Dr Larry Distiller BSc MB BCh FCP(SA) FRCP FACE Specialist Physician / Endocrinologist Centre for Diabetes and Endocrinology, Houghton Hon Visiting

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1 Dr Larry Distiller BSc MB BCh FCP(SA) FRCP FACE Specialist Physician / Endocrinologist Centre for Diabetes and Endocrinology, Houghton Hon Visiting Professor, Cardiff University School of Medicine

2 Obesity Sedentary lifestyle Aging Genetics Glucotoxicity FFA levels Insulin resistance Beta-cell function Blood glucose Adequate Insulin response Inadequate Euglycaemia Type 2 diabetes Adapted from Matthaei et al. Endocrine Reviews 2000;21: Adapted from Edelman. Adv Intern Med 1998;43:

3 And many more in development Bianchi C et al. Diabetes Voice 2011;56:28-31

4 What are the incretins and gliptins? Why should we use them? When should they be used? Should we be using them?

5 What are the incretins and gliptins?

6 Potent enhancers of glucose induced insulin secretion Glucose-dependant insulinotropic polypeptide, (GIP), formerly called gastric inhibitory polypeptide Glucagon-Like Polypeptide 1 (GLP-1)

7 L-cell (ileum) ProGIP Proglucagon GLP-1 [7 37] GIP [1 42] GLP-1 [7 36 NH 2 ] K-cell (jejunum)

8 GLP-1: Secreted upon the ingestion of food Promotes satiety and reduces appetite Alpha cells: Postprandial glucagon secretion Beta cells: Enhances glucose-dependent insulin secretion Liver: Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying Data from Flint A, et al. J Clin Invest. 1998;101: ; Data from Larsson H, et al. Acta Physiol Scand. 1997;160: Data from Nauck MA, et al. Diabetologia. 1996;39: ; Data from Drucker DJ. Diabetes. 1998;47:

9 Slower gastric emptying - Direct effect on gastric emptying Feeling of satiety - Blocks satiety centre centrally Reduction in post-prandial glucose levels - Direct effect on insulin secretion (incretin effect) - Suppression of glucagon

10 Plasma Glucose (mg/dl) C-peptide (nmol/l) Oral Glucose Intravenous (IV) Glucose * * * * Incretin Effect * * * Time (min) Time (min) N = 6; Mean (SE); *P 0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:

11 Nauck MA, Baller B, Meier JJ. Gastric inhibitory polypeptide and glucagon-like peptide-1 in the pathogenesis of type 2 diabetes. Diabetes. 2004;53(suppl 3):S190-S196. The incretin effect is severely reduced or even abolished in patients with Type 2 diabetes Secretion of GIP is near-normal in most patients with Type 2 diabetes, but insulinotropic effect of GIP is largely ablated in type 2 diabetes, even when infused at supraphysiologic levels The secretion of GLP-1 is significantly impaired Nauck MA, Baller B, Meier JJ. Diabetes.2004;53(suppl 3):S190-S196.

12 IR Insulin, mu/l IR Insulin, mu/l Control Subjects (n=8) Incretin Effect Patients With Type 2 Diabetes (n=14) The incretin effect is diminished in type 2 diabetes Time, min Oral glucose load Time, min 180 Intravenous (IV) glucose infusion Adapted from Nauck M et al. Diabetologia. 1986;29: Copyright 1986 Springer-Verlag.

13 GLP-1 (but not GIP) increases both early- and late-stage insulin secretion Data are mean±sem. GIP, gastric inhibitory peptide; type 2 diabetes patients (n=8) Vilsbøll et al. Diabetologia 2002:45:1111 9

14 Mean (SE); n=10; *p<0.05; type 2 diabetes patients (n=10) Nauck et al. Diabetologia 1993;36:741 4 Placebo (PBO) Native human GLP-1

15 The Problem Native GLP-1 and GIP are broken down by DPP-4 in 1-2 minutes The Solution? - GLP-1 analogues - DPP-4 inhibitors

