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GLP-1 and use with insulin

GLP-1 and use with insulin. Giorgio Sesti. University “Magna Graecia” of Catanzaro. T2DM anti- hyperglycaemic therapy : general recommendations. Diabetes Care 2012;35:1364-1379; Diabetologia 2012; 55:1577-1596. T2DM anti- hyperglycaemic therapy : general recommendations.

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GLP-1 and use with insulin

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  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. Mean relative β-cell volume in obese non-diabetic, IFG and diabetic subjects and lean subjects -50% β-cell volume (%) -63% Obese Lean Butler et al. Diabetes2003’52:102-110.

  6. 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) (P <0.05) Butler, A. et al Diabetes 52: 102-110, 2003 Butler AE et al. Diabetes 52:102–110,2003

  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 modelsonly.

  8. Liraglutide inhibits beta-cell apoptosis in isolated neo-natal rat islets Liraglutide GLP-1 Fatty-acid-induced apoptosis in neo-natal rat islets Cytokine-induced apoptosis 100 100 * * * * * 75 75 * ** * Apoptotic b-cells (% of control) ** * 50 50 25 25 ** ** ND ND 0 0 0 1 10 100 1000 0 1 10 100 1000 Compound (nM) Compound (nM) *p < 0.01, **p < 0.005 Bregenholt et al. BiochemBiophys Res Commun 330: 577–584, 2005

  9. Over time, glycaemic control deteriorates UKPDS ADOPT 9.0 Conventional 8.0 Glibenclamide Rosiglitazone Metformin Glibenclamide Metformin 8.5 Insulin 7.5 8.0 7.5 Median HbA1c (%) 7.0 7.0 Recommended treatment target ≤7.0% 6.5 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 6.5 6.0 6.0 6.2% – upper limit of normal range 0 0 2 4 6 8 10 0 1 2 3 4 5 Time (years) Years from randomisation UKPDS 34. Lancet 1998:352:854–865 Kahn et al. N Engl J Med 2006;355:2427–43

  10. β-cell function progressively declines –5 –4 –3 –2 –1 0 1 2 3 4 5 6 UKPDS ADOPT Diabetes diagnosis 100 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=0.67 100 80 90 60 -cell function (%, HOMA) 80 β-cell function (%) 40 70 Sulphonylurea (n=511) Annualised slope (95% CI) 20 Diet (n=110) Rosiglitazone: -2.0 (-2.6 to -1.3) Metformin (n=159) Metformin: -3.1 (-3.8 to -2.5) 60 Extrapolation of β-cell function prior to diagnosis Glyburide: -6.1 (-6.8 to -5.4) 0 0 0 1 2 3 4 5 Time (years) Years from diagnosis UKPDS 16. Diabetes1995;44:1249-1258; Lebovitz1999;7:139-153. Kahn et al. N Engl J Med2006;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 Nauck & Meier. J Nat Rev Endocrinol 2011;7:193-195. *Shown in rodents or in vitro modelsonly.

  12. Liraglutide increased first-phase insulin secretion p=0.05 20 p<0.02 First-phase insulin secretion Meanchange vs.baseline(pmol/l/hr) 15 10 5 0 0.65 mg/day(n=5) 1.25 mg/day(n=9) 1.90 mg/day (n=6) Placebo(n=5) Vilsbøllet al. Diabet Med2008;25:152-156.

  13. Insulin and Glucagon Dynamics in Response to Meals Are Abnormal in Type 2 Diabetes 360 Meal 330 300 Glucose (mg%) 270 Type 2 diabetes 240 Normals 110 80 120 90 Insulin (μ/ml) 60 30 Delayed/depressed insulin response 140 0 130 Non-suppressed glucagon 120 110 Glucagon (μIμ/ml) 100 90 (minutes) -60 0 60 120 180 240 Normals, n=11; Type 2 diabetes, n=12. Muller WA et al. N Engl J Med. 283:109–115, 1970.

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

  15. 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 modelsonly.

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

  17. Change in FPG over time: LEAD-3 2-year completers 8.54 mmol/l FPG (mmol/l) 7.58 mmol/l 7.45 mmol/l 0 Observed mean±2SE, no imputation for missing values. Garber et al. Diabetes ObesMetab2011;13:348-356.

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

  19. 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 modelsonly.

