The Pathophysiology of Type 2 Diabetes Includes Three Main Defects

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1 The Pathophysiology of Type 2 Diabetes Includes Three Main Defects
1/Buse, p 1429, C1, ¶3, L8-13, C2, ¶1, L11-16; p 1441, C2, ¶3, L1-3; p 1442, Fig legend C1, ¶2, L2-4 2/Buchanan, p B35, ¶1, L1-4 3/Powers, p 2157, C1, ¶3, L1-3, 8-16 5/Rhodes, p 383, C2, ¶1, L5-8 Islet Insulin deficiency Sulfonylurea ; Novonorm Alpha cell produces excess glucagon Beta cell produces less insulin Pancreas 1/Buse, p 1429, C1, ¶3, L8-13 2/Buchanan, p B35, ¶1, L1-4 3/Powers, p 2157, C1, ¶3, L1-3 4/Del Prato, p 719, C2, L2-8 p 2157, C1, ¶3, L11-16 p 719, C2, L8-12 5/Rhodes, p 383, C2, ¶1, L5-8 6/Williams, p 28, ¶2, L1-2 p 1442, Fig legend, L2-5, C1, ¶2, L2-4 C2, ¶2, L5-8 C2, ¶2, L1-3, 13-15 The pathophysiology of hyperglycemia in type 2 diabetes involves three main defects: (1) insulin deficiency due to insufficient pancreatic insulin release; (2) excess hepatic glucose output; and (3) insulin resistance (decreased glucose uptake) in peripheral tissues (including muscle and fat) and the liver.1-3 Two pancreatic islet cell defects contribute to this pathology: Beta cells produce insulin, which facilitates glucose entry into tissues.4 In type 2 diabetes mellitus, a decline in functional beta-cell mass causes insulin deficiency, which in turn contributes to hyperglycemia.3-5 Alpha cells produce glucagon.6 Elevated glucagon levels promote increased hepatic glucose output.1 In type 2 diabetes mellitus, excess glucagon and diminished insulin secretion drive hepatic glucose output and contribute to hyperglycemia.1 Diminished insulin Excess glucagon Hyperglycemia Muscle and fat Excess glucose output Insulin resistance (decreased glucose uptake) Liver Metformin glitazonen 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. References Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR, Kronenberg HM, Melmed S et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:1427–1483. Buchanan TA. Pancreatic beta-cell loss and preservation in type 2 diabetes. Clin Ther 2003;25(suppl B):B32–B46.  Powers AC. Diabetes mellitus. In: Kasper DL, Braunwald E, Fauci A et al, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:2152–2180.  Del Prato S, Marchetti P. Targeting insulin resistance and β-cell dysfunction: The role of thiazolidinediones. Diabetes Technol Ther 2004;6:719–731. Rhodes CJ. Type 2 diabetes—a matter of β-cell life and death? Science 2005;307:380–384. Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, Massachusetts: Blackwell Publishing, 2004.

2 Incretins Regulate Glucose Homeostasis Through Effects on Islet Cell Function
1/Brubaker, p 2653, C1, ¶2, L1-6, C2, L3-7 2/Zander 2002, p 828, C2, ¶2, L10-14; p 829, C1, ¶2, L1-6, C2, L1, 10-12, 15-23 3/Ahrén, p 366, C2, ¶3, L1-3,8-9; p 370, C1, ¶2, L1-4 5/Buse, p 1441, C2, ¶2, L1-7, ¶3, L1-7 CMK Ingestion of food Glucose dependent Insulin from beta cells (GLP-1 and GIP) Beta cells Insulin increases peripheral glucose uptake GI tract Active GLP-1 and GIP Release of incretin gut hormones Pancreas 1/Brubaker, p 2653, C1, ¶2, L1-6, C2, L3-7 2/Zander 2002, p 828, C2, ¶2, L10-14; p 829, C1, ¶2, L1-6, C2,L1,10-12,15-23 3/Ahrén, p 366, C2, ¶3, L1-3,8-9; p 370, C1, ¶2, L1-4 4/Drucker 2002, p 535, C1, ¶1, L1-7 5/Buse, p 1441, C2, ¶2, L1-7, ¶3, L1-7 The presence of nutrients in the gastrointestinal tract rapidly stimulates the release of incretins: GLP-1 from L cells located primarily in the distal gut (ileum and colon), and GIP from K cells in the proximal gut (duodenum).1,2 Collectively, these incretins exert several beneficial actions, including stimulating the insulin response in pancreatic beta cells and reducing glucagon production from pancreatic alpha cells when glucose levels are elevated.3,4 Increased insulin levels improve glucose uptake by peripheral tissues; the combination of increased insulin and decreased glucagon reduces hepatic glucose output.5 Blood glucose control Glucagon from alpha cells (GLP-1) Glucose dependent Alpha cells Increased insulin and decreased glucagon reduce hepatic glucose output References Brubaker PL, Drucker DJ. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology 2004;145: 2653–2659. Zander M, Madsbad S, Madsen JL et al. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: A parallel-group study. Lancet 2002;359:824–830. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep 2003;3:365–372. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology 2002;122:531–544. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR, Kronenberg HM, Melmed S et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:1427–1483. 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;3:365–372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.