16 Exenatide (Byetta, Eli Lilly) Liraglutide (Victoza, NovoNordisk) Others in the pipeline

17 Synthetic version of the salivary protein found in the Gila monster More than 50 % amino acid sequence identity with human GLP-1 Binds to known human GLP-1 receptors Resistant to DPP-4 inactivation Following injection, exenatide is measurable in plasma for up to 10 hours Nielsen LL, et al. Regul Pept. 2004;117:77-88 Kolterman OG, et al. Am J Health-Syst Pharm. 2005;62:

18 A slightly modified version of the GLP-1 molecule that attaches to albumin and therefore is released slowly, adopting the pharmacokinetic profile of albumin The plasma half-life for this compound is 12 hours. It therefore provides exposure for over 24 hours following a single subcutaneous injection

19 Vildagliptin (Galvus,Novartis) Saxagliptin (Onglyza, AstraZenica) Sitagliptin (Javunia, Merck) Linagliptin (Tradjenta, BI / Eli Lilly) Alogliptin

20 Ingestion of food Release of active incretins GI tract GLP-1 and GIP Pancreas Beta cells Alpha cells Glucose dependent Insulin (GLP-1 & GIP) Glucose uptake by peripheral tissue Blood glucose in fasting and postprandial states DPP-4 inhibitor Inactive GLP-1 X DPP-4 enzyme Inactive GIP Glucosedependent Glucagon (GLP-1) Hepatic glucose production GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

21 GLP-1 Analogues Supra-physiological levels of GLP-1 DPP4-Inhibitors Approaches physiological levels of GLP-1

22 *GLP-1 levels for liraglutide calculated as 1.5% free liraglutide Degn et al. Diabetes 2004;53: ; Mari et al. J Clin Endocrinol Metab 2005;90:

23 GLP-1 Analogues Supra-physiological levels of GLP-1 Significant and sustained weight loss Injected therapy Potential GIT Side-effects Low rates of hypoglycaemia Improved CV risk factors insulin secretion glucagon release food intake, slow gastric emptying DPP4-Inhibitors Approaches physiological levels of GLP-1 Weight neutral Oral therapy Minimal GIT side-effects Low rates of hypoglycaemia Limited data on CV risk factors insulin secretion glucagon release

24 What are the incretins and gliptins? Why should we use them? When should they be used? Should we be using them?

25 Why should we use them?

26 Exenatide (twice daily) Liraglutide (once daily)

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28 Change from baseline to 30 weeks HbA 1c (%) Body weight (kg) Existing oral therapy Exenatide 5 µg bid Exenatide 10µg bid Exenatide 5 µg bid Exenatide 10 µg bid Sulphonylurea * Metformin Metformin sulphonylurea 3 *p<0.05; p 0.01; p<0.002; p<0.001; p<0.0001; all versus placebo 1. Buse J, et al DeFronzo R, et al Kendall D, et al

29 A1C (%) Weight (kg) 104-Week Completers at Week Week Completers at Week Mean baseline A1C: 8.2% 0 Mean baseline weight: 101 kg wk Completers; N = 195; Mean (SE); Weight is a secondary endpoint Data on file, Amylin Pharmaceuticals, Inc.

30 Significant *vs. comparator; # Change in HbA 1c from baseline for overall population (LEAD-4,-5) add-on to diet and exercise failure (LEAD-3); or add-on to previous OAD monotherapy (LEAD-2,-1) Marre et al. Diabetic Medicine 2009;26; (LEAD-1); Nauck et al. Diabetes Care 2009;32;84 90 (LEAD-2); Garber et al. Lancet 2009;373: (LEAD-3); Zinman et al. Diabetes Care 2009; 32: (LEAD-4); Russell-Jones et al. Diabetologia 2009;52: (LEAD-5)

31 Weight and blood pressure did not differ between add-on and switch concept *Change calculated by ANCOVA analysis Nauck et al. Diabetes 2009;58(Suppl. 1):A122 (abstract 459-P)

32 Waist circumference was reduced from baseline by 3.0 cm with liraglutide 1.8 mg Waist circumference increased by 0.4 cm with glimepiride (p<0.0001) Glimepiride 8 mg/day Liraglutide 1.2 mg/day Liraglutide 1.8 mg/day ***p< for change from baseline Garber et al. Lancet 2009;373(9662): (LEAD-3)

