1. GLP-1 and use with insulin Giorgio Sesti University “Magna Graecia” of Catanzaro

2. T2DM anti-hyperglycaemic therapy: general recommendations Diabetes Care 2012;35:1364-1379; Diabetologia 2012;55:1577-1596.

3. T2DM anti-hyperglycaemic therapy: general recommendations Diabetes Care 2012;35:1364-1379; Diabetologia 2012;55:1577-1596.

4. Why treating with a combination of a glucagon-like peptide 1 (GLP ‑ 1) receptor agonist and long-acting insulin ?

5. Butler et al. Diabetes 2003’52:102-110. ObeseLean -50% -63% β-cell volume (%) Mean relative β-cell volume in obese non-diabetic, IFG and diabetic subjects and lean subjects

6. Butler, A. et al Diabetes 52: 102-110, 2003 Butler AE et al. Diabetes 52:102–110,2003 β-cell apoptosis was 3- fold increased in obese with type 2 diabetes and 10-fold increased in lean with type 2 diabetes vs. their respective control groups (P <0.05)

7. Schematic view of mechanisms of action of GLP ‑ 1 analogues and long-acting insulin with respect to the pathophysiological phenotype of T2DM Nauck & Meier. J Nat Rev Endocrinol 2011;7:193-195. *Shown in rodents or in vitro models only.

8. Liraglutide GLP-1 Compound (nM) Apoptotic b-cells (% of control) 0 25 50 75 100 01101001000 ** * * * ND *p < 0.01, **p < 0.005 Bregenholt et al. Biochem Biophys Res Commun 330: 577–584, 2005 Cytokine-induced apoptosis 0 25 50 75 100 01101001000 ND * ** * * * * Fatty-acid-induced apoptosis in neo-natal rat islets Compound (nM) Liraglutide inhibits beta-cell apoptosis in isolated neo-natal rat islets

9. UKPDS 34. Lancet 1998:352:854–865 6.2% – upper limit of normal range 8.0 6.0 7.5 7.0 6.5 Time (years) 0 023451 Rosiglitazone Metformin Glibenclamide Rosiglitazone vs. metformin –0.13 (–0.22 to –0.05), p=0.002 Rosiglitazone vs. glibenclamide –0.42 (–0.50 to –0.33), p<0.001 6.0 7.0 8.0 9.0 Median HbA 1c (%) Years from randomisation Conventional Glibenclamide Metformin Insulin Recommended treatment target ≤7.0% 2468100 ADOPT UKPDS 7.5 8.5 6.5 Over time, glycaemic control deteriorates Kahn et al. N Engl J Med 2006;355:2427–43

10. UKPDS 16. Diabetes 1995;44:1249-1258; Lebovitz 1999;7:139-153. Years from diagnosis  -cell function (%, HOMA) Diabetes diagnosis β-cell function progressively declines ADOPT UKPDS 0 20 40 60 80 100 Diet (n=110) Sulphonylurea (n=511) Metformin (n=159) –5–4–3–2–10123456 Extrapolation of β-cell function prior to diagnosis 012345 0 60 70 80 90 100 Rosiglitazone: -2.0 (-2.6 to -1.3) Metformin: -3.1 (-3.8 to -2.5) Glyburide: -6.1 (-6.8 to -5.4) Annualised slope (95% CI) Treatment difference (95% CI) Rosiglitazone vs. metformin, 5.8 (1.9 to 9.8); p=0.003 Rosiglitazone vs. glyburide, -0.8 (-4.7 to 3.1)); p=0.67 Time (years) β-cell function (%) Kahn et al. N Engl J Med 2006;355:2427-2443.

11. Schematic view of mechanisms of action of GLP ‑ 1 analogues and long-acting insulin with respect to the pathophysiological phenotype of T2DM *Shown in rodents or in vitro models only. Nauck & Meier. J Nat Rev Endocrinol 2011;7:193-195.