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

  21. PPG profile of liraglutide 1.8 mg (baseline corrected) 5 Liraglutide 1.8 mg Placebo 4 3 2 Change from baseline (mmol/l) 1 0 -1 3.0 4.0 0.0 0.5 1.0 1.5 2.0 2.5 3.5 4.5 5.0 -0.5 Time since start of meal (hours) Flint et al. Adv Ther 2011;28:213-226.

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

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

  24. Change in body weight over time — 2-year completers of LEAD-3 +1.0 kg Change in body weight (kg) -2.3 kg -2.8 kg Time (weeks) Observed mean±2SE (standard error), no imputation for missing values Garber et al. Diabetes ObesMetab2011;13:348–56 (LEAD-3 2-year extension)

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

  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) At least one event of overall hypoglycaemia (odds ratio) SU Glinides TZDs Acarbose DPP-4 GLP-1 BasalBiphasic inhibitorsagonistsinsulininsulin Liu S-C et al. Diabetes Obes and Metab 14: 810–820, 2012

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

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

  31. Trial design Randomisation Run-in period: 12 weeks Randomised period: 26 weeks Adults 18–80 years with T2DM HbA1c: 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, Canadaand the US HbA1c <7.0% Observational group 61%of run-in completers had HbA1c <7.0% Liraglutide 1.8 mg (n=498) Liraglutide 1.8 mg HbA1c ≥7.0% (1:1 randomisation) Randomised treatment group IDet + liraglutide 1.8 mg (n=162) Liraglutide 1.2 mg 1 week Liraglutide 0.6 mg 1 week 39%of run-in completers had HbA1c ≥7.0% Randomised control group Liraglutide 1.8 mg (n=161) Metformin ≥1500 mg/day; SU discontinued IDet, insulin detemir; MET, metformin; SU, sulphonylurea DeVrieset al. Diabetes Care 2012;35:1446-1454.

  32. Mean change in HbA1c by week Run-in (Weeks -12 to 0) Randomised period (Weeks 0 to 26) Time (weeks) RC: -0.66 RT: -0.60 Change in HbA1c (%) (final value 7.5) RC: -0.76 (final value 7.1) RT: -1.13 (final value 6.6) O: -1.12 RC: 8.29 RT: 8.22 O: 7.72 O: -1.34 Mean (2SE); data are from the FAS, no imputation. DeVrieset al. Diabetes Care 2012;35:1446-1454.

  33. Seven-point glucose profiles Randomisation (Week 0) Week 26 Randomised control group (metformin+liraglutide1.8 mg) Randomised control group (metformin+liraglutide1.8 mg) Randomised treatment group (metformin+IDet+liraglutide1.8 mg) Randomised treatment group (metformin+IDet+liraglutide1.8 mg) Self-measured plasma glucose (mmol/l) p=0.0003 p=0.0244 p=0.0141 0 Before breakfast 90 min after breakfast Before lunch 90 min after lunch Before dinner 90 min after dinner Bedtime 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) DeVrieset al. Diabetes Care 2012;35:1446-1454.

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

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

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

  37. Study design Randomisation Screening Insulin Titration Endpoint Exenatide Exenatide 5 µg BID 10 µg BID * * + + Insulin glargine + OAMs continued throughout study Placebo Placebo (volume equivalent) (volume equivalent) T T T T T T T T T T T T T T T T T T T T T T T T Visit 1 1 1 1 1 2 2 2 3 3 3 3 3 4 4 4 4 4 5 5 5 5 5 6 6 6 6 6 7 7 7 8 8 8 8 8 9 9 9 9 9 10 10 10 11 11 11 12 12 12 13 13 13 13 13 Week of 2 2 2 1 1 0 0 0 0 0 2 2 2 2 4 4 4 4 4 6 6 6 6 6 8 8 8 10 10 10 10 14 14 14 18 18 18 22 22 22 26 26 26 30 30 30 30 30 − treatment 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. aInsulintitrated 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 Care2003;26(11):3080-3086. bValuesfor at least 1 FPG since the last assessment. cBasedon 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. Buseet al. Ann Intern Med 2011;154:103-112.

  38. HbA1c reduction: patients taking exenatide or placebo with insulin glargine Difference in HbA1c at 30 weeks: -0.69% (95% CI -0.93 to -0.46%; p<0.001) Data are mean±95% CI. Buseet al. Ann Intern Med 2011;154:103-112.

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

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

  41. Increase insulin dosage from baseline was greater in the placebo group Between-group Difference -6.5 (95% CI 12.3 to 0.8); p=0.030 Change in insulin dose (U/d) Insulin glargine+exenatide Insulin glargine+placebo 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 HbA1c 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

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