33 Both liraglutide and exenatide were combined with met and/or SU Buse et al. Lancet 2009;374:39 47 (LEAD-6)

34 Buse et al. Lancet 2009;374:39 47 (LEAD-6)

35 Mean (2SE) Buse et al. Lancet 2009;374:39 47 (LEAD-6)

36 Buse et al. Lancet 2009;374:39 47 (LEAD-6)

37 GLP-1 receptors are expressed in multiple organs including: Pancreas Peripheral tissue Central nervous system Heart Kidney Lung Gastrointestinal tract GLP-1 appears to have a range of neurotrophic neuroprotective and cardioprotective effects

38 GLP-1 receptors have been localized t0: Cardiomyocytes Endocardium Microvascular endothelium Coronary artery smooth muscle cells;

39 Heart (myocardium) Protects against Ischaemia / reperfusion injury Improves myocardial function Vascular System Improves Endothelial function Vasorelaxation GLP-1 The Kidney Increased diuresis and Na + excretion Adapted from: Chilton R et al. The American Journal of Medicine 2011;124, S35 S53

40 Promote Weight loss Lower Triglyceride and raise HDL Lower Blood pressure (?) Improve endothelial dysfunction Reduce CRP and other inflammatory markers Increase myocardial insulin sensitivity Increase myocardial glucose uptake Koska J et al Diabetes Care 2010;33: Courreges JP et al Diabetes Medicine 2008;25: Nikolaidis LA st al. Circulation 2004;110: Bhashyam S. Et al Circ Heart Fail 2010;3:

41 In Addition: Reduced monocyte adhesion to endothelial cells promoted by inhibition of the inflammatory response to macrophages Development of atherosclerotic lesions was suppressed in mice GLP-1 was found to enhance coronary blood flow after induced ischaemia in rats In one study, exenatide treated animals were shown to have as much as 40 % reduction in MI size when compared with controls Chilton R et al. The American Journal of Medicine 2011;124, S35 S53

42 No effect of Exenatide 10 µg on QT interval No relevant increases in the QTc interval using liraglutide once daily No prolongation of the QT interval using exenatide once weekly Chatterjee DJ et al. J Clin Pharmacol 2009;49: Amylin Pharmaceuticals. Data on file.

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44 LifeLink Study 39,000 patients treated with exenatide were compared with [approximately] 390,000 patients treated with all other interventional strategies Significant decrease in cardiovascular events with Exenatide (hazard ratio, 0.81; [95 % confidence interval, ; P=0.01]), indicating a 16 % decrease in cardiovascular events Best JH et al. Diabetes Care 2011;34:90-95

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47 Vilsboll T et al. BMJ 2012;344:d7771doi: Published Jan 2012

48 Vilsboll T et al. BMJ 2012;344:d7771doi: Published Jan 2012

49 Exenatide Liraglutide Administration s.c. Twice daily s.c. Once daily Mean Reduction in HbA 1c ~o % ~ % Mean reduction in FPG ~0.6 mmol/l ~1.7 mmol/l Mean reduction in body weight 2.87 kg 3.24 kg Persistence of nausea (after 26 weeks) 10 % 5 % Liraglutide appears the better option on all fronts, but this may change with once-weekly exenatide which seems better than daily liraglutide Adapted from: Buse et al. Lancet 2009;374:39 47 (LEAD-6)

50 Vildagliptin (Galvus,Novartis) Saxagliptin (Onglyza, AstraZenica) Sitagliptin (Javunia, Merck) Linagliptin (Tradjenta, BI / Eli Lilly) Alogliptin

51 Change in A1C, % Change in FPG, mg/dl Change in 2-hr PPG, mg/dl A1C Mean Baseline: 8.0 % P<0.001* 0.8 n=229 (95 % CI: 1.0, 0.6) FPG Mean Baseline: 170 mg/dl P <0.001* 17 (95 % CI: 24, 10) n= hr PPG Mean Baseline: 257 mg/dl P<0.001* 47 n=201 (95 % CI: 59, 34) * Compared with placebo. Least squares means adjusted for prior antihyperglycaemic therapy status & baseline value. Difference from placebo.