12. Vilsbøll et al. Diabet Med 2008;25:152-156. First-phase insulin secretion Mean change vs. baseline (pmol/l/hr) p=0.05 Placebo (n=5) 0.65 mg/day (n=5) 1.25 mg/day (n=9) 1.90 mg/day (n=6) p<0.02 0 5 10 15 20 Liraglutide increased first-phase insulin secretion

13. Normals, n=11; Type 2 diabetes, n=12. Muller WA et al. N Engl J Med. 283:109–115, 1970. Insulin and Glucagon Dynamics in Response to Meals Are Abnormal in Type 2 Diabetes -60060120180240 360 330 300 270 240 110 80 140 130 120 110 100 90 120 90 60 30 0 Glucose (mg%) Insulin (μ/ml) Glucagon (μIμ/ml) Meal (minutes) Type 2 diabetes Normals Delayed/depressed insulin response Non-suppressed glucagon

14. Glucagon secretion Pancreatic cells:  -cell  -cell  -cell Hepatic glucose production Insulin secretion Excessive hepatic glucose production

15. Schematic view of mechanisms of action of GLP ‑ 1 analogues and long-acting insulin with respect to the pathophysiological phenotype of T2DM *Shown in rodents or in vitro models only. Nauck & Meier. J Nat Rev Endocrinol 2011;7:193-195.

16. Liraglutide significantly reduced the 24-h AUC of glucagon in T2DM Placebo Liraglutide Degn KB et al. Diabetes 53:1187–1194, 2004

17. Garber et al. Diabetes Obes Metab 2011;13:348-356. Change in FPG over time: LEAD-3 2-year completers FPG (mmol/l) Observed mean±2SE, no imputation for missing values. 7.45 mmol/l 7.58 mmol/l 8.54 mmol/l 0

18. Jones KL, et al. J Nucl Med 37:1643-1648, 1996 Gastric emptying rate is an important determinant of PPG in early Type 2 Diabetes

19. Schematic view of mechanisms of action of GLP ‑ 1 analogues and long-acting insulin with respect to the pathophysiological phenotype of T2DM *Shown in rodents or in vitro models only. Nauck & Meier. J Nat Rev Endocrinol 2011;7:193-195.

20. Gastric emptying is inhibited in a dose-dependent manner by GLP ‑ 1 administration Meier J J et al. J. Clin. Endocrinol. 88: 2716–2725, 2003

21. Flint et al. Adv Ther 2011;28:213-226. PPG profile of liraglutide 1.8 mg (baseline corrected) Change from baseline (mmol/l) Time since start of meal (hours) 2 1 0 3 4 5 -0.5 0.00.51.01.52.02.5 3.0 3.5 4.0 4.55.0 Liraglutide 1.8 mg Placebo

22. GLP-1 Energy intake Satiety Gastric emptying GLP-1 action on the GI and central nervous systems

23. In the arcuate nucleus, mRNA expression of the anorectic neurotransmitter CART was significantly increased following liraglutide treatment. Liraglutide prevented the increase in orexigenic NPY mRNA seen in weight-matched (food- restricted) rats. CART 0 2.5 0.5 1.0 Gene expression (arbitrary units) VehicleLiraglutide 2.0 1.5 Weight- matched P<0.05 0 2.5 0.5 1.0 Gene expression (arbitrary units) Vehicle Liraglutide 2.0 1.5 Weight- matched p<0.05 NPY Vrang et al. Diabetes 59 (Suppl 1) 583 P, 2010 Liraglutide increases anorectic neurotransmitter CART mRNA expression and prevents fasting induced orexigenic NPY mRNA expression in rats

24. Change in body weight (kg) -2.8 kg -2.3 kg +1.0 kg Time (weeks) Change in body weight over time — 2-year completers of LEAD-3 Observed mean±2SE (standard error), no imputation for missing values Garber et al. Diabetes Obes Metab 2011;13:348–56 (LEAD-3 2-year extension)

