SC, GLP-1 analogen) 

– Byetta (Exenatide) 5 -10 µg 2 x per dag SC 

– Victoza (Liraglutide) 1 x SC per dag (? Begin 2010) 

– Exanatide QW 1 X SC per week (? 2011)



3.Incretines: exenatide

Exenatide (BYETTA) 

Synthetische versie van een 

proteïne dat wordt gevonden in 

het speeksel van een hagedis 

(Gila monster) 

Ongeveer 50% overeenkomst 

met het humane GLP-1 

Heeft een gelijkaardige 

bindingsaffiniteit met de GLP-1 

receptoren van de β-cellen 

Resistent aan de inactivatie door 

DPP-4 

Adapted from Nielsen LL, et al. Regulatory Peptides. 2004;117:77-88.; Fineman MS, et al. Diabetes Care. 2003;26:2370-2377. 

Reproduced from Regulatory Peptides, 117, Nielsen LL, et al, Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved 

glycemic control of type 2 diabetes, 77-88, 2004, with the permission of Elsevier.

Exenatide Effects on Diabetes, Obesity, 

Cardiovascular Risk Factors, and Hepatic 

Biomarkers in Patients with Type 2 Diabetes 

Treated for at least 3 years 

David C. Klonoff, MD, FACP 1 ; John B. Buse, MD, PhD 2 ; Loretta L. Nielsen, PhD 3 ; 

Xuesong Guan, MS 3 ; Christopher L. Bowlus, MD 4 ; John H. Holcombe, MD 5 ; 

Matthew E. Wintle, MD 3 ; David G. Maggs, MD 3 . 

1 Diabetes Res Inst., Mills-Peninsula Hlth. Services, San Mateo, CA; 2 Division of 

Endocrinology, Dept. of Medicine, Univ. North Carolina School Med., Chapel Hill, 

NC; 3 Amylin Pharmaceuticals, Inc., San Diego, CA; 4 Univ. California-Davis, Davis, 

CA; 5 Eli Lilly and Co., Indianapolis, IN.

Exenatide: 

Exenatide: 

verlaging Hba1c 

% ∆ HbA 1c 

0.0 

-1.0 

-2.0 

-3.0 

HbA1c < 9% HbA1c ≥ 9% 

-0.6% 

-2.1% 

Klonoff DC, et al. Curr Med Res Opin 2008;24:275-286. 

♦ - 0.6% decrease with baseline 

HbA1c < 9% (mean 7.8%) 

♦ - 2.1% decrease with baseline 

HbA1c ≥ 9% (mean 9.7%)

Exenatide: 

Exenatide: 


Hba1c blijft laag !!! 

1c (%) 

HbA 

10 

9 

Baseline 8.2 ± 0.1% 

Week 156 

-1.0% (95% CI:-1.1 to -0.8%) 

8 

7 

6 

5 

4 

0 26 52 78 104 130 156 

Duur (weken) 

Klonoff DC, et al. Curr Med Res Opin 2008;24:275-286.

Hba1c < 7% blijft niet 

Median HbA 1c (%) 

UKPDS 

9 

8.5 

8 

7.5 

7 

6.5 

6 

0 

Conventional* 

Glibenclamide 

Metformin 

Insulin 

Recommended 

treatment 

target 15 mmol/L; †ADA clinical practice recommendations. UKPDS 

34, n=1704 

UKPDS 34. Lancet 1998:352:854–65; Kahn et al. (ADOPT). NEJM 2006;355:2427–43 

8 

7.5 

7 

6.5 

6 

ADOPT 

0 1 2 3 4 5 

Time (years) 

Rosiglitazone 

Metformin 

Glibenclamide

Exenatide: 

Exenatide: 


en gewicht 

Gewichtsverandering sinds Baseline (kg) 

0 

-2 

-4 

Baseline 99.3 ± 1.2 kg 

-6 

0 26 52 78 104 130 156 

N=217 Mean±SE 

Week 156 

-5.3 kg (95% CI: -6.0 to -4.5 kg) 

Duur (weken) 

1c (%) 

HbA 

10 

9 


Week 156 

-1.0% (95% CI:-1.1 to -0.8%) 

8 

7 

6 

5 

4 

0 26 52 78 104 130 156 

Duur (weken) 


R/ type 2 DM en 

gewichtstoename 

Change in weight (kg) 