3 GLP-1 and GIP zijn de twee belangrijkste Incretines
2/Ahren 2003, p 366, Table 1; p 367, C1, ¶2, L1-14 3/Drucker 2002, p 535, C1, ¶1, L1-9 1/Drucker 2003B, p 2930, C1, L4-5,24-26 p 2931, C3, ¶1, L1-33; p 2932, C1, L1-3, ¶1, L1-23 5/Farilla 2003, p 5150, C1, ¶1, L4-6; p 5157, C1, ¶1, L1-3 6/Farilla 2002, p 4397, C2, ¶2, L1-3 2/Ahren 2003, p 370, C1, ¶2, L8-9 9/Trümper 2001, p 1567, C1, ¶2, L14-16 10/Trümper 2002, p 244, C2, ¶2, L1-3 GLP-1 Glucagon-like peptide 1 GIP Glucose-dependent insulinotropic polypeptide Secretie door L-cellen in distale darm (ileum en colon) Stimuleert glucose-dependente insulinevrijzetting Secretied door K-cellen in de proximale darm (duodenum) Stimulateert glucose-dependente insulinevrijzetting Suppressie van de hepatische glucoseproduktie door inhibitie van de glucagon secretie (effect op adipocyten) verhoogt beta-cel proliferatie en overleving in diermodellen en geisoleerde humane eilandjes verhoogt beta-celproliferatie en overleving in eiladjes cellijnen 1/Drucker 2003B, p 2934, Table 1; p 2929, C1, ¶1, L1-8, ¶1, L23-26; p 2930, C1, L4-5,24-26 2/Ahren 2003, p 366, Table 1 p 2929,C3, L6-9 3/Drucker 2002, p 535, C1, ¶1, L1-9 p 535, C1, ¶1, L6-9 4/Nauck 1997, p E985, C1, ¶5, L1-6 p 2931, C3, ¶1, L1-33; p 2932, C1, L1-3, ¶1, L1-23 5/Farilla 2003, p 5150, C1, ¶1, L4-6; p 5157, C2, ¶1, L1-3 6/Farilla 2002, p 4397, C2, ¶2, L1-3 p 370, C1, ¶2, L8-9 7/Meier, p E624, C2, L4-5 8/Nauck 1993A, p 302, C1, ¶2, L9-12; p 306, C2, ¶1, L4-7 p 2934, Table 1 9/Trümper 2001, p 1567, C1, ¶2, L14-16 10/Trümper 2002, p 244, C2, ¶2, L1-3 Incretins are gut hormones released in response to ingestion of a meal, the most important of which are glucagon-like peptide 1 (GLP-1), which is synthesized by L cells in the distal gut (ileum and colon), and glucose-dependent insulinotropic polypeptide (GIP), which is secreted by K cells in the proximal gut (duodenum).1,2 GLP-1 and GIP are the major incretins that play a role in the insulin response as nutrients are absorbed by the body.1 In addition to stimulating insulin release when glucose is elevated, GLP-1 inhibits glucagon secretion.3 These actions are highly glucose dependent.3 In healthy volunteers, administration of GLP-1, at levels surpassing physiologic production, has been shown to exert profound, dose-dependent inhibition of gastric emptying.4 In in vitro and in vivo rodent studies and isolated human islets, GLP-1 has been shown to promote the expansion of beta-cell mass through proliferative and anti-apoptotic pathways.1,5,6 Whereas GIP also stimulates a glucose-dependent insulin response,2 this hormone does not appear to affect gastric emptying.7 When given at supraphysiologic doses to patients with type 2 diabetes, the insulinotropic activity of GIP was less than that observed in normal subjects.8 GIP does not appear to affect satiety or body weight.1 In islet cell lines, GIP has been shown to enhance beta-cell proliferation and survival.9,10 GLP-1=glucagon-like peptide 1; GIP=glucose-dependent insulinotropic polypeptide Adapted from Drucker DJ Diabetes Care 2003;26:2929–2940; Ahrén B Curr Diab Rep 2003;3:365–372; Drucker DJ Gastroenterology 2002;122: 531–544; Farilla L et al Endocrinology 2003;144:5149–5158; Trümper A et al Mol Endocrinol 2001;15:1559–1570; Trümper A et al J Endocrinol 2002;174:233–246. References Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003;26:2929–2940. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep 2003;3:365–372. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology 2002;122:531–544. Nauck MA, Niedereichholz U, Ettler R et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 1997;273(5 pt 1):E981–E988. Farilla L, Bulotta A, Hirshberg B et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 2003;144:5149–5158. Farilla L, Hui H, Bertolotto C et al. Glucagon-like peptide-1 promotes islet growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology 2002;143:4397–4408. Meier JJ, Goetze O, Anstipp J et al. Gastric inhibitory polypeptide does not inhibit gastric emptying in humans. Am J Physiol Endocrinol Metab 2004;286:E621–E625. Nauck MA, Heimesaat MM, Ørskov C et al. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 1993;91:301–307. Trümper A, Trümper K, Trusheim H et al. Glucose-dependent insulinotropic polypeptide is a growth factor for beta (INS-1) cells by pleiotropic signaling. Mol Endocrinol 2001;15:1559–1570. Trümper A, Trümper K, Hörsch D. Mechanisms of mitogenic and anti-apoptotic signaling by glucose-dependent insulinotropic polypeptide in β(INS-1)-cells. J Endocrinol 2002;174:233–246.