25. Pratley RE et al. Lancet 375: 1447–1456, 2010 Liraglutide vs. sitagliptin for type 2 diabetes patients who did not have adequate glycaemic control with metformin: Change in body weight –3.38 kg –2.86 kg –0.96 kg

26. Dose–response relationships for the effects of GLP-1 Holst JJ et al Trends in Mol Med 2008

27. Network meta-analysis of pairwise comparisons of randomized controlled trials evaluating the use of anti-hyperglycemic agents in addition to metformin vs. placebo: At least one event of overall hypoglycaemia (odds ratio) Liu S-C et al. Diabetes Obes and Metab 14: 810–820, 2012 SU Glinides TZDs AcarboseDPP-4 GLP-1 Basal Biphasic inhibitors agonists insulin insulin At least one event of overall hypoglycaemia (odds ratio)

28. The combination of basal insulin and GLP ‑ 1-based therapies addresses complimentary targets such as:  Fasting and pre-prandial glucose by suppressing hepatic glucose production and improving β-cell function  Post-prandial glucose by decelerating gastric emptying …and may help alleviate some of the problems of insulin therapy:  Weight gain  Hypoglycaemia  Elevated doses of insulin

29. In clinical practice, combination therapy could arise: 1.By adding insulin to pre-existing GLP-1RA therapy 2.By adding GLP-1RAs to established insulin therapy Clinical outcomes

30. DeVries et al. Diabetes Care 2012;35:1446-1454.

31. IDet + liraglutide 1.8 mg (n=162) Liraglutide 1.8 mg (n=161) Adults 18–80 years with T2DM HbA 1c : 7.0–10.0% (MET only) 7.0–8.5% (MET + SU) MET (≥1500 mg) or MET (≥1500 mg) + SU (≤50% max. dose) for ≥3 months Open-label study with two randomised and one non-randomised treatment arm Conducted in 7 European countries, Canada and the US Liraglutide 1.8 mg Run-in period: 12 weeks Randomisation Liraglutide 1.8 mg (n=498) Liraglutide 0.6 mg 1 week HbA 1c <7.0% Observational group Randomised period: 26 weeks IDet, insulin detemir; MET, metformin; SU, sulphonylurea Liraglutide 1.2 mg 1 week Metformin ≥1500 mg/day; SU discontinued DeVries et al. Diabetes Care 2012;35:1446-1454. 39% 39% of run-in completers had HbA 1c ≥7.0% 61% 61% of run-in completers had HbA 1c <7.0% HbA 1c ≥7.0% (1:1 randomisation) Randomised treatment group Randomised control group Trial design

32. Mean (2SE); data are from the FAS, no imputation. Change in HbA 1c (%) Time (weeks) Run-in (Weeks -12 to 0) Randomised period (Weeks 0 to 26) RC: 8.29 RT: 8.22 O: 7.72 RC: -0.66 RT: -0.60 O: -1.34 (final value 7.5) RC: -0.76 (final value 7.1) RT: -1.13 (final value 6.6) O: -1.12 Mean change in HbA 1c by week DeVries et al. Diabetes Care 2012;35:1446-1454.

33. Mean (2SE); data are from the FAS, no imputation. p-values are for treatment differences in changes from randomisation (Week 0) for the meal (FAS LOCF) Self-measured plasma glucose (mmol/l) p=0.0003 Randomisation (Week 0) Randomised control group (metformin+liraglutide 1.8 mg) Randomised treatment group (metformin+IDet+liraglutide 1.8 mg) 0 p=0.0244p=0.0141 Week 26 Randomised control group (metformin+liraglutide 1.8 mg) Randomised treatment group (metformin+IDet+liraglutide 1.8 mg) Before breakfast 90 min after breakfast Before lunch Before dinner 90 min after lunch 90 min after dinner Bedtime Seven-point glucose profiles DeVries et al. Diabetes Care 2012;35:1446-1454.

