Orale Antidiabetika Bruno Müller.

Präsentation zum Thema: "Orale Antidiabetika Bruno Müller."—  Präsentation transkript:

1 Orale Antidiabetika Bruno Müller

2 www. DerEndokrinologe.ch
Bruno Müller

3 Therapieziele

4 Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the
Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy David M. Nathan, M.D., John B. Buse, M.D., Ph.D., Mayer B. Davidson, M.D., Ele Ferrannini, M.D., Rury R. Holman, F.R.C.P., Robert Sherwin, M.D., and Bernard Zinman, M.D. Several reviews on the management of type 2 diabetes have been published in recent years (refs below). To provide a clear therapeutic path in choosing the most appropriate interventions to manage hyperglycemia in nonpregnant adult patients with type 2 diabetes, this consensus approach was developed (p. 1, 2nd para) Refs: Nathan DM: Initial management of glycemia in type 2 diabetes mellitus. N Engl J Med 347:1342–1349, 2002 Sheehan MT: Current therapeutic options in type 2 diabetes mellitus: a practical approach. Clin Med Res 1:189 –200, 2003 Inzucchi SE: Oral antihyperglycemic therapy for type 2 diabetes. JAMA 287:360 –372, 2002 Published at care.diabetesjournals.org October 22, 2008 Nathan DM, et al. Diabetes Care 2008;31(12):1-11.

5 Glycemic goal of therapy
An A1C level of ≥7% should serve as a call to action to initiate or change therapy with the goal of achieving an A1C <7%* *This goal is “not appropriate or practical for some patients, and clinical judgment based on the potential benefits and risks of a more intensified regimen needs to be applied for every patient.” (pg 2) For each patient, factors such as life expectancy, risk of hypoglycemia, and the presence of CVD need to be taken into consideration before intensifying the therapeutic regimen. Sources: p 2, 2nd para Controlled clinical trials, such as the Diabetes Control and Complications Trial (DCCT) and the Stockholm Diabetes Study (both T1DM) and the UKPDS and Kumamoto studies (both T2DM) helped establish glycemic goals of therapy for improved long-term outcomes, though the goals were in the non-diabetic A1C range (p. 1, 1st para) Several recent clinical trials have aimed for A1C levels ≤6.5% The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study had the primary objective of decreasing CVD with interventions aimed at achieving an A1C level <6.0% vs. interventions aimed at achieving an A1C <7.9%. It reported excess CVD mortality in the intensive treatment group The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial and the Veterans Affairs Diabetes Trial (VADT) had different interventions and study populations than ACCORD and did not demonstrate any excess total or CVD mortality despite intensive treatment regimens that achieved a A1C of 6.5%, comparable to ACCORD However, none of the studies demonstrated a benefit of intensive glycemic control on their primary CVD outcomes (p. 2, 2nd para) The consensus of this group is that an A1C level ≥7% should serve as a call to action to initiate or change therapy with the goal of achieving an A1C level <7%. This goal is “not appropriate or practical for some patients, and clinical judgment based on the potential benefits and risks of a more intensified regimen needs to be applied for every patient.” Life expectancy, risk of hypoglycemia, the presence of CVD, and other factors need to be taken into consideration before intensifying treatment (p. 2, 2nd para) Sources DCCT: Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329: Stockholm: Reichard P, et al. N Engl J Med 1993;329: UKPDS 1: UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352: UKPDS 2: UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352: Kumamoto: Ohkubo Y, et al. Diabetes Res Clin Pract 1995;28: ACCORD: The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358: ADVANCE: The ADVANCE Collaborative Group. N Engl J Med 2008;358: Nathan DM, et al. Diabetes Care 2008;31(12):1-11.

6 Algorithm for type 2 diabetes
Tier 1: well-validated core therapies Lifestyle + Metformin + Intensive insulin Lifestyle + Metformin + Basal insulin At Diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Sulfonylurea a Step 1 Step 2 Step 3 Tier 2: less well-validated core therapies Lifestyle + Metformin + Pioglitazone Sulfonylurea a Lifestyle + Metformin + Pioglitazone (no hypoglycemia /edema (CHF)/ bone loss) Sources: p. 8, Fig 2, including legend a Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide b Insufficient clinical use to be confident regarding safety Algorithm for the metabolic management of type 2 diabetes Reinforce lifestyle interventions at every visit, check A1C every 3 months until A1C is <7% & then check A1C at least every 6 months If A1C is ≥7%, the interventions should be changed with rapid addition of medications, and transition to new regimens, when target glycemic goals not achieved or sustained (p. 7, 6th para) For Tier 2, if hypoglycemia is especially undesirable or if weight loss is a major consideration and A1C is <8.0%, exenatide is an option (p. 8, 3rd column, Tier 2) Lifestyle + Metformin + GLP-1 agonist b (no hypoglycemia/weight loss /nausea/vomiting ) Lifestyle + Metformin + Basal insulin Nathan DM, et al. Diabetes Care 2008;31(12):1-11. a,b See speaker notes