UKPDS: up to 8 kg in 12 years 

8 

7 

6 

5 

4 

3 

2 

1 

0 

Insulin (n=409) 

Glibenclamide (n=277) 

Metformin (n=342) 

0 3 6 9 12 

Years from randomisation 

Conventional treatment (n=411); 

diet initially then sulphonylureas, insulin and/or 

metformin if FPG >15 mmol/L 

Weight (kg) 

100 

ADOPT: up to 4.8 kg in 5 years 

96 

92 

88 

0 

0 1 

Rosiglitazone 

Metformin 

Glibenclamide 

UKPDS 34. Lancet 1998:352:854–65. n=at baseline; Kahn et al. (ADOPT). NEJM 2006;355:2427–43 

2 3 4 

Years 

5

Hoera: vermagering !!!

Exenatide vs Insuline 

BYETTA: glycemische controle vergelijkbaar met insuline glargine 

% ∆ HbA 1c 

Verandering HbA1C (%) na 26W 

0.0 

-0.5 

-1.0 

-1.5 

-1.1% -1.1% 

Bevolking Per Protocol 

BYETTA 10µg 2/d (n=228) 

Insuline glargine (n=227) 

Heine RJ, et al. Ann Intern Med. 2005;143:559-569. 

% Patiënten die een 

HbA1c ≤ 7% halen 

60 

50 

40 

30 

20 

10 

0 

Bevolking ITT 

BYETTA 10µg 2/d (n=275) 

Insuline glargine (n=260) 

46% 48% 

% Patiënten die een 

HbA 1c ≤ 7% halen op 26 weken

Exenatide vs insuline 

Progressief gewichtsverlies vs. insuline 

∆ gewicht (kg) 

Gewichtsschommeling (kg) na 26 weken 

3 

2 

1 

0 

-1 

-2 

-3 

* * 

0 2 4 8 12 18 26 

ITT-bevolking; Het gewicht bij de opname was ( gemiddeld ± ET) : exenatide 87,5 ± 16,9 kg 

en insulineglargine 88,3 ± 17,9 kg; Gemiddeld ± SE; *p

Exenatide verbetert 

lipidenprofiel 

Mean Change (%) 

30 

25 

20 

15 

10 

5 

0 

-5 

-10 

-15 

-20 

Placebo-controlled/Open-label Extension (Combined) 

TG LDL TC 

-12% 

* 

-6% 

* 

TG = triglycerides; SBP = systolic BP; DBP = diastolic BP 

From : Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286. 

-5% 

* 

* 

+24% 

HDL 

N=151; *p

Toediening van Byetta 

Voorgevulde pen: 60 dosissen voor 30 dagen 

2 VASTE doseringen: 5µg en 10µg 

2x / dag vóór de maaltijd 

De BYETTA-dosis moet niet aangepast 

worden noch aan de maaltijden noch aan de 

lichamelijke activiteit noch aan de resultaten 

van glycemische zelfcontrole.

Nevenwerkingen Byetta 

Nausea 

Geef advies aan patiënten om nausea te verminderen: 

– Eet langzamer 

– Verminder het volume van de maaltijden 

– Stop met eten vanaf het moment dat u zich verzadigd voelt 

– Korte bij maaltijd inspuiten 

Hypoglycemie 

Om het risico op hypoglycemie te verminderen kan een vermindering van 

de dosis van sulfonylurea overwogen worden. 

Pancreatitis

Contra-indicaties 

Contra indicaties Byetta 

Bij ernstige of terminale nierinsufficiëntie (creatinineklaring < 30 ml/min.). 

Bij een ernstige gastro-intestinale ziekte, inclusief gastroparese (beperkte 

ervaring en verhoogd risico op spijsverteringsstoornissen). 

Zwangere vrouw of vrouw die borstvoeding geeft 

Kinderen en adolescenten jonger dan 18 jaar 

In combinatie met insuline of inhibitoren van alfa-glucosidase (ontbreken 

van gegevens). 

Interactie met medicatie: antibiotica, immuunsuppressiva, vit-k 

antagonisten



Exenatide ( Byetta ): 

1. Verlaging Hba1c en langdurig 

2. Gewichtsverlies 

3. Minder hypoglycemies 

4. Gemakkelijk te gebruiken



3.Incretines: exenatide 

4.Incretines: liraglutide

Liraglutide = Victoza 

97% amino acid 

homology to human 

GLP-1 

Native human GLP-1 

53% amino acid 

homology to human 

GLP-1 

Study duration: Liraglutide 26 weeks; exenatide 30 weeks. 