52 Triangle, sitagliptin (100 mg qd) Circle, vildagliptin (50 mg bid or 100 mg qd) Square, saxagliptin (5 mg qd); Diamond, alogliptin (25 mg qd) Star, linagliptin (5 mg qd) C. F. Deacon CF. Diabetes, Obesity and Metabolism 2010;13:7-18

53 Sitagliptin administration at a single dose of 100 mg in patients with CAD: Preserved LV function Enhanced LV response to stress Improved global and regional LV performance compared with placebo Read PA. Circ Cardiovasc Imaging 2010; 3:

54 No definitive evidence for this as yet. Awaiting outcome of TECOS, SAVOR and other trials.

55 Why should we use them? When should they be used? Should we be using them?

56 When should they be used?

57 While the effects on glucagon, gastric emptying and satiety may well persist, the major effect of these drugs is still on insulin secretion Therefore, the better the residual insulin secretory capacity (the more β-cell reserve), the better the expected response

58 None of these drugs are registered for first-line or monotherapy But that is probably where they will prove to be most beneficial

59 Makes therapeutic sense: Basal insulin to target FPG; incretin to target PPG. Sitagliptin has registration for use with insulin. Exenatide has FDA approval for use with basal insulin. Liraglutide has been shown to be effective when combined with basal insulin.

60 When should they be used? Should we be using them?

61 DPP-4 is found on endothelial and epithelial cells throughout the vascular bed, and in the kidneys, intestines, exocrine pancreas, gastrointestinal tract, biliary tract, thymus, lymph nodes, uterus, placenta, prostate, myocardium, and brain, as well as the adrenal, sweat, salivary, and mammary glands. In addition, DPP-4 is also expressed on circulating T- lymphocytes and is found in soluble form in seminal and cerebrospinal fluid and plasma.

62 DPP-4 inhibition has not, as yet, been associated with any human disease. 96 DPP-4 inhibitors have shown a very positive safety and tolerability profile in clinical studies involving thousands of patients with type 2 diabetes DPP-4 inhibitor treatment has been associated with slightly elevated risks of nasopharyngitis, bronchitis, urinary tract infection and headaches

63 The debate rages! Case reports have raised concerns about an increased risk of acute pancreatitis in patients treated with GLP-1 agonists But Type 2 diabetes itself is said to be associated with a 3-fold increased risk of developing pancreatitis So - is the incidence of pancreatitis higher with GLP-1 analogues or is it just a case of awareness?

64 A review of 10,000 patients on 19 clinical trials in patients on sitagliptin showed no increased risk of pancreatitis In all animal studies, there is no evidence that DPP4-I cause pancreatitis Engel SS et al. In J Clin Pract 2010;64: C. F. Deacon CF. Diabetes, Obesity and Metabolism 2010;13:7-18

65 German data base identified 11 cases of pancreatic cancer in association with exenatide No such signal with DPP4-I Exenatide promotes pancreatic ductal hyperplasia However, the time between tumour induction, tumour growth and clinical diagnosis is > 10 years Exenatide exposure was 2-33 months? does exenatide promote tumour progression rather than initiation

66 Liraglutide induces thyroid C-cell focal hyperplasia and C-cell tumours in a dose-related manner in rats, which may lead to medullary thyroid cancer In a 104-week exenatide carcinogenicity study in rats, an increased incidence of benign thyroid C-cell adenomas was seen (Rats develop spontaneous C-cell lesions at a high frequency, while C-cell neoplasia is extremely rare in humans) This has not been seen in any of the clinical studies performed to date Knudsen LB. Endocrinology 2010; 151: Parks M. N Engl J Med 2010; 362:

67 Elashoff M et al Gastroenterology 2011;141:

68 We don t know! There are those who remain opposed to these drugs on basis of uncertainty There are those who believe in these drugs implicitly And many in-between! The jury is still out

69 History has taught us that enthusiasm for new classes of drugs, heavily promoted by the pharmaceutical companies that market them, can obscure the caution that should be exercised when long-term consequences are unknown Peter Butler. Diabetes Care 2010

70 We are constantly being pressurised by industry to prescribe newer and more expensive drugs For most of us, there are intangible rewards for doing this

71 Don t trust me, I m a doctor As to the honour and conscience of doctors, they have as much as any other class of men, no more and no less And what other men dare pretend to be impartial where they have a strong pecuniary interest on one side? George Bernard Shaw, 1911

72 Thank you for your attention Prediction is very difficult, especially about the future Niels Bohr