34. Mean (2SE); data are from the FAS, no imputation. Change in body weight (kg) Time (weeks) Run-in (Weeks −12 to 0) Randomised period (Weeks 0 to 26) Baseline: RC: 98.6 RT: 99.5 O: 99.0 RC:  3.46 RT:  3.53 O:  4.35 RC:  4.74 O:  4.78 RT:  4.00 Mean body weight change by week DeVries et al. Diabetes Care 2012;35:1446-1454.

35. Clinical outcomes In clinical practice, combination therapy could arise: 1.By adding insulin to pre-existing GLP-1RA therapy 2.By adding GLP-1RAs to established insulin therapy

36. Buse et al. Ann Intern Med 2011;154:103-112.

37. Insulin Titration FPG Algorithm (mmol/l) Dose Change (U) <3.1 b −4 3.1-3.9 b −2 4.0-5.5 c 0 5.6-6.6 c +2 6.7-7.7 c +4 7.8-9.9 c +6 ≥10 c +8 BID, twice daily (≤60 min before morning and evening meals); FPG, fasting plasma glucose; OAMs, oral antihyperglycaemic medications (metformin and/or pioglitazone); T, telephone call. a Insulin titrated to FPG of <5.6 mmol/l 5 weeks after randomisation and throughout remainder of study using "Treat to Target" algorithm adapted from Riddle et al. Diabetes Care 2003;26(11):3080-3086. b Values for at least 1 FPG since the last assessment. c Based on the average of FPGs during the last 3 to 7 days. Note: The increase in the total daily dose should not exceed more than 10 U/day or 10% of the current total daily dose, whichever is greater. * Screening Randomisation 5 µg BID Insulinglargine+OAMscontinued throughout study Endpoint Placebo (volume equivalent) 10 µg BID TTT Visit Week of treatment 1 2 3 0 5 4 4 2 6 630 13 10 8 14 9 18 10 22 1112 268 72 1 TTTTTTT + TT 1 2 3 0 5 4 4 2 6 630 13 10 8 14 9 18 10 22 1112 268 72 1 1 2 3 0 5 4 4 2 6 630 13 10 8 14 9 * Exenatide + (volume equivalent) TTT 13 0 5 4 4 2 6 630 13 10 89 18 10 22 1112 268 72 TTTTTTTTT 13 0 5 4 46 630 1389 Placebo Insulin Titration − Study design Buse et al. Ann Intern Med 2011;154:103-112.

38. Data are mean±95% CI. Difference in HbA 1c at 30 weeks: -0.69% (95% CI -0.93 to -0.46%; p<0.001) HbA 1c reduction: patients taking exenatide or placebo with insulin glargine Buse et al. Ann Intern Med 2011;154:103-112.

39. Data are mean±95% CI. Body weight change over 30 weeks (p<0.001; all time points) Body weight change: patients taking exenatide or placebo with insulin glargine Buse et al. Ann Intern Med 2011;154:103-112.

40. Insulin glargine+exenatide Insulin glargine+placebo Proportion of patients experiencing hypoglycaemia (%) Minor Minor nocturnal Major Hypoglycaemic events Buse et al. Ann Intern Med 2011;154:103-112.

41. Between-group Difference -6.5 (95% CI 12.3 to 0.8); p=0.030 Change in insulin dose (U/d) Insulin glargine+exenatideInsulin glargine+placebo Increase insulin dosage from baseline was greater in the placebo group Buse et al. Ann Intern Med 154:103-112, 2011

42. Overall conclusions  Adding basal insulin to pre-existing GLP-1RA therapy or adding GLP-1RAs to established insulin therapy may help improve glycaemic control and reduce glycaemic excursions  Improvement in HbA 1c by combining GLP-1RAs with insulin is associated with:  Weight loss  No increased risk of hypoglycaemia  Reduction in insulin doses

43. THANK YOU ! Sesti lecture