7 Initiation and adjustment of insulin regimens
Start with bedtime intermediate-acting insulin or bedtime or morning long-acting insulin (can initiate with 10 units or 0.2 units per kg) Check fasting glucose (fingerstick) usually daily and increase dose, typically by 2 units every 3 days until fasting levels are consistently in target range (3.9–7.2 mmol/l [70–130 mg/dl]). Can increase dose in larger increments, e.g., by 4 units every 3 days, if fasting glucose is >10 mmol/l (180 mg/dl) If hypoglycemia occurs, or fasting glucose level <3.9 mmol/l (70 mg/dl), reduce bedtime dose by 4 units or 10% - whichever is greater A1C ≥7% after 2-3 months Yes No If fasting BG is in target range (3.9–7.2 mmol/l [70–130 mg/dl]), check BG before lunch, dinner, and bed. Depending on BG results, add second injection as below. Can usually begin with ~4 units and adjust by 2 units every 3 days until BG in range Pre-lunch BG out of range. Add rapid-acting insulin at breakfasta Pre-dinner BG out of range. Add NPH insulin at breakfast or rapid-acting at lunch Pre-bed BG out of range. Add rapid-acting insulin at dinnera Continue regimen. Check A1C every 3 mo Sources: p 6, Figure 1 including legend a Premixed insulins not recommended during adjustments of doses; however, they can be used conveniently, usually before breakfast and/or dinner, if proportion of rapid- and intermediate-acting insulins is similar to the fixed proportions available Insulin regimens should be designed taking lifestyle, including meal schedule, into account The algorithm only provides basic guidelines Self-monitoring of BG is important in adjusting and adding new interventions (p. 7, 3rd para) BG=blood glucose No A1C ≥7% after 3 months Yes Recheck premeal BG levels and if out of range, may need to add another injection. If A1C continues to be out of range, check 2 h postprandial levels and adjust preprandial rapid-acting insulin Nathan DM, et al. Diabetes Care 2008;31(12):1-11. a See speaker notes

8 Achievement and maintenance of near normoglycemia (A1C <7.0%)
Summary The guidelines and treatment algorithm presented here emphasize the following: Achievement and maintenance of near normoglycemia (A1C <7.0%) Initial therapy with lifestyle intervention and metformin Rapid addition of medications, and transition to new regimens, when target glycemic goals not achieved or sustained Timely addition of insulin therapy to patients who do not meet target goals Sources: p 9, 3rd para Type 2 diabetes is epidemic with enormous long-term societal and economic consequences However, much of the morbidity associated with long-term microvascular and neuropathic complications can be substantially reduced by achieving glucose levels close to the nondiabetic range The guidelines and treatment algorithm presented here emphasize the following: Achievement and maintenance of near normoglycemia (A1C <7.0%) Initial therapy with lifestyle intervention and metformin Rapid addition of medications, and transition to new regimens, when target glycemic goals not achieved or sustained Timely addition of insulin therapy in patients who do not meet target goals Nathan DM, et al. Diabetes Care 2008;31(12):1-11.

9 Other Considerations Target glycemic goals can only be sustained by appropriate dose escalation and/or addition of other glucose-lowering medications Preference should be given to glucose-lowering drugs that provide additional benefits No notes

10 Pathophysiologie

11 Two pancreatic islet cell defects contribute to this pathology:
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 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 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.