1 Data on file; 2 DeFronzo et al. Diabetes Care 2005;28:1092 

Liraglutide 

Exenatide 

97 % overeenkomst humane GLP1 

Percentage of patients 

with increase in 

antibodies 

100 

80 

60 

40 

20 

0 

8.6% 

Liraglutide 1 

43% 

• There was no blunting of 

efficacy by liraglutide 

antibodies 

Exenatide + 

metformin 2

Liraglutide verlaagt Hba1c 

LEAD-3, previous diet and exercise-treated 

patients 

HbA 1c (%) 

9.0 

8.5 

8.0 

7.5 

7.0 

6.5 

Glimepiride 8 mg 

Liraglutide 1.2 mg monotherapy 

Liraglutide 1.8 mg monotherapy 

0 4 8 12 16 20 24 28 32 36 40 44 48 52 Weeks 

Garber et al. Lancet 2009;373:473–81 (LEAD-3). Data are mean (SD) 

Change in HbA 1c (%)* 

-0.2 

-0.4 

-0.6 

-0.8 

-1.0 

-1.2 

-1.4 

-1.6 

-1.2 

-1.6 

-0.9

Liraglutide verlaagt 

gewicht 

***p

Steady state levels 

van liraglutide en exenatide 

Normalised concentration (%) 

100 

80 

60 

40 

20 

0 

exenatide BD 

T½ 2.4 h 

liraglutide OD 

T½ 13 h 

4.0 4.5 5.0 5.5 6.0 6.5 7.0 

Time after first dose (days) 

Modelling of plasma concentration of active drug vs. maximal concentration at steady state achieved following clinically relevant doses 

OD or BD. Based on published exenatide data and modelled liraglutide data. 

Jonker et al. Diabetes 56(Suppl. 1):A160 

50 

40 

30 

20 

10 

pM nM 

0 

28 

24 

20 

16 

12 

8 

0 

Absolute concentration

Liraglutide verlaagt post- 

prandiale en nuchtere glycemie 

Liraglutide reduces FPG (before 2 weeks) Mean PPG reduction over 3 meals 

FPG (mmol/L) 

10 

9 

8 

7 

LEAD-5 

Liraglutide 1.8 mg + met + SU 

Insulin glargine + met + SU 

0 2 8 12 18 26 

Week 

PPG reduction (mmol/L) 

0 

1 

2 

Mono 

LEAD-3 

Met 

combi LEAD- 

2 

Liraglutide 1.2 mg 

Liraglutide 1.8 mg 

SU 

combi 

LEAD-1 

Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 

2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009; DOI:10.2337/dc08-2124 (LEAD-4); Russell-Jones et al. Diabetes 

2008;57(Suppl. 1):A159 (LEAD-5) 

3 

Met 

+ TZD 

combi 

LEAD-4 

Met 

+ SU 

combi 

LEAD-5

Liraglutide verlaagt systolische 

BD 

Change in SBP (mmHg) 

1 

0 

-1 

-2 

-3 

-4 

-5 

-6 

-7 

-2.1 

Monotherapy 

LEAD-3 

-3.6 

* 

-0.7 

Met 

combination 

LEAD-2 

-2.8 

-2.3 

* * 

0.4 

SU combination 

LEAD-1 

-2.6 

-2.8 

Met + TZD 

combination 

LEAD-4 

-6.6 

Met + SU 

combination 

LEAD-5 

Liraglutide 1.2 mg Liraglutide 1.8 mg Glimepiride 8 mg Rosiglitazone 4 mg Glargine 

***p

Exenatide LAR 

• 1 x per week subcutaan vs placebo 

• Hba1c -1.5 % vs -0.4% na 15 wk



3.Incretines: exenatide 

4.Incretines: liraglutide 

5.Incretines: DPP4-inhibitoren

Incretines 

DPP-4 inhibitoren: (oraal, incretine enhancers) 

– Januvia (Sitagliptine) 

– Galvus (Vildagliptine) 

– Saxaglipitine (Onglyza) 

Incretinemimetica: (SC, GLP-1 analogen) 