4 Effect van 6 weken behandeling met GLP-1 infuus bij patiënten met type 2 diabetes
Verlaging van nuchtere glycemie met 77 mg/dl en gemiddelde glycemie met 100 mg/dl Verlaging van HbA1c met 1,3 % Gewichtsdaling met 2-3 kg Verbetering van de insulinegevoeligheid met 77 % Snelle inactivatie (enzyme DPP-4), Korte eliminatie : t 1/2 ~1-2 min GLP-1 moet via continu infuus toegediend worden Ongeschikt voor behandeling van een chronische ziekte zoals type 2 diabetes Drucker DJ, et al. Diabetes Care. 2003;26:

5 Strategieën voor Verbetering van het Therapeutisch Potentieel van GLP-1
Produkten die de werking van GLP-1 nabootsen (incretin mimetics) DPP-4–resistente GLP-1 derivaten bv: GLP-1 analogen, albuminegebonden GLP-1 Nieuwe peptiden met glucoseregulerende werking gelijkaardig aan GLP-1 Exenatide Produkten die de activiteit van endogeen GLP-1 verlengen (incretin enhancers) DPP-4 inhibitors Bv sitagliptine (Januvia, Merck), vildagliptine (Galvus, Novartis), SYR 322 (Takeda, fase 3 studies) DISCUSSION Two classes of agents have been developed that are based on the therapeutic potential of glucagon-like peptide 1 (GLP-1): Incretin mimetics – exenatide is the first agent in this class used for the treatment of patients with type 2 diabetes Protease dipeptidyl peptidase-4 (DPP-4) inhibitors – sitagliptin and vildagliptin are examples of DPP-4 inhibitors Drucker DJ, et al. Diabetes Care. 2003;26: ; Baggio LL, et al. Diabetes. 2004;53:

6 52-week Sitagliptin vs Sulfonylureaa Add-on Therapy to Metformin Study Sitagliptin Once Daily Showed Comparable Glycemic Efficacy to Sulfonylurea When Added to Metformin (52 Weeks) 7.8 LS mean change from baseline (for both groups): –0.67% 7.6 R.1-p201-F.2A R1-p197-Col2- Par.Last-L1-L9 7.4 7.2 7.0 R.1-p197-Col 2 Par.Last- L1-L9 Sitagliptin 100 mg once daily with metformin was similar (noninferior) to sulfonylurea (glipizide) with metformin in lowering HbA1c, the primary efficacy endpoint of the study.1 At week 52, the least squares (LS) mean change from baseline in HbA1c was –0.67% in both groups in the per-protocol population.1 The graph shows that the reduction in HbA1c obtained with sitagliptin 100 mg once daily with metformin was sustained over the study period of 52 weeks. An estimate of durability from 24 to 52 weeks (coefficient of durability, [COD]) showed a lower COD for sitagliptin with metformin (0.008%/week) than for sulfonylurea (glipizide) with metformin (0.011%/week), indicating that durability was better for sitagliptin 100 mg once daily with metformin compared with sulfonylurea with metformin (COD difference between treatments was –0.003%).1 HbA1c (% ± SE) 6.8 R.1-p197-Col2 Par.Last-L14-L18 6.6 Achieved primary hypothesis of noninferiority to sulfonylurea 6.4 R.1-p198-Par.Cont- L1-L7 6.2 Sulfonylureaa + metformin (n=411) 6.0 Sitagliptinb + metformin (n=382) 5.8 6 12 18 24 30 38 46 52 Weeks aSpecifically glipizide; bSitagliptin (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. Reference: 1. Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205.