12 Insulinsensitivität 
Reversibel durch: Insulinsekretion Insulinsensitivität  Hyperglykämie Insulin- Sekretagoga Metformin, Glitazone Gewichtskontrolle Körperliche Aktivität Blutzuckerkontrolle Extrapankreatische Wirkung der Insulin Sekretagoga

13 Schwache / verzögerte Insulinantwort Nicht supprimiertes Glucagon
Insulin- und Glucagon-Antwort auf eine stark kohlenhydrathaltige Mahlzeit bei Diabetes Typ 2 Diabetes mellitus Typ 2 (n=12)* Nicht diabetische Kontrollen (n=11) 360 330 Meal (mg/100 ml) Glukose 300 270 240 110 80 150 Schwache / verzögerte Insulinantwort 120 A clinical study elucidated postprandial glucose, insulin, and glucagon dynamics in patients with type 2 diabetes mellitus (n=12) versus nondiabetic control subjects (n=11). The study also recruited 12 patients with type 1 (juvenile) diabetes; results for this group are not shown.1 After a large carbohydrate meal, mean plasma glucose concentrations rose from 228 mg/100 ml to a peak of 353 mg/100 ml in patients with type 2 diabetes mellitus, compared with an increase from 84 mg/100 ml to a peak of 137 mg/100 ml in nondiabetic subjects.1 In the 12 patients with type 2 diabetes mellitus, mean insulin values represent measurements from five patients in the group; insulin antibodies resulting from prior insulin therapy precluded insulin immunoassay in the other seven patients in the group. Insulin rose in normal subjects from a mean fasting level of 13 µU/ml to a peak of 136 µU/ml at 45 minutes after the meal. The insulin response in patients with type 2 diabetes mellitus was delayed and suppressed in comparison, increasing from a fasting level of 21 µU/ml to a peak of only 50 µU/ml at 60 minutes.1 Mean plasma glucagon levels declined significantly from the fasting value of 126 µµg/ml to 90 µµg/ml at 90 minutes (p<0.01) in the control group. In contrast, no significant fall in glucagon was observed in patients with type 2 diabetes mellitus; in fact, the mean plasma glucagon level rose slightly from the fasting level of 124 µµg/ml to 142 µµg/ml at 60 minutes and returned to 124 µµg/ml at 180 minutes.1 Therefore, this study showed that patients with type 2 diabetes mellitus had a delayed and suppressed insulin response and failed to exhibit normal postprandial declines in glucagon concentrations despite their marked hyperglycemia. These abnormalities contribute markedly to hyperglycemia both at the level of body tissues where insulin is not sufficient to drive glucose uptake and at the level of the liver where increased glucagon and decreased insulin spur the liver to release glucose into the blood.1 Insulin (µU/ml) 90 60 30 140 130 Nicht supprimiertes Glucagon Glucagon (µµg/ml) 120 110 100 90 –60 60 120 180 240 Zeit (Minuten) *Insulin in fünf Patienten bestimmt Adaptiert von Müller WA et al N Engl J Med 1970;283:109–115. Reference Müller WA, Faloona GR, Aguilar-Parada E et al. Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion. N Engl J Med 1970;283:109–115.

14 Bei Diabetes Typ 2 ist die Beta-Zellfunktion abnormal
Eine ganze Reihe von Funktionsstörungen sind beschrieben worden Abnormale oszillatorische Insulinfreisetzung Gesteigerte Proinsulin-Spiegel Verlust der ersten Phase der Insulinantwort Abnormale 2. Phase der Insulinantwort Progressive Reduktion der Anzahl von funktionsfähigen Beta-Zellen Beta-cell dysfunction in patients with type 2 diabetes is manifested by a range of functional abnormalities. The normal pulsed oscillatory release of insulin is impaired, and proinsulin levels are increased due to inefficient conversion to insulin and quantitative reduction in insulin release.1,2 The first-phase insulin response is essentially absent, whereas the second-phase insulin response is slow and blunted.3,4 These abnormalities in the pattern of insulin response are accompanied by a progressive loss of beta-cell functional mass, leading to further deterioration.4 Adaptiert von Buchanan TA Clin Ther 2003;25(suppl B):B32–B46; Polonsky KS et al N Engl J Med 1988;318:1231–1239; Quddusi S et al Diabetes Care 2003;26:791–798; Porte D Jr, Kahn SE Diabetes 2001;50(suppl 1):S160–S163. References Buchanan TA. Pancreatic beta-cell loss and preservation in type 2 diabetes. Clin Ther 2003;25(suppl B):B32–B46.  Polonsky KS, Given BD, Hirsch LJ et al. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med 1988;318:1231–1239. Quddusi S, Vahl TP, Hanson K et al. Differential effects of acute and extended infusions of glucagon-like peptide-1 on first- and second-phase insulin secretion in diabetic and nondiabetic humans. Diabetes Care 2003;26:791–798. Porte D Jr, Kahn SE. -cell dysfunction and failure in type 2 diabetes: Potential mechanisms. Diabetes 2001;50(suppl 1):S160–S163.