– Byetta (Exenatide) 5 -10 µg 2 x per dag SC 

– Victoza (Liraglutide) 1 x SC per dag (? Begin 2010) 

– Exanatide QW 1 X SC per week (? 2011)

DPP4 - verlagen Hba1c 

Sitagliptin Once Daily Showed Comparable Glycemic Efficacy to 

Sulfonylurea When Added to Metformin (52 Weeks) 

HbA 1c (% ± SE) 

7.8 

7.6 

7.4 

7.2 

7.0 

6.8 

6.6 

6.4 

6.2 

6.0 

5.8 

Sulfonylurea a + metformin (n=411) 

Sitagliptin b + metformin (n=382) 

Weeks 

a Specifically glipizide; b Sitagliptin (100 mg/day) with metformin (≥1500 mg/day); 

Per-protocol population; LS = least squares 

Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205. 

LS mean change from baseline 

(for both groups): –0.67% 

Achieved primary 

hypothesis of 

noninferiority to 

sulfonylurea 

0 6 12 18 24 30 38 46 52

DPP4 - gewicht stabiel 

Sitagliptin Provided Weight Reduction (vs ( vs Weight Gain) and 

a Much Lower Incidence of Hypoglycemia 

Body weight (kg ± SE) 

3 

2 

1 

0 

-1 

-2 

LS mean change in body weight over time b 

Sulfonylurea + metformin (n=416) 

Sitagliptin 100 mg/day + metformin (n=389) 

-3 

0 12 24 38 52 

Weeks 

Incidence (%) 

50 

40 

30 

20 

10 

0 

Hypoglycemia b 

32% 

Week 52 

P

DPP4 - minder hypoglycemie 

Sitagliptin Provided Weight Reduction (vs ( vs Weight Gain) and 

a Much Lower Incidence of Hypoglycemia 

Body weight (kg ± SE) 

3 

2 

1 

0 

-1 

-2 

LS mean change in body weight over time b 

Sulfonylurea + metformin (n=416) 

Sitagliptin 100 mg/day + metformin (n=389) 

-3 

0 12 24 38 52 

Weeks 

Incidence (%) 

50 

40 

30 

20 

10 

0 

Hypoglycemia b 

32% 

Week 52 

P

Exenatide vs Sitagliptine 

PPG (mg/dL) 

280 

240 

200 

160 

Standard Meal 

Primary Endpoint 

120 

-30 0 30 60 90 120 150 180 210 240 

* 

Time (min) 

Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE; * LS mean ± SE, P



DDP-4 inhibitoren ( Januvia/ Galvus ): 

1.Verlaging Hba1c 

2.Gewicht stabiel tot lichte afname

Nieuw algoritme voor type 2 DM 

(2008) 

Tier 1: well-validated core therapies 

At Diagnosis: 

Lifestyle 

+ 

Metformin 

Lifestyle + Metformin 

+ 

Basal insulin (Hba1c>8.5%) 


+ 

Sulfonylurea 

Tier 2: less well-validated core therapies 


+ 

Pioglitazone 

(no hypoglycemia /edema (CHF)/ bone loss) 


+ 

GLP-1 agonist 

(no hypoglycemia/weight loss /nausea/vomiting ) 


+ 

Pioglitazone 

+ 

Sulfonylurea a 


+ 

Basal insulin 

Nathan DM, et al. Diabetes Care 2008;31(12):1-11. 


+ 

Intensive insulin

Management of DM type 2 

diet & 

exercise 

oral monotherapy 

oral plus insulin 

oral combination 

+ 

insulin 

++

Management of DM type 2 

Life style + 

metformines 

oral combination 

Oral plus 

Byetta/insuline 

++



AZ Turnhout

Nieuw algoritme voor type 2 DM 

(2008) 

Tier 1: well-validated core therapies 

At Diagnosis: 

Lifestyle 

+ 

Metformin 


+ 

Basal insulin (Hba1c>8.5%) 


+ 

Sulfonylurea 

Tier 2: less well-validated core therapies 


+ 

Pioglitazone 

(no hypoglycemia /edema (CHF)/ bone loss) 


+ 

GLP-1 agonist 

(no hypoglycemia/weight loss /nausea/vomiting ) 


+ 

Pioglitazone 

+ 

Sulfonylurea a 


+ 

Basal insulin 

Nathan DM, et al. Diabetes Care 2008;31(12):1-11. 