7 LS mean change in body weight over timeb
52-week Sitagliptin vs Sulfonylureaa Add-on Therapy to Metformin Study Sitagliptin Provided Weight Reduction (vs Weight Gain) and a Much Lower Incidence of Hypoglycemia R.1/Nauck, p202-F.4 R.1/Nauck, p200-Par.1-L1 p200-Par.2-L1 R.1/Nauck, p202-T.3 R.1/Nauck, p194-Results-L4 Hypoglycemiab LS mean change in body weight over timeb P<0.001 32% 5% 10 20 30 40 50 Week 52 Incidence (%) Sulfonylurea + metformin (n=416) Sitagliptin 100 mg/day + metformin (n=389) R.1/Nauck, p197-Par.2-L1 R.1/Nauck, p200-Par.2- L1-6 The graph on the left shows the change in body weight observed during the study period of 52 weeks with sitagliptin (100 mg/day) with metformin (≥1500 mg/day) and sulfonylurea* with metformin.1 Sitagliptin (100 mg/day) with metformin (≥1500 mg/day) induced a significant decrease in body weight that was maintained through week 52 of the study (–1.5 kg), whereas sulfonylurea with metformin induced a significant increase in body weight compared with baseline values (1.1 kg).1 The difference in body weight between the sitagliptin (100 mg/day) with metformin (≥1500 mg/day) and the sulfonylurea with metformin treatment groups was significant (–2.5 kg, P<0.001).1 The graph on the right shows that sitagliptin (100 mg/day) with metformin (≥1500 mg/day) induced a significantly lower incidence of hypoglycemic episodes compared with sulfonylurea with metformin (5% vs 32%, respectively).1 The difference in hypoglycemia between the sitagliptin (100 mg/day) with metformin (≥1500 mg/day) and sulfonylurea with metformin treatment groups was significant (27%, P<0.001).1 *Specifically glipizide Body weight (kg ± SE) R.1/Nauck, p200-Par.2-L1 R.1/Nauck, p200-Par.2-L1 R.1/Nauck, p202-Par.Last- L1 R.1/Nauck, p200-Par.1-L1 R.1/Nauck, p194-Results-L4 Sulfonylurea + metformin (n=584) Sitagliptin 100 mg/day + metformin (n=588) aSpecifically glipizide; bAll-patients-as-treated population. LS = least squares; LSM between-group difference at week 52 (95% CI):  in body weight = –2.5 kg [–3.1, –2.0] (P<0.001); LSM change from baseline at week 52: glipizide: +1.1 kg; sitagliptin: –1.5 kg (P<0.001) Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205. Reference: 1. Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: A randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205.

8 Strategieën voor Verbetering van het Therapeutisch Potentieel van GLP-1
Produkten die de werking van GLP-1 nabootsen (incretin mimetics) DPP-4–resistente GLP-1 derivaten bv: GLP-1 analogen, albuminegebonden GLP-1 Nieuwe peptiden met glucoseregulerende werking gelijkaardig aan GLP-1 Exenatide Produkten die de activiteit van endogeen GLP-1 verlengen (incretin enhancers) DPP-4 inhibitors Bv sitagliptine (Januvia, Merck), vildagliptine (Galvus, Novartis), SYR 322 (Takeda, fase 3 studies) DISCUSSION Two classes of agents have been developed that are based on the therapeutic potential of glucagon-like peptide 1 (GLP-1): Incretin mimetics – exenatide is the first agent in this class used for the treatment of patients with type 2 diabetes Protease dipeptidyl peptidase-4 (DPP-4) inhibitors – sitagliptin and vildagliptin are examples of DPP-4 inhibitors Drucker DJ, et al. Diabetes Care. 2003;26: ; Baggio LL, et al. Diabetes. 2004;53:

9 Development of Exenatide: An Incretin Mimetic
Exenatide (Exendin-4) Synthetic version of salivary protein found in the Gila monster Approximately 50% identity with human GLP-1 Resistant to DPP-4 inactivation DISCUSSION Exenatide (exendin-4) is the synthetic version of salivary protein found in the Gila monster Position 2 of the amino acid sequence is different between glucagon-like peptide 1 (GLP-1) and exenatide, making exenatide resistant to dipeptidyl peptidase-4 (DPP-4) enzymatic degradation BACKGROUND Exendin-4 is a naturally occurring incretin hormone in the Gila monster Heloderma suspectum Gila monsters produce exendin-4, which is a separate and distinct protein compared to human GLP-1 Exendin-4 mimics some of the actions of GLP-1 in vivo Exendin-4 exerts some of its antidiabetic actions via unknown mechanisms Exenatide H G E G T F T S D L S K Q M E E E A V R L F I E W L K N G G P S S G A P P P S – NH2 GLP-1 Human H A E G T F T S D V S S Y L E G Q A A K E F I A W L V K G R – NH2 Site of DPP-4 Inactivation Adapted from Nielsen LL, et al. Regulatory Peptides. 2004;117: Reprinted from Regulatory Peptides, 117, Nielsen LL, et al, Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycaemic control of type 2 diabetes, 77-88, 2004, with permission from Elsevier for English use only.

10 Large Phase 3 Clinical Studies: Exenatide bid Reduced HbA1c and Weight Over 30 Weeks
Placebo BID Exenatide 5 µg BID Exenatide 10 µg BID Combined Results of 3 Exenatide Phase 3 , Placebo-controlled Studies* -0.5 -1.5 -1 -0.9 * -0.6 +0.1 -0.7 -1.4 * -1.9 -2.0 -1.5 -1.0 -0.5 DISCUSSION Combined results from all 3 AMIGO studies demonstrated that exenatide significantly improved glycaemic control based on reduced HbA1c levels, and significantly reduced body weight regardless of treatment regimen (5 µg or increase to 10 µg) BACKGROUND The 3 AMIGO studies were undertaken to evaluate the ability of exenatide to improve glycaemic control in patients with type 2 diabetes failing to achieve glycaemic control with maximally effective doses of metformin (MET), sulphonylurea (SFU), or MET + SFU Three 30-week, placebo-controlled, double-blind, Phase 3 studies were completed in the United States This slide presents combined data Subjects with type 2 diabetes (currently taking MET, SFU, or MET + SFU) were randomised to Placebo (PBO), n = 483; 5 µg exenatide BID, n = 480; or 10 µg exenatide twice daily (BID), n = 483; N = All subjects also continued current medication. Baseline HbA1c: placebo, 8.5%; 5 μg exenatide BID, 8.4%; 10 μg exenatide BID, 8.5% Baseline weight: placebo, 99 kgs (218 lbs); 5 μg exenatide BID, 97 kgs (213 lbs); 10 μg exenatide BID, 98 kgs (216 lbs) The Last Observation Carried Forward (LOCF) method was applied to the data Weight change was a secondary endpoint Change in Weight (kg) Change in HbA1c(%) ITT 30-week data; N = 1446; Mean (SE); *p<0.005; Weight was a secondary endpoint. Data on file, Amylin Pharmaceuticals, Inc. * DeFronzo RA, et al. Diabetes Care. 2005;28: ; Buse JB, et al. Diabetes Care. 2004;27: ;Kendall DM, et al. Diabetes Care. 2005;28:

11 Lange termijn effecten van Byetta op HbA1c en gewicht
10 20 30 40 50 60 70 80 90 100 110 6.5 7.0 7.5 8.0 8.5 8.3% -1.1 % 10 20 30 40 50 60 70 80 90 100 110 -7 -6 -5 -4 -3 -2 -1 1 100 kg -4.7 kg

12 Waar situeren ? Gliptines in 2de lijn na metformin
Gewicht Geen risico op hypo’s Weinig neveneffecten “instapmodel” Af : HbA1c > 7 % onder metformine Starten met staal ! GLP-1 analogen vóór insuline Minder risico op hypo’s Cave misselijkheid Af : HbA1c > 7,5 % onder metformine + sulfonylureum Drempel vooral financieel en Af