15 Belfast Diät-Studie Bei gleichbleibender Insulinsensitivität verschlechterte sich die Beta-Zellfunktion im Diabetes Typ 2 Insulinsensitivität 60 Beta-Zellfunktion 80 60 40 HOMA % beta HOMA % Sensitivität 40 The Belfast Diet Study monitored a large cohort of patients aged 40 to 69 years (N=432) with newly diagnosed type 2 diabetes (referred to Royal Victoria Hospital Diabetes Clinic). Patients were monitored for 10 years while they maintained active dietary management; drug therapy (insulin, tolbutamide, or metformin) was instituted on the basis of weight and blood glucose according to well-defined and uniform criteria, allowing for investigation of the natural history and progression of type 2 diabetes. In the study, assessment of fasting glucose and insulin levels was based on fasting blood samples taken every three months over the first six years of the study. These measures provided ongoing indices of beta-cell function and insulin sensitivity.1 The investigators assessed beta-cell function and insulin sensitivity by using Homeostasis Model Assessment (HOMA) analysis of fasting plasma glucose (FPG) and insulin concentrations. Beta-cell function and insulin sensitivity were expressed as percentages of values in a lean young nondiabetic reference population.1 Patient were divided into four cohorts on the basis of the date of failure of diet therapy:1 • Diet therapy failure years 2 to 4: 41 patients • Diet therapy failure years 5 to 7: 67 patients • Diet therapy failure years 8 to 10: 51 patients • No diet therapy failure after 10 years: 173 patients Analysis of the complete data showed that patients continuing on diet alone for the first 10 years after diagnosis had a small but progressive rise in FPG, associated with an equally progressive fall in beta-cell function, but not with a change in obesity or insulin sensitivity. Further, it demonstrated that failure of dietary therapy within the first 10 years was associated with higher rates of glucose rise and beta-cell decline. Failure of dietary therapy occurred earlier with higher initial glucose concentration, lower initial beta-cell function, and younger age, and for patients maintained on diet alone for ≥6 months, greater obesity.1 The rate of rise in FPG was inversely related to the duration of successful dietary therapy. Following the initial fall in weight during the first months of dietary therapy, weight was maintained in all groups while on dietary therapy alone. Beta-cell function during the first six years of follow-up closely mirrored the increase in FPG. There was no difference in insulin sensitivity in any group at six months and no change during the further course of dietary therapy.1 The two graphs on the slide, showing data for the 67 patients who required additional treatment with either oral antihyperglycemic therapy or insulin during years 5 to 7, demonstrate the greater contribution of progressive beta-cell dysfunction versus insulin sensitivity to disease progression. Beta-cell function, which was <50% at diagnosis, continuously declined thereafter. In contrast, insulin sensitivity remained almost unchanged.1 20 20 2 4 6 2 4 6 Jahre nach Diagnose Jahre nach Diagnose Daten der ersten sechs Jahre aus der 10-jährigen Verlaufskontrolle in der Belfast Diät-Studie: Daten von 67 neu diagnostizierten Probanden mit Diabetes Typ 2 (N=432), die aufgrund eines sekundären Versagens der Diätbehandlung während der Jahre 5 bis 7 eine Behandlung mit oralen Antidiabetika oder Insulin benötigten. HOMA=Homeostasis Model Assessment; Daten gerechnet als Prozentsatz der Werte in einer mageren, nicht diabetischen, Referenzpopulation. Adaptiert von Levy J et al Diabet Med 1998;15:290–296. Reference Levy J, Atkinson B, Bell PM et al. Beta-cell deterioration determines the onset and rate of progression of secondary dietary failure in type 2 diabetes mellitus: The 10-year follow-up of the Belfast Diet Study. Diabet Med 1998;15:290–296.