+ 

Intensive insulin

Behandelingskeuze type 2 DM 

Selecting Specific Diabetes Interventions 

Hba1c Non- Hba1c 

See information about hypoglycemia, nausea, or pancreatitis and the Important Safety Information included in this 

presentation, and the accompanying full Prescribing Information. 

De Fronzo, Diabetes, vol 58, april 2009 

o Vermagering 

o Veiligheid: hypoglycemies 

o Pancreassparend 

o Cardiovasculaire morbi en mortaliteit 

o Prijs







o Vermagering 




o Prijs




o Vermagering: 

incretines (metformines) 




o Prijs 



De Fronzo, Diabetes, vol 58, april 2009







o Vermagering 

o Hypoglycemies 



o Prijs




o Vermagering 

o Hypoglycemies: 

incretines/ metformines 



o Prijs 







o Vermagering 




o Prijs 




Diabetes type 2, een ziekte 

met een stille evolutie 

progressieve vermindering van 

insulinesecretie 

Functie van 

de ß-cellen (%) 

100 

75 

50 

25 

0 

jaren sinds de diagnose 

Lebovitz Diabetes Reviews 1999; 7: 139-153 

Glucose intolerantie 

Verhoogde postprandiale glycemie 

Verhoogde nuchtere glycemie 

-12 -10 -6 -2 0 2 6 10 14

Exenatide: 

Exenatide: 


en gewicht 

Gewichtsverandering sinds Baseline (kg) 

0 

-2 

-4 

Baseline 99.3 ± 1.2 kg 

-6 

0 26 52 78 104 130 156 

N=217 Mean±SE 

Week 156 

-5.3 kg (95% CI: -6.0 to -4.5 kg) 

Duur (weken) 

1c (%) 

HbA 

10 

9 


Week 156 

-1.0% (95% CI:-1.1 to -0.8%) 

8 

7 

6 

5 

4 

0 26 52 78 104 130 156 

Duur (weken) 


Liraglutide verbetert 

B-cel cel functie 

Treatment differences in changes: 

*p







o Vermagering 


o Pancreassparend: 

incretines/ glitazones ? 


o Prijs




o Vermagering 



o Cardiovasculaire morbi-mortaliteit 

o Prijs 







o Vermagering 



o Cardiovasculaire morbi-mortaliteit: 

metformines 

o Prijs 







o Vermagering 



o Cardiovasculaire morbi-mortaliteit: 

metformines. 

Incretines? 

Pioglitazone? 






Steno - studie 

Gaude P, Vedel P, Larsen N, Jensen GVH, Parving H, Pedersen O: Multifactorial 

interventions and cardiovascular disease in patients with type 2 diabetes. 

N Engl J Med 348:383–393, 2003

STENO-studie 

STENO studie 

DM type 2 met microalbuminurie: 

•Hba1c < 6.5 % 

•BD < 130/80 mmHg 

•TC< 175 mg/dL 

•LDL< 100 mg/dL 

•ACE en ASA 

Absolute risico –20% 

NNT = 5



AZ Turnhout


Maag-darm 

Pancreas: 

alfa en beta-cellen 

Lever 

Carbohydrate 


Glucose 

Insulin 

(I) 

Glucose (G) 

G 

I 

G 

I 

I 

G 

I 

G 

G 

I 

G 

I 

G 

I 

G 

I 

G 

G 

I 

G 

Vetcel 

Spier


Maag-darm 

Pancreas: 

alfa en beta-cellen 

Lever 

Carbohydrate 


NIER 

Glucose 

Insulin 

(I) 

Glucose (G) 

G 

I 

G 

I 

I 

G 

I 

G 

G 

I 

G 

I 

G 

I 

G 

I 

G 

G 

I 

G 

Vetcel 

Spier

SGLT2-inhibitor: SGLT2 inhibitor: Canaglifozin 

Sodium dependent 

glucose 

cotransporter 2 

inhhibitor 

Proximale tubulus 

Tm~ 180 mg/dL 

Proximale 

tubulus

SGLT2-inhibitor: SGLT2 inhibitor: Canaglifozin 

Sodium dependent glucose 

cotransporter 2 inhhibitor 

Verlaagt Hba1c 

Vermagering 

B-cel sparend ? 

Nierinsufficiëntie 

Proximale 

tubulus

Dr. Veerle Verjans Nefroloog - Orpadt

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