16 Homeostasis Model Assessment (HOMA)
Normal: % beta-cell function: insulin resistance (R) = 1 20  insulin* (mU/ml) glucose* (mmol/l) - 3.5 Beta-cell function (%) = insulin* (mU/ml)  glucose* (mmol/l) 22.5 Insulin resistance = The model computes values from fasting insulin and glucose measurements. In homeostasis, with 100% beta-cell function, normal insulin resistance is assigned a value of 1. The percentage of beta-cell function is determined by the following equation: 20  fasting insulin level [µU/ml]  FPG level [mmol/l] - 3.5 The degree of insulin resistance is calculated by multiplying fasting insulin (µU/ml) by FPG (mmol/l) and dividing by 22.5. *fasting levels Haffner S. Diabetes Care 1996; 19: 1139

17 Homeostasis Model Assessment (HOMA)
50 40 30 20 10 b=200% Decreasing b-cell function (b) b=100% Increasing insulin resistance (R) R=16 Basal plasma insulin (mU/ml) b=50% R=8 This graphic representation of HOMA shows the model prediction of steady-state plasma glucose and insulin concentrations for a series of different beta-cell functions (red) and insulin resistance values (yellow). For any individual, FPG and fasting insulin may be entered on the grid, and the estimated beta-cell function and insulin resistance may be obtained. b=25% R=2 R=4 R=1 R=2 R=½ 2 4 6 8 10 12 14 Basal plasma glucose (mmol/l) Matthews et al. Diabetologia 1985; 28: 412

18 Übersicht OAD

19 Diabetesmedikamente 1991-2005/2009
Orale Antidiabetika Insuline (2006: 5 Klassen) Biguanide (Metformin) Tierische Insuline Sulfonylharnstoffe humane Insuline Glinide Analog-Insuline Glukosidase-Hemmer/Acarbose Glitazone Neu ab 2007/8: Gliptine Byetta

20 Diabetesmedikamente 1991-2005/2007(Beispiele)
Orale Antidiabetika Insuline Acarbose Glucobay® Lispro Humalog® Biguanide Glimepirid Amaryl® Aspart NovoRapid® Repaglinid NovoNorm® Glargin Lantus® Nateglinid Starlix® Detemir Levemir® Rosiglitazon Avandia® Pioglitazon Actos® Glulisine Apidra®

21 Neue Therapieformen, Inkretine
Gliptine, sog. DPP-4-Inhibitoren GLP-1 Exenatide (GLP-1-Analog)

22 Orale Antidiabetika im direkten Vergleich
*Obstr. Atemw. Erk.- Niereninsuff.- Leberinsuff.

23 Sulfonylharnstoffe im Vergleich
1 Drouin P. J Diabetes Complications 2000;14(4):185-91 2 Ashcroft FM, J Diabetes Complications 2000;14(4):192-6 3 Song DK Br J Pharmacol 2001;133(1):193-9; Circulation 2001;103: ; European Heart Journal 1999;20: 4 Korytkowski M, Diabetes Care 2002;25(9): 5 Guillausseau PJ, Diabetes & Metabolism, 2001; 27: 6 Rosenkranz B. Diabetologia 1996; 39: * Arzneimittelkompendium der Schweiz

24 Gefahr einer akute myokardialen Ischämie
Potenzielles Problem Gefahr einer akute myokardialen Ischämie Ischämische Präkonditionierung Öffnen kardialer Kaliumkanäle (Kir6.2/Sur2A)* *Schutzmechanismus, der durch nicht selektive Insulinsekretagoga behindert werden könnte - Diese Substanzen schliessen Kaliumkanäle und behindern das Öffnen.

25 Inkretine

26 GLP-1 und GIP sind die zwei wichtigsten Inkretine
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 GIP Sezerniert durch die L-Zellen im distalen Darm (Ileum und Colon) Stimuliert die glukoseabhängige Insulinfreisetzung Sezerniert durch K-Zellen im proximalen Darm (Duodenum) Supprimiert die hepatische Glukosefreisetzung durch die glukoseabhängige Hemmung der Glukagonsekretion Fördert die Proliferation und das Überleben der Beta-Zellen, in Tiermodellen und isolierten menschlichen Inseln Fördert die Proliferation und das Überleben der Beta-Zellen in Insel-Zelllinien 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 Adaptiert von 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.

27 Inkretine regulieren die Glukose-Homöostase durch Wirkungen auf die Funktion der Inselzellen
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 Adaptiert von 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. 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.

28 GLP-1 Effects in Humans: Understanding the Glucoregulatory Role of Incretins
Promotes satiety and reduces appetite Alpha cells: ↓ Postprandial glucagon secretion DISCUSSION By decreasing β-cell workload and improving β-cell response, the incretin glucagon-like peptide 1 (GLP-1) is an important regulator of glucose homeostasis A thorough understanding of the five GLP-1 glucoregulatory effects is important to assess the value of GLP-1 in controlling glucose levels, particularly during the postprandial period Upon ingestion of food, GLP-1 is secreted in into the bloodstream and enhances glucose dependent insulin secretion from β-cells GLP-1 suppresses inappropriately elevated glucagon secretion from alpha cells Lower levels of glucagon lead to a reduction of glucose output from the liver and indirectly reduce the β-cell workload By slowing the gastric emptying rate, GLP-1 slows the release of nutrients into the gut allowing more time to control the postprandial increase in glucose levels GLP-1 promotes satiety, potentially through centrally mediated mechanisms BACKGROUND GLP-1 is secreted from L cells of the small intestine GLP-1 decreases β-cell workload, hence the demand for insulin secretion, by: Regulating the rate of gastric emptying such that meal nutrients are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand (β-cell workload) Decreasing postprandial glucagon secretion from pancreatic alpha cells, which helps to maintain the counterregulatory balance between insulin and glucagon Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on β-cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose output Having effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake Effect on Beta cell: Drucker DJ. Diabetes. 1998;47: Effect on Alpha cell: Larsson H, et al. Acta Physiol Scand. 1997;160: Effects on Liver: Larsson H, et al. Acta Physiol Scand. 1997;160: Effects on Stomach: Nauck MA, et al. Diabetologia. 1996;39: Effects on CNS: Flint A, et al. J Clin Invest. 1998;101: Liver: ↓ Glucagon reduces hepatic glucose output Beta cells: Enhances glucose-dependent insulin secretion Stomach: Helps regulate gastric emptying Adapted from Flint A, et al. J Clin Invest. 1998;101: ; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160: ; Adapted from Nauck MA, et al. Diabetologia. 1996;39: ; Adapted from Drucker DJ. Diabetes. 1998;47:

29 Studie mit Verabreichung von Glukose per os / IV
Nach oraler Verabreichung von Glukose war der Inkretin-Effekt bei Diabetes Typ 2 reduziert Gesunde Kontrollen (n=8) Diabetes Typ 2 (n=14) Glukose, oral (50 g/400 ml) Isoglykämisches Glukose, intravenös 20 20 * 15 15 Venöser plasmatischer Glukosespiegel (mmol/L) Venöser plasmatischer Glukosespiegel (mmol/L) 10 10 5 5 An oral glucose load results in a greater insulin response than the response caused by an intravenous glucose load matched to produce a similar glycemic profile. This phenomenon is termed “the incretin effect” because it is attributable to the release of incretin hormones that occurs after oral but not intravenous administration of glucose.1-3 Studies in humans and animal models have shown that the incretin hormones GLP-1 and GIP are believed to account for almost the entire incretin effect that facilitates disposal of ingested nutrients.2 A clinical study showed that the incretin effect was diminished in patients with type 2 diabetes (n=14) compared with metabolically healthy control subjects (n=8).4 As shown on the graphs, glucose profiles were closely mimicked at similar levels after oral versus intravenous glucose administration.4 This matching of intravenous glucose loads to oral glucose loads after ingestion was achieved in both control subjects and patients with diabetes.4 Beta-cell secretory responses, reflected by increases in plasma levels of immunoreactive (IR) insulin, are shown on the bottom graphs in the slide. These graphs show that plasma IR insulin peaks were delayed and diminished in patients with type 2 diabetes. Although insulin levels were greater after oral glucose ingestion versus intravenous administration in both groups, the incretin effects were markedly less pronounced in diabetic patients.4 –10 –5 60 120 180 –10 –5 60 120 180 80 Normaler Inkretin-Effekt 80 60 60 Reduzierter Inkretin-Effekt IR Insulin (mU/L) IR Insulin (mU/L) 40 40 20 20 –10 –5 60 120 180 –10 –5 60 120 180 Zeit (Minuten) Zeit (Minuten) *p0.05 vs. respektiver Wert nach oraler Gabe IR=Immunreaktiv Adaptiert von Nauck M et al Diabetologia 1986;29:46–52. References Vilsbøll T, Holst JJ. Incretins, insulin secretion and type 2 diabetes mellitus. Diabetologia 2004;47:357–366.  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. Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab 2004;287:E199–E206. Nauck M, Stöckmann F, Ebert R et al. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 1986;29:46–52.

30 GLP-1 förderte die Proliferation und hemmte die Apoptose der Beta-Zellen bei diabetischen Zucker-Ratten Beta-Zellen Proliferation Beta-Zellen Apoptose 2.5 30 25 2.0 Zunahme x1.4 (p<0.05) 20 1.5 The effects of infused GLP-1 on glucose control and islet cells were investigated in Zucker diabetic fatty (ZDF) rats, an animal model in which the onset of diabetes occurs when the rate of beta-cell proliferation no longer compensates for the rate of cell death (apoptosis). The diabetic rats received a two-day infusion of human recombinant GLP-1 (n=8) or saline control (n=8) starting on day 1; on day 6, they received a glucose tolerance test, and on day 7, they were killed and the pancreas harvested (pancreatic sections were harvested from 4 rats in each group) so that investigators could study the effects of GLP-1 on islet cell mass, beta-cell proliferation, and beta-cell apoptosis.1 The infusion of GLP-1 significantly reduced glucose levels (p<0.01) and significantly increased beta-cell mass 1.6-fold (p<0.01). The effect of GLP-1 on beta-cell mass reflects a 1.4-fold increase (p<0.05) in beta-cell proliferation (the number of actively dividing beta cells) and a 3.6-fold reduction (p<0.001) in beta-cell apoptosis (the number of apoptotic beta cells) versus control. The study authors concluded that GLP-1 ameliorates the glucose tolerance of ZDF rats by inhibiting cell apoptosis and promoting islet-cell proliferation.1 Abnahme x3.6 (p<0.001) Proliferierende Beta-Zellen (%) Apoptotische Beta-Zellen (%) 15 1.0 10 0.5 5 Kontrolle GLP-1 Behandlung Kontrolle GLP-1 Behandlung Studie mit diabetischen Zucker-Ratten, die eine zweitägige Infusion von GLP-1 oder von einer Kochsalzlösung erhielten, gefolgt von einem oralen Glukose-Toleranz-Test. Die Bestimmung der Insel-Masse, der Beta-Zellen-Proliferation und der Apoptose beruhte auf histologische Schnitte des Pankreas. Adaptiert von Farilla L et al Endocrinology 2002;143:4397–4408. Reference Farilla L, Hui H, Bertolotto C et al. Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology 2002;143:4397–4408.

31 GLP-1 bewahrte die Morphologie von humanen Inselzellen in vitro
Kontrolle GLP-1 behandelte Zellen Tag 1 Mit GLP-1 behandelte Inseln, in Kultur, konnten ihre Integrität länger erhalten. An in vitro study was conducted to evaluate the potential of GLP-1 to improve the viability and function of freshly isolated human islets. Islets were maintained in culture for five days in the presence or absence of GLP-1.1 During the five days of culture, islets in the control group showed important morphologic changes. At day 1, islets maintained their physiologic spherical shape (panel A). By day 3, many islets showed a progressive loss of structure, losing the acellular membrane that surrounds them (panel C). At day 5, the three-dimensional structure of many cell aggregates had deteriorated to a two-dimensional structure typical of a cell monolayer (panel E). In contrast, islets treated with GLP-1 retained their three-dimensional organization for a longer period of time (panels B, D, and F). Overall, the number of islets with a preserved three-dimensional structure by day 5 had declined by 45% in the control group versus a 15% reduction in the GLP-1–treated islets (p<0.01).1 Additional analyses showed that the number of apoptotic cells was significantly lower in GLP-1–treated islets versus control islets at day 3 (6.1% vs. 15.5%, respectively; p<0.01) and day 5 (8.9% vs. 18.9%, respectively; p<0.01), and that intracellular insulin content was markedly enhanced in islets cultured with GLP-1 versus control (p<0.001 at day 5).1 These results help to provide evidence that GLP-1 preserves morphology and function and inhibits apoptosis of islet cells.1 Tag 3 Tag 5 Adaptiert von Farilla L et al Endocrinology 2003;144:5149–5158. Reference 1. Farilla L, Bulotta A, Hirshberg B et al. Glucagon-like peptide inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 2003;144:5149–5158.

32

33 Byetta® (Lilly) Zulassung 6.12.2006
für Diabetes mellitus Typ 2 in Kombination mit Metformin oder Sulfonylharnstoff Dosierung: 5-10 ug 2x/d sc

34 Sitagliptin (Januvia®) MSD
Zulassung: EU Schweiz seit Juni 07 Dosierung: 100 mg 1x/d p.o. Vildagliptin (Galvus) Novartis

35 Sitagliptin (Januvia®) MSD
Vildagliptin (Galvus®) Novartis Exanetide (Byetta®) Lilly Vorteile gegenüber herkömmlichen Antidiabetika? -Betazell-Funktion -Gewicht

36 Ein klarer Fall!?

37 Fallbeispiel Konsultation 2003
30j 40j 50j 60j 70j Konsultation 2003 K.B., Metzger, körperl. nicht mehr sehr aktiv, kinderlos, verheiratet Pos. FA für Diabetes mellitus Typ 2 (Mutter, mit Beinamputationen) Weitere Diagnosen: Hypertonie, hypertensive (und eventuell koronare) Kardiopathie (formal St. nach inferiorem MI möglich), Hyopogonadismus Diskussion Diabetes Prävention

38 Fallbeispiel Konsultation 2003
30j 40j 50j 60j 70j Konsultation 2003 Medikamente: Andriol, 2-1-2, Coversum Combi, Glucophage 2mal 850mg Grösse 190 cm, G 129 kg, BMI 36 kg/m2 BD 145/90 Diskussion Diabetes Prävention

39 Fallbeispiel Konsultation 2003 Nüchtern-Glucose (Plasma) 7.5 mmol/l
30j 40j 50j 60j 70j Konsultation 2003 Nüchtern-Glucose (Plasma) 7.5 mmol/l Cholesterin Gesamt mmol/l HDL Cholesterin mmol/l Nü-Triglyzeride < 0.8 mmol/l Kreatinin umol/l HbA1c % Diskussion Diabetes Prävention

40 Verlaufskontrolle 4 Jahre später
30j 40j 50j 60j 70j Verlaufskontrolle 4 Jahre später Nun unter Sulfonylharnstoff (Diamicron MR 30mg 2-0-1) und Metformin (3mal 850) BMI 38 kg/m2 (190 cm, 137 kg) Blutdruck 145/90 mmHg, normokard HbA1c 6.7% BZ-Profil im Durchschnitt (kapillär): Erhöhter Nü-BZ -> Diskussion Monotherapie first line (Metformin) Morgen Mittag Abend Vor Bettruhe 7-8 mmol/l 6-9 mmol/l 6-8 mmol/l Nicht gemessen

41 Neu Schlaf-Apnoe-Syndrom
30j 40j 50j 60j 70j ... Zufrieden? Probleme? Gewichtszunahme von 129 kg, BMI 36 kg/m2 auf aktuelle 137 kg, BMI neu 38 Lipide gut !! Hat Aspirin Neu Schlaf-Apnoe-Syndrom Erhöhter Nü-BZ -> Diskussion Monotherapie first line (Metformin)

42 SH kontraindiziert (Gewichtszunahme)
30j 40j 50j 60j 70j Probleme SH kontraindiziert (Gewichtszunahme) Was ist wichtiger: HbA1c-Verbesserung (von 8.2 auf 6.7) oder aber ungünstiger Gewichtsverlauf? Güterabwägung…. Wie Gewicht reduzieren? SAS gerichtet angehen? Erhöhter Nü-BZ -> Diskussion Monotherapie first line (Metformin)

43 ... Gewicht reduzieren, aber wie?
30j 40j 50j 60j 70j ... Gewicht reduzieren, aber wie? Erhöhter Nü-BZ -> Diskussion Monotherapie first line (Metformin)

44 ... Gewicht reduzieren, aber wie?
30j 40j 50j 60j 70j ... Gewicht reduzieren, aber wie? Beginn mit Byetta Oktober 2007, Gewicht 137 kg HbA1c 6.6% Stand 09/08: Byetta 10 ug morgens/abends, Diamicron gestoppt, Glucophage unverändert Gewicht 111.9, Reduktion von 25kg innerhalb von rund 10 Monaten Kein Schlaf-Apnoe-Syndrom Erhöhter Nü-BZ -> Diskussion Monotherapie first line (Metformin)

45 Vorschlag fürs Procedere?
30j 40j 50j 60j 70j Vorschlag fürs Procedere? Erhöhter Nü-BZ -> Diskussion Monotherapie first line (Metformin)

46 Alles klar?

47 Auf jeden Fall!